download pegs cocamine

BUFF

PEGs Cocamine

CIR EXPERT PANEL MEETING

DECEMBER 10-11, 2012

Memorandum

To: CIR Expert Panel

From: Director, CIR Subject: New data on PEGs Cocamine Date November 16, 2012

In 1999, the CIR Expert Panel concluded that the available data were insufficient to support the safety of PEGs Cocamine (PEG-2, -3, -5, -10, -15, and -20 Cocamine). Additional data needed were: (1) physical and chemical properties, including impurities (especially nitrosamines); (2) genotoxicity in a mammalian system; (3) 28-day dermal toxicity using PEG-2 Cocamine; and (4) dermal sensitization data on PEG-2 Cocamine. In 2011, the Panel determined to not reopen this safety assessment. Minutes from that discussion are included.

The Council’s CIR Science and Support Committee again has submitted still further data and analyses relating to these PEGs Cocamine ingredients and has asked that the Panel consider these to determine if the available data now are sufficient. Other sources of information also have been provided: (1) the American Chemistry Council’s Fatty Nitrogen Derivatives Panel, Amines Task Group has prepared an assessment of data availability for the fatty nitrogen derived amines category, including robust summaries for reliable studies; (2) the EPA’s human health risk assessment to support proposed exemption of alkyl amine polyalkoxylates from the requirement of a tolerance when used as inert ingredients in pesticide formulations; (3) ) the EPA’s human health risk assessment to support proposed exemption of phosphate ester, tallowamine, ethoxylated from the requirement of a tolerance when used as inert ingredients in pesticide formulations; (4) a poster presentation on read-across and computer-based analysis to support the safety of PEGs cocamine in cosmetics; and (5) current use concentration data. After considering these new data, the Panel should determine if these data are sufficient to reopen this safety assessment. If yes, CIR staff will prepare a draft tentative amended safety assessment for review by the Panel. In addition to the fundamental question of reopening this safety assessment to amend the conclusion, there are 3 additional PEGs Cocamine that now are identified as cosmetic ingredients (PEG-4, -8, and -12 Cocamine). If we reopen this report, we should consider including these additional 3 PEGs Cocamine ingredients. Also, other PEG fatty acid amines which differ from PEGs Cocamine group only by length of alkyl chain and degree of saturation may be included if this report is reopened. These would include an additional 38 ingredients:

PEG-2, -7, -11, -15, -20, -22, -25 and -30 Tallow Amine, PEG-2, -5, -8, -10, -15, -20, -30, -40, and -50 Hydrogenated Tallow Amine;

PEG-2 Lauramine; PEG-2, -5, -6, -10, -15, -20, -25, and -30 Oleamine; PEG-12 Palmitamine; PEG-2 Rapseedamine; PEG-2, -5, -8, -10, and -15 Soyamine; and PEG-2, -5, -10, -15, and -50 Stearamine.

Min

utes

June 2011 Panel Meeting Minutes PEGs Cocamine – not reopened In 1999, the CIR Expert Panel concluded that the available data were insufficient to support the safety of PEGs Cocamine (PEG-2, -3, -5, -10, -15, and - 20 Cocamine). Additional data needed were: · physical and chemical properties, including impurities (especially N-nitrosamines); · genotoxicity in a mammalian system · 28-day dermal toxicity using PEG-2 Cocamine · dermal sensitization data on PEG-2 Cocamine The Personal Care Products Council’s CIR Science and Support Committee submitted data and structure/activity analyses for these PEGs Cocamine ingredients. The Expert Panel determined that the structure/activity analysis approaches were not well enough established to substitute for actual study data that had been requested. The Panel recognized the potential of such analyses and recommended that a part of an upcoming meeting agenda (on the order of ½ day) be devoted to discussing how such approaches might be used by CIR in the future. June 2011 CIR Expert Panel Meeting transcript Belsito Team transcript DR. BELSITO: Tentative final. Okay, PEGs cocamine. In '99, we concluded the data were insufficient. Industry has provided data and the question is whether that industry data is sufficient. I would just like to point out that we really asked for data on the lower molecular weight PEGs, namely PEG-2, and most of the data we got were structural activity relationships based upon higher molecular weight PEGs. So if we want to cut things to the chase, I didn't think the data were adequate. And I chose not to reopen this, which therefore means that we don't add any ingredients to the report either. But I'd like to hear from people who -- DR. EISENMANN: But see, PEG-2 is nothing really of interest to the industry. It's really the higher ones that are of interest -- DR. BELSITO: Well, then recommend -- DR. EISENMANN: So it's also acceptable, you know, take PEG -- the small one out. DR. BELSITO: That wasn't put on the table here. DR. EISENMANN: Okay, well something you can consider. DR. BELSITO: I'm just saying I'm trying to move this report along and this was my opinion when I read it. DR. LIEBLER: So I agree with your opinion. I'd like to make a suggestion. And it's not necessarily limited to this family of compounds, but it really addresses, I think, an issue that Wilma raised at the beginning of the meeting, which is this issue of how we approach or read across with an ever-expanding list of ingredients, different structures across the chemical space. And let me just read a comment I wrote on my copy of the report. "The approach to employ model compounds for more standardized read-across has merit, but I'd like to discuss the merits of the tools and whether CIR could move toward standard tools and approaches to do this." Don't have to do this today, but we should put it on the agenda. They would help us cover more chemical space, but we need to avoid an ad hoc approach of just pulling data sets and software packages off the shelf and plugging them in differently for each problem. So this triggers for me the suggestion that perhaps a medium-term project for the Panel and the chemists is to consider whether or not there could be a sort of set of standardized ways in which we approach this use of software tools to model across the chemical space to assist in read-across. Because right now, for us, read-across is simply us looking at tables, using

Distrubted for Comment Only -- Do Not Cite or Quote

CIR Panel Book Page 1

whatever intuition we bring to the process, and that's inherently subjective. And if we begin to employ software tools and other stuff to assist this process, I think we should have some type of discussion perhaps at a meeting when we have less on the agenda of how we actually would approach that. And I think it would help us have a little more faith in the process. DR. BELSITO: But there was also, I mean, whole data areas where they used SAR just to provide the data. There was no baseline even. DR. LIEBLER: Right, so my question is how much of that can we accept? And, you know, we can either like it or not like it from meeting to meeting, and our standards for accepting or rejecting that approach could change a lot. Or we could actually talk about what would we feel are the appropriate standards for using modeling SAR? DR. BELSITO: I mean, I agree. At this point, you know, perhaps the best approach here would be to A, table this; have the scientific committee come up and tell us where they want us to start with PEG numbers. And prior to ever seeing this back, unless you can provide us some data in these large areas of data gaps -- I think genotoxicity was one where you had absolutely no data and you're using SAR. Sensitization was another where you had very little data; you were using SAR. Before we ever come to that, perhaps we need to devote a meeting where we look at, you know, what are the different software systems out there? What are the pluses and minuses of them? Are we under any circumstances going to use SAR for data where we have absolutely zero data on an entire family, like structure activity suggests this would not be a genotoxic risk? This entire family, without having one genotox study on at least some chemical in the family? So at this point, I think that the data for this report in my mind are still insufficient. And probably before you even come back with a list of what ones you want to be dropped because they're not being used -- and we're going to ask for data on the lower molecular weights that we have this SAR -- you know, how far do we go with in silico techniques in assessing safety of these chemicals? DR. LIEBLER: I think this -- we could treat this a little bit like we're treated our approach to quantitative risk assessment because quantitative risk assessment, I think we would agree, is a valuable tool, but we really need to know what we're doing. And I think that we're using, you know, we're pulling these software tools out and we're kind of using them in an ad hoc way so far. And they may have value; we just don't know what the limits are. If we might even consider having a couple of speakers -- like come to mind possibly Anne Richards or Bob Kavlock from EPA. Bob's going to be a keynote speaker at American Chemical Society Division of Chemical Tox meeting in Denver this August, and his group has done a lot of work on the integration of high-throughput screening, in silico evaluation tools for assessing risk. And I think this area has really evolved quite a long ways, and what they've been learning could actually be valuable to this Panel. DR. ANDERSEN: I think the part of the feedback that's most useful to me is the idea that as a group effort, I see it between the CIR Science and Support Committee that proposed this and CIR which is trying to figure out how do you make use of this? "There's work yet to be done" is the message I'm receiving. This doesn't convince the Panel that there is a reason to reopen and explore changing this conclusion. More is needed, and you wouldn't be unhappy if CIR and the Science and Support Committee worked together to try to develop that. We can try to do that. I don't see any reason not to include as part of that Dan's suggestion of bringing in outside people to talk about it. DR. BELSITO: I think this is, you know, it's an area where at least -- my limited familiarity with it is that there are a number of different software programs out there. There are a number of different ways of approaching it. And if industry actually has an interest in us beginning to perhaps dabble with using this to assess safety, a meeting of that kind is not going to be a meeting that we get an update as we did from Julie in one hour. That's going be a half- day or a full-day meeting. So I think it would be something where we would either have to have a fifth meeting someplace where we get together just to discuss this or look at the potential for one of the meetings being a three-day meeting with the first day actually spent on looking pretty much at that issue because it's a very complex issue. I think it depends upon what toxicologic endpoint you're looking at as to what factor you key-in on with a molecule. And, you know, again, if industry thinks that this is something they want this Panel to begin looking at, then I think we all need to really understand what's out there, and it's really complex.



DR. BERGFELD: Well, let's look again at what's driving this, and the drive is to increase the numbers that we're reviewing. DR. BELSITO: Well, the drive is not only to increase the numbers, but the drive is the fact that, you know, there are all these chemicals we haven't looked at. The drive is that you, you know, really can't do a lot of animal studies anymore. The drive is that it costs $100,000 to do a simple HRIPT. So the drive is on many different levels if you don't have to use humans or animals and to save costs if it's reliable data. DR. ANDERSEN: Let's not forget the fundamental issue here is the Panel has found these ingredients insufficient, and that's where they will stand unless that's changed. So the industry is in a bind with current ongoing use of PEGs cocamine. And I think the message back to them is well, these data aren't going to fix that. DR. BRONAUGH: What's missing here is the validation of these techniques basically in a few words. DR. KLAASSEN: I think the other thing is when we see some of this "extrapolation, et cetera," we almost subconsciously think that it's data. And I think, you know, we need to make sure when it's extrapolated data and where it's real data. And after a while, it gets kind of blurred. DR. BELSITO: Any other comments? Okay, so -- DR. BERGFELD: So excuse me -- you're leaving this as -- DR. BELSITO: Insufficient. We're not reopening it. DR. BERGFELD: But you're not -- we've reopened it. So now -- DR. BELSITO: No, we have not reopened it. Industry has asked us -- industry submitted data on a prior insufficient request, and we've decided the data aren't sufficient to allow reopening the -- DR. BERGFELD: So we're not reopening or going back to -- DR. BELSITO: We're not doing anything. DR. BERGFELD: Not reopening? DR. BELSITO: No. DR. BERGFELD: Okay, that's fine. DR. BELSITO: The data weren't sufficient to address our request, and we're not dealing with it. But our comments were we'd be willing to look at the -- you know, have PCPC to delete the lower molecular weight PEGs if they want. But if they're still going to ask us to look at and accept carcinogenicity data based off of SAR, before we ever do that I think we need a meeting where we sign off on our level of comfort because I don't know what the -- I mean I'm sure structure has something to do with alerts for carcinogenicity just as it does for alerts for allergic contact dermatitis, but I don't know what all goes into that aspect. So I would need -- I'm on a steep learning curve for education for structural activity models. Marks Team transcript DR. MARKS: It's not the last ingredient. We have a review summary, but getting close, and this is the PEGs cocamine. In 1999, the Panel concluded the data were insufficient and we've received now new data that's in the memo from Alan. And do we have enough now to, one, declare that this ingredient is safe? And then do we want to add 37 additional compounds? DR. SHANK: Yes. To both questions.



DR. MARKS: Okay. DR. HILL: Well, okay, yes, on safe. No question, no worry. DR. SHANK: I agree with you, Ron. DR. HILL: The question I had was the data needed to identify in 1999 was dermal sensitization on PEG-2 cocamine. And the supplied data was an SAR analysis and HRIPT data for PEG-15 cocamine. I'm thinking they're going to be a big difference in terms of dermal exposure between those two, but I don't care if you want to reopen it because what we've got in the document is a bunch of predictive stuff with some qualifications on all those predictions and no data. DR. MARKS: What do you mean "no data?" DR. HILL: There's no experimental data that goes to PEG-2 sensitization. And PEG-15 is large. It's not going to penetrate anywhere and sensitize anything, but PEG-2 might be another story. DR. SLAGA: We're on page 4, right? DR. HILL: Yeah. DR. MARKS: I thought there was enough. I wasn't too concerned about the PEG-2, but I hear you, Ron. DR. ANDERSEN: We have looked as low as PEG-3, aka triethylene glycol, and that was included when we redid the PEGs report. So we have some sense that at least down to PEG-3, sensitization is not a red flag. DR. HILL: And my response to that is that these aren't PEGs. DR. ANDERSEN: No. That's true. DR. HILL: These aren't PEGs. Those are the nitrogens. DR. ANDERSEN: Yeah. DR. MARKS: Come on up, Tom. MR. GREGORY: Tom Gregory, L'Oreal USA. I just want to make a couple points. One, I don't think PEG-2 is being used anymore. And the other thing is I suggest you read the definition in the dictionary. It says that PEG-2 is the average of the two glycol treatments if you add them together. So if you add together one and one, you get two. So that does not -- that makes PEG-2 not a glycol. DR. HILL: Correct. Yeah. That's why they're relying on data on the N,N-bis-(2-hydroxyethyl)-alkylamine. MR. GREGORY: Right. MR. GREGORY: I'm not even sure that PEG-2 should be included in the report at all. DR. HILL: No. Except the only experimental data we have is for the N,N-bis-(2-hydroxyethyl)-tallow alkylamine because, again, these are not PEGs. So any reference to actual PEGS I assert doesn't apply here. They're not PEGs period because of that nitrogen. Everything changes. DR. MARKS: So you said that, yes, you would reopen. DR. HILL: Yeah. I think there's enough data from the bis-2-hydroxyethyl, although when you extend that chain to add -- now we have an ether, another hydroxyethyl moiety, things are changing. And so, again, my point is relying on any information on any PEGs that are not – that don't have that nitrogen there is both -- it's not relevant. So what



we have to go on is science-based on this bis-(2-hydroxyethyl)-tallow alkylamine. I'm not totally compelled and really convinced that that's enough information to go gorward. And then the next one up is a PEG-15. But I wrote, "Okay. Reopen and add all," is the note I had here in front of me. DR. ANDERSEN: And take the next step -- DR. HILL: Take the next step. DR. ANDERSEN: -- to see what it looks like. DR. MARKS: So we don't -- is there anything going forward, Ron, you would particularly like to see going -- so that we can alert industry to supply it? Because I got the sense, if I heard incorrectly, Ron and Tom, you would just reopen. And then there's enough data now that this is safe and the add-ons would be similar and not raise new toxicologic alerts? DR. SHANK: That's right. DR. HILL: I'm not willing to go so far as to say no problem and it's safe, but I think it needs to be reopened. DR. MARKS: Okay. So going down here, of the data is there anything -- the data needs identified in '99, you had identified the issue of sensitization. DR. HILL: No. They really don't, except for the nitrogen there, again, I think. DR. MARKS: Anything else in here that raises -- we should be alerted to? DR. HILL: And I say the nitrogen there. The nitrogen there in conjunction with the possibility of metabolism going formaldehydes, I think we just really don’t know. DR. MARKS: Okay. So -- DR. HILL: Because the limits to the prediction and the degree of confidence, actually the answer for the (inaudible) prediction is we got no information from that, but the other program, which is quite new, is probably more robust, but it presents a qualified conclusion. DR. MARKS: Is there anything on the add-ons? Do we need to look at those now or just wait until the next time? DR. ANDERSEN: My comment is add all. DR. MARKS: Okay, good. Okay. So reopen tending to, I would say at this point, safe, and I'll put a question mark with Ron Hill there. And then we'll see what the next rendition is. DR. ANDERSEN: This would be another discussion I predict. DR. MARKS: Okay. DR. HILL: Yeah. DR. MARKS: Okay. Full Panel transcript Moving on to the PEGs cocamide. Don Belsito? DR. BELSITO: Yeah, in '99, we concluded the data were insufficient for PEGs cocamine 2, 3, 5, 10, 15, 20. There were four data needs:



Physical and chemical properties, especially nitrosamines; genotoxicity in a mammalian system; 28-day dermal tox using PEG-2 cocamine; and dermal sensitization data on PEG-2 cocamine. We did receive some data submissions. However, there was none on PEG-2 cocamine. And furthermore, much of it was all based on structure-activity relationships, and our group was very uncomfortable accepting that data to support safety and felt that there was no need to pursue reopening this. However, because much of the data on structural activity relationships came from the council, we thought that it would be very helpful for the panel to have a seminar, for lack of a better word, on what the various structure - activity relationships are out there for measuring different toxicity endpoints, whether they be genotoxicity, dermal sensitization, et cetera, and that that would be more than just a 45- minute presentation because it would involve different model systems for different endpoints and probably would actually be more of a half a day type of session with all the questions and answers. But having said that, we felt there was no need to reopen it at this point because we didn't feel the data justified the safety. DR. BERGFELD: And that's a motion? DR. BELSITO: That's a motion. DR. MARKS: Second. DR. BERGFELD: Second. Any further discussion? Dan. DR. LIEBLER: Yeah, let me just elaborate on this. I think, as I read this, the issue is that there are -- there's been continuing development of algorithms and software to reason across chemical space for different types of effects. There's obviously been a lot of stuff done in risk assessment and toxicology, but I think there's even software and algorithms that would predict metabolism, predict other features, biological effects. And my feeling was that the tools that were used to try and do this in this report may have been appropriate and may not have been, and we don't have enough information to be familiar with that. I think in the near future I would hope that this panel is -- at least Ron and I, are as familiar with these as the rest of the panel is with RIPTs and other kinds of standard measures, and there has been enough development in this area that I think it would be very informative to have a workshop of the type that Don just described. DR. BERGFELD: Ron Hill, I see you agreeing? DR. HILL: Yes. DR. BERGFELD: Any other comment? Linda? DR. LORETZ: It's just a point that I'm happy to bring that request back to the CIRS, see that was involved in this and, you know, stands behind it, so -- the idea of a workshop and what -- how we can help that. DR. BERGFELD: Thank you. I don't think we voted on this. We'll call for a vote to not reopen this ingredient. Thank you. Unanimous.



Orig

inal R

epo

rt

Final Report on the Safety Assessmentof PEG-2, -3, -5, -10, -15, and -20 Cocamine’

The PEGS Cocamine are the polyethylene glycol ethers of theprimary aliphatic amine derived from coconut oil. These ingredi-ents are used in cosmetic formulations as surfactants which func-tion as emulsifying and solubilizing agents. Very little data wereavailable on metabolism and toxicity, and no clinical data werefound or provided. Toxicity data, including reproductive and de-velopmental toxicity, carcinogenesis data, and clinical testing dataavailable from previous safety assessments on Polyethylene Glycoland Coconut Oil were summarized. The principal finding relatedto PEGS was based on clinical data in burn patients; PEGS weremild irritant/sensitizers and there was evidence of nephrotoxicity.No such effects were seen in animal studies on intact skin. Cos-metic manufacturers should adjust product formulations contain-ing Polyethylene Glycol to minimize any untoward effects whenproducts are used on damaged skin. Various PEGS Cocamine werefound to be mild to moderate skin irritants and were ocular ir-ritants. PEG-15 Cocamine was negative in bacterial mutagenicitystudies. Although metabolites of ethylene glycol monoalkyl ethersare reproductive and developmental toxins, it was considered un-likely that the relevant metabolites would be found in or producedfrom the use of PEGS Cocamine in cosmetic formulations. Of con-cern was the possible presence of 1,4-dioxane and ethylene oxide im-purities. The importance of using the necessary purification proce-dures to remove these impurities was stressed. The limited data onPEGS Cocamine and the related data on other ingredients, however,were not sufficient to support the safety of PEGS Cocamine for usein cosmetic formulations. Additional data needs include: (1) phys-ical and chemical properties, including impurities, and especiallynitrosamines; (2) genotoxicity in a mammalian system; if the re-sults are positive, then a dermal carcinogenesis study using NationalToxicology Program (NTP) methods may be needed; (3) 2%day der-ma1 toxicity using PEG-2 Cocamine; and (4) dermal sensitizationdata on PEG-2 Cocamine.

INTRODUCTION

The following report is a review of the safety data on PEG-2,-3, -5, -10, - 15, and -20 Cocamine. These cosmetic ingredientsare surfactants used as emulsifying and solubilizing agents.Chemically, these ingredients are the polyethylene glycol (PEG)ethers of the primary aliphatic amine derived from coconutoil. Note that the different chain length PEGS are formed bycondensing ethylene oxide and water, with the average number

Received 28 November 1998; accepted 25 January 1999.‘Reviewed by the Cosmetic Ingredient Review Expert Panel.

Rebecca S. Lanigan, former Scientific Analyst and Writer, preparedthis report. Address correspondence to Dr. F. Alan Andersen, Director,CIR, 1101 17th Street, NW, Suite 3 10, Washington, DC 20036, USA.

International Journal of Toxicology, 18(Suppl. 1):43-50, 1999Copyright ? 1999 Cosmetic Ingredient Review1091-5818/99 $12.00 + .oo

of moles of ethylene oxide used corresponding to the number inthe name.

These two basic components have been reviewed previouslyby the Cosmetic Ingredient Review (CIR) Expert Panel and FinalReports have been published. The following conclusions weremade:

PEG-6, -8, -32, -75, 150, -14M, and -2OM are safe for use at theconcentrations reflected in the Cosmetic Use section and in the prod-uct formulation safety test data included in the Final Report. The Ex-pert Panel recommends that cosmetic formulations containing thesePEGS not be used on damaged skin (Andersen 1993).

Coconut Oil, and its derivatives, Coconut Acid, HydrogenatedCoconut Oil, Hydrogenated Coconut Acid are safe for use as cos-metic ingredients (Elder 1986).

The relevant data from the Final Safety Assessments of thePEGS and Coconut Oil and its derivatives have been summarizedin this review as a further basis for the assessment of safety ofPEG-2-20 Cocamine.

CHEMISTRY

Definition and Structure

PEG-2, -3, -5, -10, -15, and -20 (CAS No. 61791-14-8[generic]) Cocamine are the polyethylene glycol ethers of theprimary aliphatic amine derived from Coconut Oil. These in-gredients conform to the formula shown in Figure 1, whereR represents the alkyl groups derived from Coconut Oil andx + y has an average value equal to the number in the name(see Method of Manufacture) (Wenninger and McEwen 1997).Other names for these compounds include Polyethylene Gly-co1 (x + y) Coconut Amine, Polyoxyethylene (x + y) CoconutAmine (Wenninger and McEwen 1997), and Polyoxyethylene(POE) Cocamine (Newburger, Jones, and Kottemann 1995).

Physical and Chemical Properties

PEG-15 Cocamine is a clear, light brown, oily liquid. It issoluble in water, isopropyl alcohol, and benzene. The specificgravity ranges from 1.040 to 1.046. Allowable moisture andash are 3% and 0.5% maximum, respectively (Nikitakis andMcEwen 1990).

The properties of the different chain length PEGS vary as afunction of molecular weight, with PEG-32 being a solid andPEG-8 being a viscous liquid (Andersen 1993). Coconut Oil isa pale yellow, semisolid, edible oil that is stable in air at roomtemperature. It is miscible in carbon disulfide, chloroform, ether,and petroleum benzin. Coconut Oil and Coconut Acid are both

43



44 COSMETIC INGREDIENT REVIEW

,G H 2C H 2O jXH

R - N\

( C H 2CH *O+H

FIGURE 1Chemical formula for PEGS Cocamine polymers (Wenninger

and McEwen 1997). R represents the alkyl groups derivedfrom Coconut Oil and x + y has an average value equal to the

number in the name.

soluble in mineral oil and isopropyl myristate, but are alcoholand water insoluble. Due to its high degree of saturation, CoconutOil is resistant to atmospheric oxidation at room temperature(Elder 1986).

Method of Manufacture

The PEG-n Cocamine polymers are manufactured by con-densing Coconut Acid with the ingredient’s corresponding num-ber of moles (n) of ethylene (Hunting 1983).

PEGS are formed by condensing ethylene oxide and water,with the average number of moles of ethylene oxide polymerizedindicated by the number in the name (Andersen 1993).

Coconut Acid is a mixture of fatty acids derived from CoconutOil. Coconut Oil is obtained by expression from the kernelsof the seeds of Cocos nuciferu. The primary constituents ofCoconut Oil are trimyristin, trilaurin, tripalmitin, tristearin, andvarious other triglycerides. About 90% of the oil is saturated.The expressed material has a water content of 4-10%. The fattymaterial is isolated after hydrolysis of Coconut Oil and thendistilled to form Coconut Acid (Elder 1986).

Analytical Methods

Newburger, Jones, and Kottemann (1995) determined PEG-1.5 Cocamine in cosmetic formulations containing polyethyleneglycols and/or propylene glycols using partition chromatogra-phy on Celite and infrared spectrometry.

Impurities

Silverstein et al. (1984) reported that PEG-6 may containsmall amounts of monomer and dimers. The amounts were notquantified. Peroxides, formed as a result of autoxidation, arefound in PEG-32 and PEG-75 (Hamburger, Azaz, and Donbrow1975). The amount of peroxide in PEG is dependent upon themolecular weight of the PEG and its age. The older the com-pound, the greater the concentration of peroxides. In a colori-metric assay used to determine the peroxide concentrations inseveral production lots of PEG, PEG-6 and PEG-8 were eachadded to acidified potassium iodide solution, and the iodine lib-erated was titrated against a standard thiosulfate solution. PEG-6had peroxide concentrations ranging from 1.4 to 9.3 PEq thio-

sulfate/ml glycol. PEG-8 had concentrations ranging from 3.24to 5.7 PEq thiosulfate/ml glycol. The specific peroxides presentin the PEGS were not determined, but they were thought to be or-ganic peroxides rather than hydrogen peroxide (McGinity, Hill,and La Via 1975).

Ethoxylated surfactants may also contain 1,4-dioxane, a by-product of ethoxylation (Robinson and Ciurczak 1980). 1,4-Dioxane is a known animal carcinogen (Kociba et al. 1974;Hoch-Ligeti, Argus, and Arcos 1970; Argus, Arcos, and Hoch-Ligeti 1965). In the CIR safety assessment of the PEGS Stearate,the cosmetic industry reported that it is aware that 1,4-dioxanemay be an impurity in PEGS and, thus, uses additional purifica-tion steps to remove it from the ingredient before blending intocosmetic formulations (Elder 1983).

Coconut Oil is usually low in color bodies, pigments, phos-phatides, gums, and other nonglyceride substances commonlyfound in larger quantities in other vegetable oils. It may containfree fatty acids, low concentrations of sterols, tocopherol, andsqualene. The characteristic coconut flavor is due to the presenceof approximately 150 ppm lactones that are present as a seriesof d-lactones with 6, 8, 10, 12, and 14 carbon atoms. Crudesamples of Coconut Oil contain traces of polycyclic aromatichydrocarbons, particularly when the copra is smoke-dried. Acombination of activated charcoal treatment and steam vacuumdeodorization are the common refining methods most likely toremove the hydrocarbons from the edible oils. Aflatoxin con-tamination of raw and dried copra have been reported. Improperdrying, handling, and storage greatly increase the possibility ofcontamination by aflatoxins, secondary metabolites of the moldAspergillus jlavus, which grows on copra. Smoke drying of co-pra inhibited aflatoxin formation (Elder 1986).

USE

Cosmetic

The PEGS Cocamine are surfactants used as emulsifyingand solubilizing agents (Wenninger and McEwen 1997). Theproduct formulation data submitted to the Food and Drug Ad-ministration (FDA) in 1996 indicated that only PEG-2, -3,-15, and -20 Cocamine are in use, and that they are collec-tively used in 95 cosmetic formulations (Table 1) (FDA 1996).Concentration of use data submitted by Cosmetic, Toiletry, andFragrance Association (CTFA) in 1995 reported generically thatPEGS Cocamine were used in hair bleach and hair color at con-centrations of 20% and 88, respectively (CTFA 1995a), andthat specifically, PEG- 15 Cocamine was used at concentrationsup to 1.3% in various products (CTFA 1995b) as shown inTable 2.

International

PEG-2 Cocamine is listed in the ComprehensiLte LicensingStandards of Cosmetics by Category (CLS) and must conform to



PEGS COCAMINE

TABLE 1Cosmetic product formulation data (FDA 1996)

Total no. formulations Total no. of formulationsProduct category in category containing ingredient

PEG-2 CocamineHair dyes and colors 1612 5Hair tints 57 101996 total 15

PEG-3 CocamineHair dyes and colors 1612 I41996 total 14

PEG-15 CocamineColognes and toilet waters 834 2Powders 307 1Other fragrance preparations 195 1Tonics, dressings, and other hair grooming aids 604 6Other personal cleanliness products 339 2Aftershave lotion 268 ICleansing preparations 820 3Body and hand preparations (excluding shaving) 1012 2Moisturizing preparations 942 4Skin fresheners 244 31996 total 28

PEG-20 CocamineBubble baths 211 1Hair conditioners 715 2Hair dyes and colors 1612 34Hair lighteners with color 9 11996 total 38

45

the standards of the Japanese Cosmetic Ingredient Codex (JCIC)(Yakuji Nippo, Ltd. 1994). It can be used in all CLS categoriesexcept eyeliners, lipsticks and lip creams, and dentifrices withoutrestriction.

TABLE 2Concentration of use of PEGS Cocamide polymers

in cosmetic formulations (CTFA 1995a,b)

Formulation Concentration (%)

PEGS CocamineHair bleach 20Hair color 8

PEG-15 CocamineShower gel 1.0Eyeshadow 1.3Fragranced body freshener 1.0Shampoo 0.8Hair dressing 0.8Hair fixative tl

BIOLOGICAL PROPERTIES

Absorption, Metabolism, Distribution, and Excretion

Gastrointestinal absorption of PEG is dependent on the mole-cular weight of the compound. In general, the larger the molec-ular weight of the PEG compound, the lesser absorption thatoccurs. In both oral and intravenous studies, no metabolismwas observed and the PEGS were rapidly eliminated unchangedin the urine and feces. In a study with human bum patients.monomeric ethylene glycol was isolated in the serum followingtopical exposure to a PEG-based antimicrobial cream, indicatingthat PEGS are readily absorbed through damaged skin (Andersen1993).

Results of clinical dietary studies suggest that 95-98%of ingested Coconut Oil is absorbed. When Coconut Oil wasused as a saturated fat control for metabolism studies with rats,it caused slight increases in serum cholesterol concentrations.Longevity was not affected by diets containing Coconut Oil.In another study using rats, 60% of a 6 g/kg dose CoconutOil adminstered by intubation was absorbed within 6 h (Elder1986).



46 COSMETIC INGREDIENT REVIEW

ANIMAL TOXICOLOGY

Acute Toxicity

The oral LD50 of PEG-2 Cocamine was approximately 1.3 g/kg for rats (CTFA 1978a). In similar studies, the LD50 was0.75 g/kg (Goater et al. 1970) and 1 g/kg for PEG-2 Cocamine(CTFA 1978b), and 1.2 g/kg for PEG-15 Cocamine (CTFA1978~).

The acute oral LD50 in rabbits of 100% PEG-6 was 17.3 g/kg;that of 100% PEG-75 was 76 g/kg. Acute dermal toxicity studiesdid not result in mortality after rabbits were given 20 ml/kg dosesof undiluted PEG-6 or 40% PEG-20M (Andersen 1993).

No deaths occurred after undiluted Coconut Oil and Hydro-genated Coconut Oil were administered to rats via intubationin 5 g/kg doses. Undiluted Hydrogenated Coconut Oil did notcause mortality after a single 3 g/kg dermal application in guineapigs (Elder 1986).

Short-Term Toxicity

The minimum lethal daily dose of PEG-5 Cocamine admin-istered to guinea pigs for 8 days was 500 mg/kg (Goater et al.1970).

Schafer and Bowles (1985) fed 2.0% ethoxylated Cocamine(the number of moles of ethylene oxide polymerized was notspecified) treated feed to deer mice for 3 days. The LD50 was> 1200 mg/kg/day.

There was no evidence of toxicity in rabbits that receiveddaily dermal applications of PEG-20M (0.8 g/kg/day) for30 days; however, transient, mild erythema was observed. Theonly evidence of systemic toxicity that resulted from dermalexposure was renal failure in rabbits that received repeated ap-plications of an antimicrobial cream containing 63% PEG-6,5%PEG-20, and 32% PEG-75 to excised skin for 7 days (Andersen1993).

Subchronic Toxicity

Fifty female, albino Charles River CHR-CD rats were placedinto five groups of 10 rats each. The rats were housed indi-vidually in temperature-controlled cages. Feed and water wereprovided ad libitum. After a 2-week acclimation period, the ratsreceived the test materials to their shaved skin by gentle inunc-tion. Group 1, the control group, received 2.0 ml/kg mineral oilonce daily, 5 days a week, for 6 weeks. The same dose of 10%PEG-15 Cocamine was applied 30 times to group 2 rats. Theother three groups received different test materials (not listed).Observations for general appearance, behavior, pharmacologicand/or toxicologic signs were recorded daily. Initial and weeklybody weights were measured, as well as at necropsy. At the endof the study, the rats were fasted for 16 hours overnight. Bloodsamples were drawn by orbital sinus puncture while the rats wereunder ether anesthesia. Hematocrit, hemoglobin concentration,erythrocyte count, white blood cell count (both total and differ-ential), blood urea nitrogen concentration, multiple cell volume,serum alkaline phosphatase activity, serum glutamic oxaloacetic

transaminase activity, serum glutamic pyruvic transaminase. andfasting blood glucose were all determined. All rats survivedfor the length of the study. No adverse effects were observedin weight gain, physical appearance, or behavioral signs. Ap-plication sites of treated skin did not significantly differ fromuntreated controls. A few rats in each group scratched the appli-cation sites, probably due to caking of the test material or by thenicking of the skin while shaving. No evidence was found that thescratching could be attributed to the application of the chemicals.All rats were killed by ether overdose for necropsy. The brain,liver, kidneys, spleen, adrenal glands, lungs, heart, and uteruswere then weighed and portions of each preserved. Portions ofthe intestines, pancreas, skin, and stomach were also fixed. Slidesof kidneys, bile duct, liver, spleen, and skin were examined mi-croscopically, as were slides of bone marrow. Mean neutrophiland lymphocyte values of PEG- 15 Cocamine-treated rats weresignificantly higher or lower than controls, but fell within thehistorical range of the laboratory rats, and were not accompa-nied by other changes. Therefore, researchers concluded thatthe differences were not related to the treatment. At necropsy,no changes were observed that could be attributed to the test ma-terial, and no significant changes in relative or absolute organweights were observed. At microscopic examination, no lesionswere found that were related to the application of PEG-15 Co-camine. Researchers concluded that no systemic toxic effectsoccurred in the tested rats at the applied dosage (CTFA 1978h).

In 90-day oral toxicity studies involving groups of albino rats,the highest and lowest molecular weight PEGS tested (PEG-20Mand PEG-6, respectively) did not induce toxicity or death whenadministered daily in the diet (PEG-20M) or in drinking water(PEG-6) at concentrations of 4% or less (Andersen 1993).

In a subchronic study using rats, 25% Coconut Oil in feed wasadministered. A 20-30% higher progressive increase in liver fatcontent was observed, compared to controls. Fatty acid changeof the liver was slight and no other pathological changes wereobserved (Elder 1986).

Chronic Toxicity

Toxic effects were not observed in dogs that received 2%PEG-g, PEG-32, or PEG-75 in the diet for 1 year (Andersen1993).

Supplementation of the lifetime diet of mice with 15% Hy-drogenated Coconut Oil did not adversely affect the lifespans ofmice (Elder 1986).

Ocular Irritation

The right conjunctival sac of six New Zealand white rabbitswas instilled with 0.10 ml PEG-2 Cocamine, and observationswere made after 24, 48, and 72 hours, and after 7 days. Theirritation scores (out of a maximum possible score of 110) were:63.7 at 24 hours, 62.7 after 48 hours, 61.3 after 72 hours, and64.5 after 7 days. This ingredient was classified as an ocularirritant (CTFA 1978a).



PEGS COCAMINE 47

In another study with six rabbits, the average ocular irrita-tion scores for PEG-2 Cocamine were 27.0 at 24 hours, 36.2 at48 hours, and 39.3 at 72 hours. The investigators noted that theaverage score increased between 24 and 72 hours, which seemedto be due to a mild, but persistent, involvement of a large areaof the cornea (CTFA 1978f).

Goater et al. (1970) reported that 10% aqueous PEG-5 Co-camine caused moderate, but transient, inflammation or redden-ing of the eyes of rabbits.

A study of PEG-l 5 Cocamine (as supplied) was conducted ina similar fashion. Following instillation of this ingredient into theconjunctival sac of six rabbits, cornea1 opacity and conjunctivalinflammation, swelling, and ocular discharge were observed inall of the rabbits at all three time periods. A decreased iridicresponse to light was observed in five rabbits at the 48-hourinterval, and the remaining rabbit developed this condition at72 hours. The irises of two rabbits had no reaction to light at72 hours (CTFA 19788).

Ocular irritation scores were obtained using test methodologyprescribed in the Code of Federal Regulations (CFR Title 16Parts 1500.3, 1500.40, 1500.41, and 1500.42. Testing methods).Scores for PEG- 15 Cocamine were 32.33,39.83, and 42.0 at 24,48, and 72 hours, respectively, out of a maximum possible scoreof 110. Comeal irritation was involved at all readings (ProtameenChemicals, Inc. 1995).

PEGS -6 and -75 did not cause cornea1 injuries when instilled(undiluted, 0.5 ml) into the conjunctival sac of rabbits. PEG-8(35% solution, 0.1 ml) and PEG-32 (melted in water bath, 0.1 ml)induced mild ocular irritation in rabbits (Andersen 1993). Theresults of several studies indicate that the ocular irritation po-tential of undiluted Coconut Oil is low (Elder 1986).

Dermal Irritation and Sensitization

Six New Zealand white rabbits were treated topically with0.5 ml PEG-2 Cocamine on both abraded and intact sites ontheir back and flanks. Applications were covered with gauzepatches and taped to the skin. Irritation scores were determinedat 24 and 72 hours following application. Irritation was observedon all the rabbits. The primary skin irritation index (PII) was 3.9out of a maximum of 8 (CTFA 1978a).

In similar studies, the PIIs for PEG-2 and PEG- 15 Cocaminewere 2.4 and 1.4, respectively. The irritation score of PEG-2Cocamine was due to severe erythema, which was observed at72 hours. Erythema was also observed with PEG- 15 Cocamine.However, no edema was observed with either ingredient. PEG-2Cocamine was classified as a moderate irritant, and PEG-15Cocamine was considered a mild irritant (CTFA 1978d,e).

In another study, semiocclusive patches of 0.5 ml PEG-2Cocamine (concentration not stated) were applied to the intactskin of six New Zealand white rabbits. The patches were kept incontact with the skin for 4 hours, after which the skin was rinsed.Examinations of the skin were made at the time of patch removaland at 24 and 48 hours later. The PIIs for time intervals were 6.2at 4 hours, 7.2 at 24 hours, and 7.3 at 48 hours. Subcutaneous

hemorrhaging and blanching were observed in all of the animalsat 24 hours and in one rabbit at 48 hours. Eschar and necroticareas were observed at both the 24 and 48 hours readings. Theinvestigators concluded that PEG-2 Cocamine was corrosive tothe skin (Hazelton Laboratories America, Inc. 1985).

The PEGS were not irritating to the skin of rabbits or guineapigs, and PEG-75 was not a sensitizer. In skin irritation tests,undiluted PEG-6 was applied to the skin of rabbits for 4 hoursand 50% PEG-75 was applied to guinea pigs for 4 days andto rabbits over a 13-week period. In the guinea pig skin sen-sitization test, PEG-75 was tested at a concentration of 0.1%(Andersen 1993).

Undiluted Coconut Oil did not cause skin irritation in rab-bits during a 24-hour single-insult occlusive patch test. It wasalso nonsensitizing in a Magnusson-Kligman Maximization test.No irritation was observed when bar soaps containing 13% Co-conut Oil were evaluated in single-insult occlusive patch testsusing rabbits with abraded and intact skin. The primary irrita-tion threshold of Hydrogenated Coconut Oil was 5% in ethylalcohol, which produced slight irritation to guinea pigs upon re-peated application. This concentration was nonsensitizing in atest using a modified Buehler technique (Elder 1986).

REPRODUCTIVE AND DEVELOPMENTAL TOXICITY

Ethylene Glycol and Its Ethers

It is generally recognized that the PEG monomer, ethyleneglycol, and certain of its monoalkyl ethers (e.g., methoxyethanol,a.k.a. ethylene glycol monomethyl ether) are reproductive anddevelopmental toxins. The CIR Expert Panel undertook a sep-arate, limited scope review of these compounds in order to as-sess the possibility that PEG-derived cosmetic ingredients couldpresent similar concerns (CIR 1996). In summary, this reportconcluded that the ethylene glycol monoalkyl ethers are notthemselves toxic, but rather, that one or more alcohol or alde-hyde dehydrogenase metabolites are toxic. From the availabledata, the report also concluded that the toxicity of the monoalkylethers is inversely proportional to the length of the alkyl chain(methyl is more toxic than ethyl than propyl than butyl, etc.).

Given the methods of manufacture of the PEGS Cocamine,there is no likelihood of methoxyethanol, ethoxyethanol, etc.,being present as impurities. In particular, because the PEGS Co-camine are PEG ethers of the primary aliphatic amine derivedfrom coconut oil, and as such, are chemically different fromthe alkyl ethers, the Panel concluded there is no reproductive ordevelopmental hazard posed by these compounds.

Polyethylene Glycol

No adverse reproductive effects occurred during subchronic(90 days) and chronic (2 years) oral toxicity studies of PEG-6-32and PEG-75. In the subchronic study, PEG-75 was tested at adose of 0.23 g/kg/day. In the chronic study, PEG-75 was testedat doses up to 0.062 g/kg/day and, PEG-6-32, at doses up to1.69 g/kg/day (Andersen 1993).



MUTAGENICITY irritation in one study and mild irritation in another. No photo-

PEG- 15 Cocamine was tested for mutagenicity using the toxicity or photosensitivity was produced by these same bar soappaper-disk method. Nutrient agar was seeded with streptomycin formulations. Additionally, there was no evidence of sensitiza-dependent Sd-4-73 Escherichia coli and filter-paper disks con- tion in studies of formulations containing 2.5% Coconut Oil or

taining PEG-15 Cocamine were placed on the surface of the 10% Hydrogenated Coconut Oil (Elder 1986).cultures. The frequency of reversion from streptomycin depen-dence to independence was used as the measure of mutagenicity. SUMMARYPEG- 15 Cocamine was negative in this test (Szybalski 1958).

PEG-8 was negative in the Chinese hamster ovary cell mu-PEG-2, -3, -5, - 10, - 15, and -20 Cocamine are the polyethy-

tation test and the sister chromatid exchange test; the maxi-lene glycol ethers of the primary aliphatic amine derived from

mum test concentration in both studies was 1%. In the unsched-coconut oil. These ingredients are surfactants which function as

uled DNA synthesis assay, a statistically significant increase inemulsifying and solubilizing agents in cosmetics. Product for-

radioactive thymidine incorporation into rat hepatocyte nucleimulation data submitted to the FDA in 1996 indicate that only

was noted only at the highest concentration tested (0.1% PEG-PEG-2, -3, -15, and -20 Cocamine are in use, and that they areused in 86 cosmetic formulations.

8). PEG-150 was not mutagenic in the mouse lymphoma for-ward mutation assay when tested at concentrations up to 150 g/l

Little data on the PEGS Cocamine regarding metabolism,

(Andersen 1993).toxicity, mutagenicity, carcinogenicity, or clinical safety wereavailable. Summary data on the PEGS and Coconut Oil wereseparately provided, with the view that these data were applica-

CARCINOGENICITY ble to the PEG Cocamine compounds.

All of the carcinogenicity data available on the PEGS were PEG Cocamine absorption and metabolism data were not

specifically on PEG-g, which was used as a solvent control for available. PEG absorption is related to whether the substance is

a number of studies. PEG-8 was not carcinogenic when admin- a liquid or a solid. PEGS were readily absorbed through damaged

istered orally to mice (30 weeks of dosing), intraperitoneally to skin. Oral and intravenous studies on the PEGS indicated that

rats (6 months of dosing ), subcutaneously (20 weeks of dosing these substances were excreted, unchanged, in the urine and

to rats; 1 year of dosing to mice), or when injected into the gas- feces. Ingested Coconut Oil was almost entirely absorbed with

tric antrum of guinea pigs over a period of 6 months (Andersen no mortality.

1993). The oral LD50 value of PEG- 15 Cocamine in rats was 1.2 g/

Coconut Oil was less effective than polyunsaturated fat as a kg, and for PEG-2 Cocamine, values ranged from 0.75 g/kg to

tumor promoter for mammary tumors in rats induced by 7,12- 1.3 g/kg. No systemic toxic effects occurred in rats following a

dimethylbenz( 1)anthracene (Elder 1986). 6-week dermal application study using 10% PEG- 15 Cocamine.PEGS have low oral and dermal toxicity; generally, the greatermolecular weight PEGS appear to be less toxic than the lighter

CLINICAL STUDIES PEGS in oral studies. Coconut Oil and Hydrogenated CoconutNo clinical studies were available for the PEGS Cocamine Oil are relatively nontoxic by ingestion.

polymers. PEG-2 Cocamine was classified as a moderate cutaneous ir-In clinical studies, PEG-6 and PEG-8 induced mild sensiti- ritant, and PEG-15 Cocamine was considered a mild irritant.

zation in 9% and 4% of 23 male subjects tested, respectively. PEGS were nonirritating to the skin of rabbits and guinea pigs,However, later production lots of PEG-6, as well as PEG-75, and PEG-75 was not a sensitizer. Coconut Oil was not a skin ir-did not cause reactions in any of the 100 male and 100 female ritant or a sensitizer. PEG-2 Cocamine was considered an ocularsubjects tested. A product formulation containing 3% PEG-8 in- irritant, and PEG-15 Cocamine caused cornea1 irritation.duced minimal to mild irritation (induction phase) in over 75% In mutagenicity studies, PEG-15 Cocamine was negative.of 90 volunteers participating in a skin irritation and sensitiza- PEG-8 was negative in the Chinese hamster ovary cell muta-tion study. Responses (not classified) were noted in 22 subjects tion test and the sister chromatid exchange test. At concentra-at the 24-hour challenge reading. Cases of systemic toxicity tions up to 150 g/l, PEG-150 was not mutagenic in the mouseand contact dermatitis in burn patients were attributed to PEG- lymphoma forward mutation assay. PEG-8 was not carcinogenicbased topical ointments. The ointment that induced systemic when administered orally, intraperitoneally, or subcutaneously.toxicity contained 63% PEG-6, 5% PEG-20, and 32% PEG-75 Although monoalkyl ethers of ethylene glycol are reproduc-(Andersen 1993). tive toxins and teratogenic agents, it was considered unlikely

A variety of assays has been used in clinical assessments that the PEG Cocamine compounds would cause reproductiveof cosmetic products containing Coconut Oil. Bar soaps con- or teratogenic effects based on their structural characteristics. Intaining 13% Coconut Oil, when tested using standard Draize subchronic and chronic feeding studies, PEG-6-32 and PEG-75procedures, produced very minimal skin reactions. In a 2-week did not induce reproductive effects in rats.normal-use test, bar soaps caused no unusual irritation response. In clinical studies, PEG-8 was a mild sensitizer and irritant.The results of soap chamber tests of bar soans were minimal1 Contact dermatitis and systemic toxicity in bum patients were

48 COSMETIC INGREDIENT REVIEWDistrubted for Comment Only -- Do Not Cite or Quote


PEGS COCAMINE 49

attributed to a PEG-based topical ointment. Bar soaps contain-ing 137~ Coconut Oil, when tested using Draize procedures,produced minimal skin reactions.

DISCUSSION

Safety test data on the PEGS and on Coconut Oil and itsderivatives were considered relevant and supportive of the safetyof PEGS Cocamine polymers.

The CIR Expert Panel was concerned about the sensitizationpotential of the PEGS Cocamine (PEG-2, -3, -5, -10, -15, and-20 Cocamine) when applied to damaged skin. This concernarose because of positive patch tests and incidences of nephro-toxicity in bum patients treated with an antimicrobial cream thatcontained PEG-6, PEG-20, and PEG-75. PEG was determinedto be the causitive agent in both animal and human studies; noevidence of systemic toxicity or sensitization was found in stud-ies with intact skin. The Expert Panel concluded that cosmeticformulations containing PEG should not, therefore, be used ondamaged skin.

Also of concern to the Expert Panel was the possible pres-ence of 1,4-dioxane and ethylene oxide impurities. The Panelmembers stressed that the cosmetic industry should continue touse the necessary purification procedures to remove these impu-rities from the ingredients before blending them into cosmeticformulations.

Based on particle size and cosmetic use concentrations, it wasnot considered likely that these ingredients, in formulation, arerespirable. Thus, the Expert Panel has no concerns regarding theabsence of inhalation toxicity data, and the Panel considers thePEG Cocamine compounds safe for use in aerosolized products.

After considering the basic chemical structure of PEGS andthe negative phototoxicity and photosensitization data on barsoaps containing Coconut Oil, the CIR Expert Panel concludedthat it is unlikely that the PEGS Cocamine are either photosen-sitizers or phototoxic agents. As discussed in this report, thepossibility of reproductive and developmental effects was as-sessed and determined not to be a concern.

Citing concerns about the amine in the cocamine moiety inthese ingredients, the Panel determined that additional data werenecessary. In addition, data specifically on PEG-2 Cocamine areneeded to demonstrate that this smallest polymer in the groupdoes not exhibit toxicity. Section 1, paragraph (p) of the CIRProcedures states that “a lack of information about an ingredi-ent shall not be sufficient to justify a determination of safety.”In accordance with Section 30(j)(2)(A) of the Procedures, theExpert Panel informed the public of its decision that the dataon PEG-2, -3, -5, -10, -15, and -20 Cocamine were not suffi-cient for determining whether the ingredients, under relevantconditions of use, were either safe or unsafe. The Panel releasedan Insufficient Data Announcement on May 23, 1995, outlin-ing the data needed to assess the safety of the PEG Cocaminecompounds. Concentration of use data were received in reponseto the announcement. No other comments were received during

the YO-day public comment period. Additional data needed tomake a safety assessment are: (1) physical and chemical impu-rities, especially nitrosamines; (2) genotoxicity in a mammaliansystem; (3) 28-day dermal toxicity using PEG-2 Cocamine; and(4) dermal sensitization data on PEG-2 Cocamine.

CONCLUSION

The CIR Expert Panel concludes that the available data areinsufficient to support the safety of PEG-2, -3, -5, -10, -15, and-20 Cocamine for use in cosmetic products.

REFERENCESAndersen, E A., ed. 1993. Final report on the safety assessment of polyethylene

glycols (PEGS) -6, -8, -32, -75, -150, -14M. -2OM. J. Am. Coil. To..rirol.12~429-457.

Argus, M. F., J. C. Amos, and C. Hoch-Ligeti. 1965. Studies on the carcinogenicactivity of protein-denaturing agents: Hepatocarcinogenicity of dioxane. J.Natl. Cancer: Inst. 35:949-95X.

Cosmetic Ingredient Review (CIR). 1996. Special reporr on the reproductiveand developmental toxici@ of ethylene g!\co/ and its ether.y. Washington.DC: author.’

Cosmetic, Toiletry, and Fragrance Association (CTFA). 1978a. Acute oral toxi-city, eye irritation, skin irritation of Varonic (PEG-2 Cocamine). Unpublisheddata submitted by CTFA. (5 pages.)’

CTFA. 1978b. A study of the estimated acute oral LD50 of the test materialVaronic K202 (PEG-2 Cocamine) in rats. Unpublished data submitted byCTFA. (28 pages.)’

CTFA. 1978~. A study of the estimated acute oral (LD50) of the test materialVaronic K215 (PEG-15 Cocamine) in rats. Unpublished data submitted byCTFA. (28 pages.)2

CTFA. 1978d. FHSA primary skin irritation study of Varonic K202 (PEG-2Cocamine) in rabbits. Unpublished data submitted by CTFA. (9 pages.)’

CTFA. 1978e. Skin irritation of the test material Varonic K215 (PEG- 15 Co-camine) in rabbits. Unpublished data submitted by CTFA. (9 pages.)’

CTFA. 1978f. Eye irritation test of the test material Varonic K202 (PEG-2 Co-camine) in rabbits. Unpublished data submitted by CTFA. (9 pages.)’

CTFA. 1978g. Eye irritation of the test material Varonic K215 (PEG-15 Co-camine) in rabbits. Unpublished data submitted by CTFA. (9 pages.)’

CTFA. 1978h. Systemic toxicity studies of selected raw ingredients: 1. Bis co-coy1 amine--Code 0150/10% PEG-15 Cocamine. Six week subacute dermaltoxicity in rats. Unpublished data submitted by CTFA, 8-16-95. (7 pages.)’

CTFA. 1995a. Use levels of various ingredients. Unpublished data submitted byCTFA, 7-l 7-95. (13 pages.)’

CTFA. 1995b. Ingredient use information. Unpublished data submitted byCTFA, 7-14-95. (2 pages.)’

Elder, R. L., ed. 1983. Final report on the safety assessment of PEG-2. -6. -8.-12, -20, -32, -40, -50, -100, and -150 stearates. J. Am. Co/l. Toxicol. 2: 17-34.

Elder, R. L., ed. 1986. Final report on the safety assessment of coconut oil.coconut acid, hydrogenated coconut acid, and hydrogenated coconut oil. J.Am Coil. Toxicol. 5: 103-121.

Food and Drug Administration (FDA). 1996. Frequency of use of cosmeticingredients. FDA database. Washington, DC: author.

Goater, T. 0.. D. Griffiths, T. E McElligott, and A. A. B. Swan. 1970. Acuteoral toxicity and short term feeding studies on polyoxyethylene tallow aminein rats and dogs. Fd. Cosmer. Toxicol. 8:249-252.

Hamburger, R., E. Azaz, and M. Donbrow. 1975. Autoxidation of poly-oxyethylenic non-ionic surfactants and of polyethylene glycols. Pharm. Acra.He/\: 50: 10-17.

‘Available for review: Director, Cosmetic Ingredient Review. 1101 17thStreet, NW, Suite 310, Washington, DC 20036.4702, USA.



5 0 COSMETIC INGREDIENT REVIEW

Hazelton Laboratories America, Inc. 1985. D.O.T. Skin corrosivity-method,summary, raw data appendix for Varonic K202 (PEG-2 Cocamine). Unpub-lished data submitted by CTFA. (5 pages.)’

Hoch-Ligeti, C., M. F. Argus, and J. C. Arcos. 1970. Induction of carcinomasin the nasal cavity of rats by dioxane. BI: J. Cancer 24: 164-167.

Hunting, A. L. L. 1983. Encyclopedia of shampoo ingredients, 300, 311-312.Cranford, NJ: Micelle Press Inc.

Kociba, R. J., S. B. McCollister, C. Park, T. R. Torkelson, and P. J. Gehring.1974. 1,4-Dioxane. I. Results of a 2-year ingestion study in rats. Toxicol.Appl. Pharmacol. 30~275-286.

McGinity, J. W., J. A. Hill, and A. L. La Via. 1975. Influence of peroxide im-purities in polyethylene glycols on drug stability. J. Pharm. Sci. 64:356-357.

Newburger, S. H., J. H. Jones, C. M. Kottemann, et al. 1995. Some applications ofcolumn chromatography in cosmetic analysis. II. Analysis of polyoxyethylenesurfactants and polyethylene glycols. Submitted by the FDA in response toan FOI request dated 8-l-95. Washington, DC: FDA. (4 pages.)’

Nikitakis, J. M., and G. N. McEwen, Jr., eds. 1990. PEG-15 cocamine. Entryin CTFA compendium of cosmetic ingredient composiron-Descriptions II.Washington, DC: Cosmetic, Toiletry, and Fragrance Association.

Protameen Chemicals, Inc. 1995. Material safe& data sheer on PEG-15 co-camine. Totowa, NJ: author.

Robinson, J. J., and E. W. Ciurczak. 1980. Direct gas chromatographic deter-mination of 1.4.dioxane in ethoxylated surfactants. J. Sot. Cosmer. Chem.3 1:329-337.

Schafer, E. W., Jr., and W. A. Bowles, Jr. 1985. Acute oral toxicity and repellencyof 933 chemicals to house and deer mice. Environ. Conram. Toxicol. 14: 11 I-129.

Silverstein, B. D., P. S. Furcinitti, W. A. Cameron, J. E. Brower, and 0. White, Jr.1984. Biological effects summary report-Polyethylene glycol. Governmen?Reports Announcements & Index. Issue 15. NTIS No. DE84007984.

Szybalski, W. 1958. Special microbiological systems. II. Observations onchemical mutagenesis in microorganisms. Ann. N.Y Acad. Sci. 76:475-489.

Wenninger, J. A., and G. N. McEwen, Jr., eds. 1997. International cosmericingredient dictionary and handbook, 7th ed, vol. 2, 942-943. Washington,DC: CTFA.

Yakuji Nippo, Ltd. 1994. The comprehensive licensing standards of cosmeticsbJ caregoq, 74-75. Tokyo, Japan: author.



New

Data

r

ZOI- I4981 4 Fatty Nitrogen Derived Amines Category

High Production Volume (HPV) Chemicals Challenge

Assessment of Data Availability and Test Plan

Prepared for:

American Chemistry Council’s Fatty Nitrogen Derivatives Panel

Amines Task Group

Prepared by:

Toxicology/Regulatory Services, Inc.

December 29,2003



Fatty Nitrogen Derived Amines Category High Production Volume (HPV) Chemicals Challenge

Assessment of Data Availability and Test Plan

Table of ContentsIntroduction..................................................................................................................................... 1

Definition of Fatty Nitrogen Derived (FND) Amines Structure-Based Chemical Category.......... 1

Structural Information for the FND Amines Category and Supporting Chemicals........................ 3

Rationale for the FND Amines Structure-Based Chemical Category ............................................ 4

Available Data to Fulfill HPV Screening Information Data Set (SIDS) Endpoints ....................... 7

Approach to Evaluate the Database for the FND Amines Category .......................................... 7

Use of Structure Activity Relationships for the FND Amines Category.................................... 8

Common Features of the Models ................................................................................................ 9

Estimation of Physical/Chemical Properties............................................................................... 9

Estimation of Environmental Fate Properties ............................................................................. 9

Estimation of Environmental Distribution.................................................................................. 9

Estimation of Acute Aquatic Toxicity...................................................................................... 10

Modeling Information Specific to the FND Amine Category .................................................. 10

Physical/Chemical Properties Data ............................................................................................... 10

Summary – Physical/Chemical Properties ................................................................................ 12

Additional Testing – Physical/Chemical Properties ................................................................. 13

Environmental Fate and Ecotoxicity Data .................................................................................... 13

Summary – Environmental Fate and Ecotoxicity..................................................................... 16

Additional Testing – Environmental Fate and Ecotoxicity....................................................... 17

Human Health-Related Data ......................................................................................................... 17

Summary – Human Health-Related Data.................................................................................. 21

Additional Testing – Human Health-Related Studies............................................................... 21

References ..................................................................................................................................... 22

i



List of Tables

Table 1: Structures of FND Amines Category Chemicals .........................................................24

Table 2: Physical/Chemical Properties Data for FND Amines Category Chemicals ...................29

Table 3: Environmental Fate and Ecotoxicity Data for FND Amines Category Chemicals .............................................................................31

Table 4: Human Health-Related Data for FND Amines Category Chemicals.............................37

Table 5: Proposed Test Plan for American Chemistry Council FND Amines CategoryPhysical/Chemical Properties.....................................................................................42

Table 6: Proposed Test Plan for American Chemistry Council FND Amines CategoryEnvironmental Fate and Ecotoxicity .........................................................................44

Table 7: Proposed Test Plan for American Chemistry Council FND Amines CategoryHuman Health-Related Data......................................................................................46

Appendices

Appendix A: Robust Summaries for Reliable Studies

Index of Robust Summaries .................................................................................................A-1

Physico-chemical Properties Robust Summaries...................................................................A-34

Environmental Fate Robust Summaries.................................................................................A-74

Human Health Robust Summaries ........................................................................................A-320

Appendix B: Robust Summaries for SAR Model Data

Index of Robust Summaries .................................................................................................B-1

Robust Summaries...............................................................................................................B-3

ii



Fatty Nitrogen Derived Amines Category High Production Volume (HPV) Chemicals Challenge

Assessment of Data Availability

Introduction

Surfactants have a long history of use and have been studied extensively for environmental fate and effects and human health effects. The Fatty Nitrogen Derived (FND) Amines Category chemicals have surfactant properties (e.g. comprised of hydrophobic and hydrophilic ends, form micelles, alter/reduce surface tension, form oil/water emulsions) and are used primarily in the production of commercial surfactants such as ethoxylated amine surfactants or as chemical intermediates (e.g. for the production of quaternary amines). Some typical applications of FND Amines Category chemicals and/or their derivatives are as degreasers, metal cleaners, metal working fluids, and industrial laundry cleaners.

Definition of Fatty Nitrogen Derived (FND) Amines Structure-Based Chemical Category

The FND Amines Category is comprised of 23 chemicals with unique Chemical Abstracts Service Registry Numbers (CAS RN; see Text Table A). While these long-chain substituted amines are considered appropriately combined in a single category based on their similar properties and toxicity, for aid in review, the chemicals were placed in the following subcategories:

Subcategory I: Primary Alkylamines and Alkyldiamines: Six long-chain substituted amines (CAS RN 124-22-1, 143-27-1, 68037-91-2, 68155-38-4, 61790-18-9 and 68037-95-6). Two long-chain substituted propanediamines (CAS RN 61791-55-7 and 7173-62-8).

Subcategory II: Dimethylalkylamines: Five long-chain substituted dimethyl amines (CAS RN 112-75-4, 112-69-6, 124-28-7, 61788-95-2 and 61788-91-8).

Subcategory III: Dialkylmethylamines and Dialkylamines: Six long-chain disubstituted amines and disubstituted methyl amines (CAS RN 7396-58-9, 67700-99-6, 68153-95-7, 4088-22-6, 61788-63-4 and 68783-24-4).

Subcategory IV: Trialkylamines: Two long-chain tri-substituted amines (CAS RN 68814-95-9 and 61790-42-9) and two long-chain substituted ethanol, 2,2'-iminobis-amines (CAS RN 61791-31-9 and 61791-44-4).

Data for five primary alkylamines (CAS RN 61788-45-2*, 124-30-1*, 61788-46-3*, 61790-33-8* and 112-90-3*) sponsored by the European Oleochemicals and Allied Products Group (APAG) under the ICCA program (see Task Group letter to EPA dated November 9, 2001) that are chemically identical to the Subcategory I chemicals (albeit with different CAS RN) are included in this review. These chemicals are identified throughout this document by CAS RN and an “*” since they provide extensive supporting information to the FND Amines Category. In addition, six supporting individual chemicals and an FDA-approved



FND Amines Category HPV Chemical Challenge December 29, 2003 Page 2 of 47

(used in toothpaste) two-chemical mixture, that are not part of the US HPV Chemical Challenge Program, but are structurally closely related to the FND Amines Category chemicals, are included to provide supporting data for the category. These 12 chemicals are termed “supporting chemicals” throughout this document and are defined in Text Table A.

The FND Amines Category chemicals and supporting chemicals are described in the following table. The supporting chemicals are shaded and italicized for ease of identification.

Text Table A: CAS Registry Numbers and Chemical Names

CAS RN Chemical Name

Subcategory I: Primary Alkylamines and Alkyldiamine s 124-22-1 Dodecylamine 143-27-1 Hexadecylamine 68037-91-2 Amines, C14-18 -alkyl 61788-45-2* Amines, hydrogenated tallow alkyl 124-30-1* Octadecylamine

61788-46-3* Amines, coco alkyl 68155-38-4 Amines, C14-18 and C16-18 -unsatd. alkyl 61790-33-8* Amines, tallow alkyl 61790-18-9 Amines, soya alkyl 68037-95-6 Amines, C16-18 and C18-unsatd. alkyl 112-90-3* Cis-9-Octadecenylamine 61791-55-7 Amines, N-tallow alkyltrimethylenedi- 7173-62-8 1,3-Propanediamine, N-(9Z)-octadecenyl-

3151-59-5 + 36505-83-6

Hexadecylamine hydrofluoride (Hetaflur) 9-Octadecen-1-amine hydrofluoride

Subcategory II: Dimethylalkylamines 112-18-5 1-Dodecanamine, N,N-dimethyl

112-75-4 1-Tetradecanamine, N,N-dimethyl 112-69-6 1-Hexadecanamine, N,N-dimethyl 124-28-7 1-Octadecanamine, N,N-dimethyl 61788-93-0 Amines, coco alkyl dimethyl 61788-95-2 Amines, (hydrogenated tallow alkyl)dimethyl 61788-91-8 Amines, dimethyl soya alkyl 28061-69-0 Octadecen-1-amine, N,N-dimethyl




Text Table A: CAS Registry Numbers and Chemical Names

CAS RN Chemical Name

Subcategory III: Dialkylmethylamines and Dialkylamines

7396-58-9 1-Decanamine, N-decyl-N-methyl 67700-99-6 Amines, di-C14-18 -alkylmethyl 68153-95-7 Amines, di-C12-18 -alkyl 4088-22-6 1-Octadecanamine, N-methyl-N-octadecyl 61788-62-3 Amines, dicoco alkylmethyl 61788-63-4 Dihydrogenated tallow methylamine 61789-79-5 Amines, bis(hydrogenated tallow alkyl) 61789-76-2 Amines, dicoco alkyl

68783-24-4 Amines, ditallow alkyl

Subcategory IV: Trialkylamines 68814-95-9 Amines, tri-C8-10 -alkyl- 61790-42-9 Amines, tris (hydrogenated tallow alkyl) 61791-31-9 Ethanol, 2,2'-iminobis-, N-coco alkyl derivs. 61791-44-4 Ethanol, 2,2'-iminobis-,N-tallow alkyl derivs. * These chemicals were removed from the original FND Amines Category because they are sponsored by APAG

under the ICCA program.

Structural Information for the FND Amines Category and Supporting Chemicals

The following table presents the molecular formula and molecular weight data for the chemicals with defined structures or average molecular weight data for chemicals without defined structures. The structures for these and the remaining chemicals in the FND Amines Category are provided in Table 1.

Text Table B: Molecular Formula and Molecular Weight of Chemicals with Defined or Representative Structures

CAS RN Name Molecular Formula

Molecular Weighta

Subcategory I: Primary Alkylamines and Alkyldiamine 124-22-1 Dodecylamine C12H27N 185 143-27-1 Hexadecylamine C16H35N 241

61788-45-2* Amines, hydrogenated tallow alkyl 263 124-30-1* Octadecylamine C18H39N 270

61788-46-3* Amines, coco alkyl 200 61790-33-8* Amines, tallow alkyl 262

61790-18-9 Amines, soya alkyl 264 112-90-3* Cis-9-Octadecenylamine C18H37N 267 61791-55-7 Amines, N-tallow alkyltrimethylenedi- 320 7173-62-8 1,3-Propanediamine, N-(9Z)-octadecenyl- C21H44N2 325

3151-59-5 +36505-83-6

Hexadecylamine hydrofluoride (Hetaflur) 9-Octadecen-1-amine hydrofluoride

C16H35N.H-F C18H37N.H-F

241b

267b




Text Table B: Molecular Formula and Molecular Weight of Chemicals with Defined or Representative Structures

CAS RN Name Molecular Formula

Molecular Weighta

Subcategory II: Dimethylalkylamines 112-18-5 1-Dodecanamine, N,N-dimethyl C14H31N 213 112-75-4 1-Tetradecanamine, N,N-dimethyl C16H35N 241 112-69-6 1-Hexadecanamine, N,N-dimethyl C18H39N 270 124-28-7 1-Octadecanamine, N,N-dimethyl C20H43N 298

61788-93-0 Amines, coco alkyl dimethyl 228 61788-95-2 Amines, (hydrogenated tallow alkyl)dimethyl 291 61788-91-8 Amines, dimethyl soya alkyl 292

28061-69-0 Octadecen-1-amine, N,N-dimethyl C20H41N 296

Subcategory III: Dialkylmethylamines and Dialkylamines 7396-58-9 1-Decanamine, N-decyl-N-methyl C21H45N 312 4088-22-6 1-Octadecanamine, N-methyl-N-octadecyl C37H77N 536

61788-62-3 Amines, dicoco alkylmethyl 397 61788-63-4 Dihydrogenated tallow methylamine 523

61789-79-5 Amines, bis(hydrogenated tallow alkyl) 509 61789-76-2 Amines, dicoco alkyl 383

68783-24-4 Amines, ditallow alkyl 507

Subcategory IV: Trialkylamines 68814-95-9 Amines, tri-C8-10 -alkyl- C27H57N 396 61790-42-9 Amines, tris (hydrogenated tallow alkyl) 752 61791-31-9 Ethanol, 2,2'-iminobis-, N-coco alkyl derivs. 302 61791-44-4 Ethanol, 2,2'-iminobis-,N-tallow alkyl derivs. 364 Shaded cells with italic font indicate supporting chemicals.

* These chemicals were removed from the original FND Amines Category because they are sponsored by APAG under the ICCA program.

a Average chain length or estimated chain length is used where appropriate; where no formula is provided, the molecular weight is that generally used by the industry to define the chemical.

b Molecular weight of the alkyl chain (excludes the hydrofluoride salt).

Rationale for the FND Amines Structure-Based Chemical Category

The members of the FND Amines category are large surfactant molecules. As such, they fall into a family of surfactants, all of which have similar physical/chemical properties. The FND surfactants (amines, cationics, amides) are comprised of either defined long-chain alkyl substituents or use natural oils and fats. The following table summarizes the long-chain alkyl substituents found in the FND Amines Category chemicals:




Text Table C: Chain Length and Degree of Unsaturation for Long-Chain Substituents in the FND Amines Category Chemicals

Identifier Chain Length(s) or Average Degree of Unsaturation C8-C10 alkyl 9 None Isodecyl 10 None C9-C11 (C10 rich) 10 None Dodecyl 12 None C13 branched 13 None C11-C14 (C13 rich) 13 None Tetradecyl 14 None Hexadecyl 16 None C14-C18 Not specified None C12-C18 Not specified None C14-C18 and C16-C18 Not specified Not specified

unsaturated C16-C18 and C18-unsaturated Not specified Not specified Octadecyl 18 None Octadecenyl 18 1 Coco (coconut) C6: 0-1%

C8: 5-9% None None

C10: 5-10% None C12: 44-53% None C14: 13-19% None C16: 8-11% None C18: 1-3% None C16: 0-1% 1 C18: 5-8% 1 C18: 1-3% 2

Tallow, hydrogenated1 C14: 1-6% None C16: 23-46% None C18: 49-67% None

Tallow C14: 1-6% C16: 20-37%

None None

C18: 14-21% None C16: 3-9% 1

C18: 35-46% 1 C18: 4-10% 2 C18: 0-3% 3

Soya (soy bean) C16: 7-11% C18: 2-7%

None None

C20: 0-2% None C18: 20-30% 1 C18: 43-56% 2 C18: 8-14% 3

Based on an analysis of data across the FND chemicals (including FND cationics, amides, and nitriles submitted in separate Test Plans), the chain length and degree of unsaturation in the FND

1 Percentages assume 100% hydrogenation of the unsaturated tallow chains.




surfactants does not appear to have a significant impact on fate and effects. A careful examination of the chemical structures (Table 1) shows the close relationship of all of the chemicals in the category. In addition, the following discussion describes how interrelated the structures of the various FND Amine Category chemicals may be: The nomenclature issue described below is directly pertinent to this Test Plan in that testing is conducted under two chemical names for CAS RN 4088-22-6; specifically, dioctadecane methyl amine and ditallow methyl amine.

Nomenclature for FND Amines: Higher chain length raw materials used within the industry for the manufacture of amines in the C14 to C18 alkyl range typically include commercial stearic acid commonly sourced from tallow; tallow/tallow fatty acid, or hydrogenated tallow/hydrogenated tallow fatty acid. These fatty acid raw materials are commonly referred to in the industry by their source name tallow/hydrogenated tallow fatty acid or stearic acid. Commercial stearic acid comes in three principle grades, single pressed stearic, double pressed stearic, and triple pressed stearic acid. These technical grades are mixtures of palmitic (C16) and stearic (C18) acids, not pure C18 (octadecanoic acid). The higher grade, double and triple pressed stearic, has increasing levels of C18 fatty acid. The general chain length makeup and relative level of unsaturation, as measured by Iodine Value (IV), of the grades is as follows:

Text Table D: Effect of Processing on FND Amine Composition I.V.

(g/100 g) %C14 %C15 %C16 %C17 %C18 %C18

(monounsaturated) Double Pressed

4.0 max 2.5 0.5 50 1 40 6

Triple Pressed

2.0 max 1.5 0.5 50 1 47 <0.2

Commercial "stearic acid" is approximately a 50/50 mixture of C16/C18 saturated chain lengths indicative of the historical commercial separation process limitations and tallow composition from which it is commonly made. Most of the C18 monounsaturate and higher C18 unsaturated fatty acids have been separated away. It is an example of a Class 2 chemical substance that is known commercially by a Class 1 name. At the inception of the TSCA Inventory, the Class I IUPAC name "octadecanoic acid"--indicative of only C18 saturated fatty acid--was assigned to the trivial name, "stearic acid". As a result, many commercial "stearic acid" derivatives are named according to "octadecyl" nomenclature implying only C18 alkyl chain when the actual commercial product is an alkyl range derivative material that principally includes C16 and C18 chain lengths. An example is the class of amines referred to as ditallow methyl amines. Commercially, only a relatively few stearic acid derivatives are composed of the single, pure C18 alkyl chain.

Thus, not only are the FND Amines Category chemicals similar structurally, but also in many cases may be produced from the same starting materials. The following discussion highlights the structural similarities within and among the Subcategories of the FND Amines Category.

Subcategory I - Primary Alkylamines and Alkyldiamines: A number of the chemicals in the category are essentially identical or only differ in one or two carbons on the long-chain substituent. The alkane-substituted amines in Subcategory I have carbon chain distributions ranging from C12 to C18. Empirical data and the commonality of microbial degradation




processes indicate that degradation of these molecules would clearly result in similar by-products and metabolites. Other than unsaturation of the alkyl chain, the unsaturated substituents including tallow (primarily C16 and C18 saturated and unsaturated) and soya (primarily C18 unsaturated) are identical to the saturated chain molecules. The two alkyldiamines in this Subcategory have corresponding alkylamines. Degradation of these molecules, other than generation of an additional ammonia, would be identical to those of the corresponding monoamine.

Subcategory II - Dimethylalkylamines: Each of the Subcategory II chemicals has an identical or very similar corresponding primary alkylamine in Subcategory I. As shown by the data presented herein, the addition of the dimethyl substituents does not result in recognizable differences in environmental fate or hazard assessments.

Subcategory III - Dialkylmethylamines and Dialkylamines: The chemicals in this Subcategory are similar to those in Subcategory II with the substitution of a longer chain length for one of the methyl groups (dialkylmethylamines) or with substitution of two longer chain alkyl groups (dialkylamines). These substitutions would not be expected to result in recognizable differences in environmental fate or hazard assessments since these substituents impart no structural alerts or unusual properties different from the chemicals in the other subcategories.

Subcategory IV - Trialkylamines: The two long-chain tri-substituted members of this category (CAS RN 68814-95-9 and 61790-42-9) are essentially equivalent to the dimethyl alkyl and dialkyl amines in Subcategory II or III. As shown by the data presented herein, replacing two of the long-chain substituents with ethanol would not result in structural alerts or potential degradation products of concern.

SUMMARY: The diversity of chemical structures for the FND Amines Category results from manufacturing processes, including the use of natural oils, and the need for different application properties. This structural diversity does not result in chemicals with different structural alerts. To the contrary, based on the chemical structures and supported by the available ecotoxicity and mammalian toxicity data, these chemicals show consistent toxicity.

The goal of subcategorizing is to aid in the description and evaluation of the Category as a whole. It is considered appropriate to read-across from other Subcategories when the data are consistent. As noted above, each of the chemicals within the Subcategories is structurally similar to chemicals in one or more other Subcategories. The approach to the Test Plan for the FND Amine Category chemicals is, therefore, to provide the available information that shows that each of the Subcategories fits the overall pattern of fate and toxicity for the FND Amines Category and the FND surfactants in general. It is not necessary or appropriate to consider the Category or the Subcategories as having “ends” that, when tested, represent a continuum of structure. That is, there is no pattern of increasing or decreasing environmental fate or toxicity among these chemicals. Rather, there is a consistency of response across the entire Category.

Available Data to Fulfill HPV Screening Information Data Set (SIDS) Endpoints

Approach to Evaluate the Database for the FND Amines Category

The following approach was used to obtain and analyze data relevant to the assessment of the FND Amines Category.




1. The chemical names and CAS RN of 28 HPV FND Amines Category chemicals supported by the American Chemistry Council Fatty Nitrogen Derivatives Panel, Amines Task Group (Task Group) were provided.

2. Five Primary Alkylamines (CAS RN 61788-45-2*, 124-30-1*, 61788-46-3*, 61790-33-8* and 112-90-3*) were removed from the original list since they were sponsored by the European Chemical Industry in the ICCA Program. As discussed above, these and seven other chemicals of similar structure and function to the FND Amines Category chemicals were included as supporting chemicals. Therefore, there are a total of 23 HPV Sponsored chemicals in the category.

3. Published and unpublished reports were obtained as available from the members of the FND Amines Task Group and other chemical industry companies; they were organized and reviewed to identify studies that could fulfill SIDS endpoints.

4. Pertinent databases2 were searched and all reports considered relevant by the Panel were obtained to help establish the full extent and nature of the published literature for the 23 FND Amines Category and 12 supporting chemicals.

5. Each of the reports obtained was reviewed to determine adequacy according to EPA criteria and reliability according to Klimisch et al. (1997).

6. Robust summaries were prepared for each report with Klimisch scores of 1 or 2, according to the guidelines proposed by the EPA (U. S. EPA, 1999a) for each study type.

7. Robust summaries for the studies sponsored in the ICCA program included herein were accepted a priori from the European industry and were not generated from the original reports.

8. Where possible, estimates for physical/chemical properties, environmental fate and ecotoxicity values were developed for the HPV and supporting chemicals by using recommended approaches for developing Structure Activity Relationships (SAR).

9. Where possible, fugacity modeling was performed to estimate transport and distribution into environmental compartments for the HPV and supporting chemicals.

10. Robust summaries were generated for the SAR data.

Use of Structure Activity Relationships for the FND Amines Category

Approaches recommended in the EPA document on the use of SAR in the HPV Chemicals Challenge Program were employed in the assessment of the FND Amines Category (U. S. EPA, 1999b). Several models were employed to support the review and assessment of the FND Amines Category chemicals. The models included several based on SAR, as well as Mackay-type fugacity-based modeling. The SAR models for physical properties were used to estimate boiling points, melting points, aqueous solubility, octanol-water partition coefficients and vapor

2 Databases include ChemIDplus HSDB (Hazardous Substances Data Bank), IRIS (Integrated Risk Information System), CCRIS (Chemical Carcinogenesis Research Information System), GENE-TOX, EMIC (Environmental Mutagen Information Center), DART/ETIC (Developmental and Reproductive Toxicology and Environmental Teratology Information Center), MEDLINE, TOXLINE, RTECS (Registry of Toxic Effects of Chemical Substances), TSCATS (Toxic Substances Control Act Test Submissions), IUCLID, 1996 (International Uniform Chemical Information Database).




pressures. Other SAR models were used to estimate hydroxyl radical mediated atmospheric photo-oxidation and biodegradation potential. SAR models also were used to obtain estimates of acute toxicity to aquatic organisms.

Common Features of the Models

All of the models (except the Mackay-type models) require the input of a molecular structure to perform the calculations. The structure must be entered into the model in the form of a SMILES (Simplified Molecular Input Line Entry System) notation or string. SMILES is a chemical notation system used to represent a molecular structure by a linear string of symbols. The SMILES string allows the program to identify the presence or absence of structural features used by the submodels to determine the specific endpoint. The models contain files of structures and SMILES strings for approximately 100,000 compounds, accessible via CAS RN. SMILES strings cannot be developed for mixtures or chemicals without a single, definable structure.

Estimation of Physical/Chemical Properties

The SAR models for estimating physical properties and abiotic degradation were obtained from Syracuse Research Corporation 2000 (Estimation Programs Interface for Windows, Version 3.05 or EPIWIN v. 3.05). The models were used to calculate melting point, boiling point, vapor pressure (submodel MPBPVP), octanol-water partition coefficient (Kow) (submodel KOWWIN), and aqueous solubility (submodel WSKOWWIN). The calculation procedures are described in the program guidance and are adapted from standard procedures based on analysis of key structural features (Meylan and Howard, 1999a, b, and c).

Estimation of Environmental Fate Properties

Atmospheric photo-oxidation potential was estimated using the submodel AOPWIN (Meylan and Howard, 2000a). The estimation methods employed by AOPWIN are based on the SAR methods developed by Dr. Roger Atkinson and co-workers (Meylan and Howard, 2000a). The SAR methods rely on structural features of the subject chemical. The model calculates a second-order rate constant with units of cm3/molecules-sec. Photodegradation based on atmospheric photo-oxidation is in turn based on the rate of reaction (cm3/molecules-sec) with hydroxyl radicals (HO•), assuming first-order kinetics and an HO• concentration of 1.5 E+6 molecules/cm3 and 12 hours of daylight. Pseudo first-order half-lives (t1/2) were then calculated as follows: t1/2 = 0.693/[(kphot x HO•) x (12-hr/24-hr)].

The database that supports the modeling of water stability provides only for neutral organic compounds that have structures that can be hydrolyzed. Therefore, no model estimates for hydrolytic stability are available since the FND Amines Category chemicals do not have the necessary characteristics.

Estimation of Environmental Distribution

The Level III Mackay-type, fugacity-based models were obtained from the Trent University's Modeling Center. The specific model used was the generic Equilibrium Concentration model (EQC) Level 3, version 1.01. These models are described in Mackay et al. (1996a and b). Fugacity-based modeling is based on the "escaping" tendencies of chemicals from one phase to another. For instance, a Henry's Law constant calculated from aqueous solubility and vapor




pressure is used to describe the "escape" of a chemical from water to air or vice versa as equilibrium between the phases is attained. The key physical properties required as input parameters into the model are melting point, vapor pressure, Kow and aqueous solubility. The model also requires estimates of first-order half-lives in the air, water, soil and sediment. An additional key input parameter is loading of the chemical into the environment.

Estimation of Acute Aquatic Toxicity

Models developed by the U. S. Environmental Protection Agency (EPA) were employed to make estimates of acute toxicity to aquatic organisms, specifically a commonly tested fish, the fathead minnow (Pimephales promelas), a water column dwelling invertebrate (Daphnia magna) and a commonly tested green alga, Selenastrum capricornutum. The models are incorporated in a modeling package called ECOSAR, version 0.99f (U. S. EPA, 2000). ECOSAR may be obtained from the EPA website for the Office of Pollution Prevention and Toxics, Risk Assessment Division. The models calculate toxicity based on structural features and physical properties, mainly the Kow (Meylan and Howard, 1998).

Modeling Information Specific to the FND Amines Category

When CAS RNs were included in the files of structures, the models described above were used for the FND Amines Category chemicals and the 12 supporting chemicals. Estimations of physical properties, environmental fate and distribution, and ecotoxicity were not possible for 16 of the 23 HPV chemicals in the FND Amines Category because they do not have single definable structures and/or were not available in the files of structures of the models. Model predictions were available for five of the supporting chemicals. The model did not provide estimates of stability in water for this class of chemicals because the model cannot calculate this parameter for chemicals that do not meet the criteria of neutral organic compounds with structures that can be hydrolyzed. Since the FND Amines Category chemicals are considered to be released into wastewater treatment systems consistent with their use patterns, release to soil and air were considered to be minor avenues of entry for FND Amines Category chemicals into the environment. Therefore, for fugacity modeling, all input was assumed to be into surface water using the chemical specific parameters to attain estimates of the chemical distributions between environmental compartments. The submodel for Cationic Surfactants was initially used for the ECOSAR model output (data included on Table 3). Subsequently, the model for Aliphatic Amines was examined. In a number of cases, the Aliphatic Amines calculations are more similar to experimental values. Therefore, these values, where different, are included in Table 3 as well. In many cases the ECOSAR model indicated the chemicals were not toxic to aquatic organisms at predicted solubility. These are indicated on appropriate tables but are not discussed in this text.

Physical/Chemical Properties Data

The available reliable data and SAR estimates for physical/chemical properties of the FND Amines Category chemicals are presented in Table 2. Robust summaries for the reliable studies are provided in Appendix A and Robust Summaries for all of the SAR data are included in Appendix B. The Test Plan for Physical/Chemical Properties is outlined in Table 5.

Measurement of physical/chemical properties for surfactants is complicated by their behavior in test systems and the environment. For example, measurement of the octanol/water partition




coefficient (log Kow) is confounded by the ability of the chemicals to emulsify octanol/water solutions. The resulting values are inaccurate and of limited utility for determining environmental fate and effects. Similarly, measurements such as melting points and boiling points provide minimal information since they do not identify key characteristics of the molecules. The large size of the molecules makes these chemicals non-volatile and the determination of a precise value for vapor pressure is difficult and of little practical use.

As described above, where possible, the physical/chemical property estimation program EPIWIN version 3.05 was used to derive estimates. As with actual measurement, prediction of physical/chemical properties for surfactants is complicated. As explained above, the log Kow, a key determinant in the models, is not an appropriate hydrophobicity parameter for reliably predicting environmental behavior of surfactants. The data are, therefore, of limited value in estimating environmental fate and toxicity. The SAR estimates are based on structure and can be made only for substances for which a structure can be defined. Thus, model data were generated for seven of the 23 HPV chemicals and five supporting chemicals that have discrete structures.

The available data for physical/chemical properties are summarized below:

Subcategory I – Primary Alkylamines and Alkyldiamines: EPIWIN predicted melting points ranging from approximately 28 to 142ºC. Three reported values, for CAS RN 124-22-1, 61788-45-2* and 124-30-1*, were the same as the model values suggesting that these reported values were also calculated. The reported value for CAS RN 112-90-3* of 21ºC was lower than the model value of 93ºC. Reported values for the supporting chemical CAS RN 61790-33-8* were 34 to 40ºC and 25 to 30ºC. Model estimates made for boiling points ranged from 259 to 402ºC. Reported boiling points were identical (CAS RN 124-22-1, 61788-45-2* and 124-30-1*) or similar (CAS RN 112-90-3*) to the model values. Boiling point for CAS RN 61790-33-8* was 200 to 230�C. Decomposition at 348ºC was reported for CAS RN 61788-45-2*.

As expected, based on extensive practical experience with these and similar large organic molecules, the reported and EPIWIN estimated vapor pressures were extremely low across the FND Amines Subcategory, i.e. more than two orders of magnitude lower than water. The FND Amines Category chemicals are essentially nonvolatile, as is generally the case for molecules of this size and complexity.

Predicted or measured log Kow values are of limited practical use for the FND Amines Category chemicals. An inherent property of surfactants is that they accumulate at the interface between hydrophobic and hydrophilic phases rather than equilibrating between the two phases. Therefore, the accurate measurement of the log Kow of any surfactant is notoriously difficult. Even if such measurements were made accurately, the log Kow is not an appropriate value by which to predict the partitioning behavior of the FND Amines Category chemicals in the environment because of the tendency of surfactants to partition at lipid/aqueous interfaces. The EPIWIN estimated values for the octanol/water partition coefficient (log Kow) ranged from approximately 5 to 8. No reported values were identified for the HPV chemicals. For supporting chemicals, a measured value for CAS RN 61790-33-8* was reported to be 7.5 and a range of values from >3.11 to 8.1 was reported for CAS RN 112-90-3*.




Reported water solubility for the primary alkylamines and alkyldiamines varied from insoluble to slightly soluble. Reported values for CAS RN 124-22-1 and 124-30-1* were 2000 and 1000 mg/L, respectively although a separate report for CAS RN 124-30-1* indicated it was “not soluble”. Other reported information indicated the chemicals were “insoluble” or “very insoluble” in water. Model predictions for water solubility also ranged from virtually insoluble (< 0.1 mg/L) to slightly soluble (approximately 45 mg/L).

Subcategory II – Dimethylalkylamines: EPIWIN predicted melting points for the five chemicals that could be modeled ranged from 22 to 80ºC. There is a reported value for CAS RN 112-18-5 of –15 to –20ºC compared to the model value of 22ºC and two reported values for CAS RN 124-28-7 of approximately 20 to 23ºC similar to the model value (23ºC). Model estimates for boiling point ranged from 260 to 346ºC. There are no reported boiling point values available for HPV or supporting chemicals.

EPIWIN estimated vapor pressures were very low across this FND Amines Subcategory and ranged from 0.000052 to 0.0159 hPa. There are no reported values available for HPV or supporting chemicals. As noted above, the FND Amines Category chemicals are non-volatile.

No reported values for the octanol/water partition coefficient (log Kow) were identified for HPV or supporting chemicals. EPIWIN predicted values for log Kow ranged from 5.44 to 8.39. As noted above, the partition coefficient for these types of molecules is not appropriate for predicting partitioning in the environment.

Model predictions for water solubility ranged from 0.0089 to 8.58 mg/L. HPV chemical CAS RN 124-28-7 was reported as “not soluble.”

Subcategory III – Dialkylmethylamines and Dialkylamines: EPIWIN predicted data were available for one HPV chemical that could be modeled (CAS RN 4088-22-6). The predicted melting point was 216ºC and the predicted boiling point was 543ºC. The estimated vapor pressure was 2.0 x 10-11 hPa and estimated partition coefficient (log Kow) was 17. This chemical had a predicted water solubility of 2 x 10-11 mg/L. A reported partition coefficient and associated water solubility of 3.15 and 0.288 mg/L, respectively were identified for CAS RN 61788-63-4. In the partition coefficient determination, an apparent concentration–related difference in log Kow was indicated (see Robust Summary) again suggesting that this measurement is not appropriate for these types of chemicals.

Subcategory IV – Trialkylamines: No measured or model data were available for these chemicals.

Summary – Physical/Chemical Properties

Melting points and boiling points are of very limited value in determining the fate and toxicity of surfactant molecules. The available data and model predictions are considered adequate to define the typical ranges for these endpoints. In addition, these types of molecules tend to degrade rather than boil. Consistent with the size and nature of these molecules, measured and modeled vapor pressures are very low, and the FND Amines Category chemicals are considered to be essentially nonvolatile. Measurement and prediction of physical/chemical properties for surfactants are complicated by their behavior in test systems and the environment, and the log




Kow is not an appropriate hydrophobicity parameter for reliably predicting environmental behavior. The available values and estimates are considered of very minimal use and additional testing is not warranted. Water solubility estimates varied from slightly soluble to very insoluble. The majority of these chemicals are clearly insoluble in water and the chemicals in Subcategories I – III are adequately represented as insoluble. In addition, as noted below, water solubility is not related to the toxicity of these surfactant molecules to aquatic species. The trialkyl substituted amines in Subcategory IV would be expected to be insoluble based on similarity of structure with other members of the Category containing shorter-chain substituents. While the water solubility of the fatty acid diethanolamines (CAS RN 61791-31-9 and 61791-44-4) has not been evaluated, in testing for biodegradation (see Robust Summary for Biodegradation), it is clearly stated that CAS RN 61791-31-9 was not water soluble while CAS RN 61797-44-4 was soluble to 1 g/liter. Due to the insoluble nature of the chemical, surfactants were required to generate emulsions necessary to complete the test for CAS RN 61791-31-9. Therefore, the chemicals in Subcategory IV are also insoluble or poorly soluble. Overall, it is noted that measurement and prediction of physical/chemical properties for surfactants are complicated by their behavior in test systems and the environment, including strong adsorption and absorption properties and surface tension activity. Although predictions vary, the data and knowledge of the chemicals support the conclusion that the FND Amines Category chemicals behave similarly from the perspective of physical/chemical properties.

Additional Testing – Physical/Chemical Properties

No additional testing (Table 5) is proposed for the Category based either on the inappropriateness of the endpoint (melting point, boiling point, partition coefficient) for these surfactant molecules or adequate information (vapor pressure, water solubility) to establish the characteristics across the category.

Environmental Fate and Ecotoxicity Data

The available reliable data and SAR estimates for the environmental fate and effects of the FND Amines Category chemicals are presented in Table 3. Robust summaries for the reliable studies are provided in Appendix A and Robust Summaries for all of the SAR data are included in Appendix B. The Test Plan for the Environmental Fate and Ecotoxicity Endpoints is summarized in Table 6.

Subcategory I – Primary Alkylamines and Alkyldiamines: Models for atmospheric photodegradation were used according to EPA guidelines. However, the fugacity models predict virtually no occurrence of the FND Amines Category chemicals in air, which is consistent with the very low vapor pressures. Nonetheless, modeling of the HPV and supporting chemicals indicates that they would be expected to degrade relatively rapidly upon exposure to light (t1/2

values ranging from approximately 0.7 to 2.8 hours).

The HYDROWIN model did not provide estimates of stability in water for this class of chemicals because the model cannot calculate this parameter for chemicals that do not meet the criteria of neutral organic compounds with structures that can be hydrolyzed. These types of chemicals generally do not have hydrolysable groups.




An estimation of the transport and distribution of the FND Amines Category chemicals in environmental media (percent in air, water, soil and sediment) following entry into the environment via water is presented in Table 3. Distribution to air and soil were < 1% for all of the chemicals that could be modeled while distribution to the water compartment varied from 10 to 75% with the remainder in the sediment.

For biodegradation, guideline studies and studies similar to guidelines were available for seven of the 14 HPV and supporting chemicals in this FND Amines Subcategory. For one of the two HPV chemicals for which data are available (CAS RN 124-22-1) the 28-day biodegradation was >60% ThOD. For the HPV chemical (CAS RN 61791-55-7), 87% of the chemical was adsorbed in the sludge and 90% DOC elimination occurred in 3 hours. For the supporting chemicals, the 28-day degradation ranged from 44 to 91.1%. Overall, the Subcategory I chemicals are either readily biodegradable or attain degradation close to meeting the “readily biodegradable” criteria.

One HPV (CAS RN 124-22-1) and four supporting chemicals (CAS RN 61788-45-2*, 61788-46-3*, 61790-33-8*, and 112-90-3*) were tested for acute toxicity to fish. The LC50

values ranged from 0.11 to 9.3 mg/L. The only value >1 mg/L was for CAS RN 61790-33-8* that also had a reported LC50 value between 0.18 and 0.25 mg/L. Acute toxicity to aquatic invertebrates was determined for five of the supporting chemicals (CAS RN 61788-45-2*, 124-30-1*, 61788-46-3*, 61790-33-8*, and 112-90-3*). The EC50 values were all less than 1 mg/L with the lowest actually determined value being 0.011 mg/L (CAS RN 112-90-3*). In addition, a study evaluating the toxicity of CAS RN 61788-46-3* to the larvae and pupae of four mosquito species indicated that the chemical is moderately toxic with EC50 values ranging between 2.0 and 13.0 mg/L. Toxicity to aquatic plants was determined for these same five supporting chemicals and indicated that these amine surfactants are highly toxic to algae (EbC50

and ErC50 values ranging from < 0.00075 to 0.17 mg/L). The ECOSAR model for cationic surfactants and for some of the aliphatic amines does not predict toxicity to aquatic organisms accurately when the chemicals are poorly soluble or insoluble in water. However, the prediction for acute fish toxicity for one of the chemicals in this Subcategory as an aliphatic amine, rather than as cationic surfactant, is similar to the experimental value (0.87 mg/L predicted vs. 0.42 mg/L measured for CAS RN 124-22-1). Estimates for the toxicity to daphnia and algae similarly indicated a high order of toxicity for this chemical. While these model values are useful in support of the conclusion that the FND Amine Category chemicals are toxic to aquatic species, overall the model estimates are of minimal reliability because of the low solubility of the chemicals.

Subcategory II – Dimethylalkylamines: Modeling of three HPV and two supporting chemicals indicated they would be expected to degrade relatively rapidly upon exposure to light (t1/2 values ranging from approximately 1.0 to 1.4 hours). The model did not provide estimates of stability in water for this subclass of chemicals.

An estimation of the transport and distribution of the FND Amines Category chemicals in environmental media (percent in air, water, soil and sediment) following entry into the environment via water is presented in Table 3. Distribution to air and soil were < 1% for all of the chemicals that could be modeled while distribution to the water compartment varied from 5 to 42% with the remainder in the sediment.




Measured data for biodegradation were available for the five HPV and three supporting chemicals in this Subcategory. Four of the five HPV chemicals (CAS RN 112-69-6, 124-28-7, 61788-95-2, and 61788-91-8) were considered to be readily biodegradable. The fifth HPV chemical (CAS RN 112-75-4) had a value of � 2% degradation after 28 days. This value does not appear scientifically justifiable based on all other tests of similar chemicals, and the assay is considered invalid by the FND Amines Task Group. For the supporting chemicals, the 28-day ThOD ranged from 50 to 81%. Overall, the chemicals in this Subcategory are either readily biodegradable or closely approach ready biodegradability.

Toxicity to fish was measured for six of the eight HPV and supporting chemicals with LC50

values all less than 1.0 mg/L. For toxicity to aquatic invertebrates, one HPV chemical (CAS RN 124-28-7) and one supporting chemical (CAS RN 112-18-5) had LC50/EC50 values of 0.074 and 0.083 mg/L, respectively. CAS RN 112-18-5 was shown to be highly toxic to algae in three assays each yielding EbC50 and ErC50 values < 0.1 mg/L. In addition, a study with CAS RN 124-28-7 to establish algistatic and algicidal concentrations to two species of algae confirmed the high toxicity of this chemical to aquatic species (0.029 and 0.11 mg/L algistatic concentrations and >0.032 and 0.16 algicidal concentrations). Model values for toxicity to aquatic invertebrates (CAS RN 112-18-5 and 112-75-4) and algae (CAS RN 112-18-5) for aliphatic amines appeared to be relatively accurate with predicted EC50 values of 0.04 and 0.01 mg/L for daphnia and 0.26 mg/L for algae. Overall, however, as for the other Subcategories, the model predictions (Table 3) were considered of little value due to the low water solubility of the chemicals.

Subcategory III – Dialkylmethylamines and Dialkylamines: Modeled data were available for one HPV chemical (CAS RN 4088-22-6). The model predicted rapid photodegradation (t1/2 was 1.0 hour). Stability in water was not calculable by the model. The Level III fugacity model estimated that 5% of the chemical would be distributed to the water compartment and 95% distributed to sediment.

One HPV (CAS RN 61788-63-4) and one supporting chemical (CAS RN 61788-62-3) were shown to be readily biodegradable in high quality tests. In both of these assays, a surfactant was used in the assay to suspend the test chemical providing for adequate bioavailability. The range of values for CAS RN 61788-63-4 in six different biodegradation assays, however, shows the complexity of evaluating the degradation of these types of chemicals. The toxicity of the chemicals to the organisms, binding to organic matter, and method of introduction of the test material to the system can all have a significant impact on the ultimate biodegradation observed. These confounding factors are shown in biodegradation studies for two supporting chemicals (CAS RN 61789-79-5 and 61789-76-2) with only 16% and 20% degradation observed respectively after 28 days. In the first test, no effort was made to suspend the test chemical in the solution and the second assay employed binding of the chemical to silica gel as a means of suspension. Due to the low water solubility and the ability of these types of chemicals to tenaciously bind to solids, the FND Amines Task Group considers the results of these studies were likely significantly impacted by lack of bioavailability.

A measured LC50 value for fish toxicity was 6.15 mg/L for the supporting chemical with CAS RN 61788-62-3. Three assays for CAS RN 61788-63-4 indicated substantial differences in the measured toxicity ranging from 23 to > 1000 mg/L. Again, this range shows the complexity of testing of these types of chemicals. In the assay that provided no LC50 value (i.e. > 1000 mg/L),




the test chemical was observed to be insoluble in the test water. It is likely that the range of values represents bioavailability or physical availability (important because many surfactant-like chemicals are known to kill aquatic organisms via a physical rather than chemical mechanism) of the test chemical to the fish. Tests conducted for two other chemicals in the Subcategory (CAS RN 4088-22-6 and 61789-79-5) indicated much higher LC50 values between 100 and 500 mg/L. In each of these latter studies, however, there was evidence that the test material was not soluble in the test solutions and no remedial action was taken to emulsify the test chemicals. Similarly, tests for acute toxicity to daphnia for CAS RN 61788-63-4 were confounded by solubility problems and yielded higher EC50 values (35.2 and 790 mg/L) than expected. Further studies with this HPV chemical indicated EC50 values ranging from 3.1 to 21 mg/L. In addition, a study examining a mixture of the active ingredient (83.5% or 63% of the HPV chemical) with inert materials (e.g. as used in soap) and using two water sources indicated that river water reduced the toxicity compared to well water (EC50 = 60 vs. 22 mg/L, respectively) and that the inert ingredients tended to reduce toxicity (EC50 = 6.5 mg/L for the 83.5% material vs. 22 for the 63% material). These studies reflect the impact of adsorption/absorption of the FND Amines Category chemicals to organic material. For CAS RN 61788-63-4, the EbC50 and ErC50 in a standard algae test were 0.05 and 0.12 mg/L, respectively. A series of studies evaluating the algistatic properties of this chemical provided 5-day algistatic concentrations of 0.052 to 4.6 mg/L in four different algae species. Careful examination of the large numbers of acute toxicity to fish and aquatic invertebrate studies available for the FND Amines Category chemicals overall, indicates that when studies are carried out at low concentrations (generally less than 10 mg/L) or emulsions are made using additives, the toxicity to aquatic organisms is high with LC50/EC50 values frequently less than 1 mg/L.

Subcategory IV – Trialkylamines: No modeled data were available for chemicals in this Subcategory.

Measured biodegradation data were available for the two alkyl diethanolamines (CAS RN 61791-31-9 and 61791-44-4). In 28 days, there was 61% COD and 52% ThOD, respectively indicating these, like the other FND Amines in the category are readily or nearly readily biodegradable.

Acute and chronic fish LC50 values for CAS RN 61791-31-9 were 0.47 mg/L (48-hour) and 0.0179 mg/L (30-day). For the same chemical, the acute (48-hour) EC50 for daphnia was 0.38 mg/L and the 21-day EC50 values for growth in two separate experiments were 0.14 and 0.15 mg/L. These data indicate that the FND Amine Category chemicals in Subcategory IV have similar toxicity profiles in aquatic species as the other chemicals in the Category as well as other FND chemicals (cationics, amides) in other HPV Categories.

Summary – Environmental Fate and Ecotoxicity

As anticipated in the EPA guidance for HPV chemicals, only model estimates were available for photodegradation and fugacity. The other exclusively modeled value, stability in water, could not be calculated for this category of chemicals. Atmospheric photodegradation was predicted to be rapid although fugacity models suggested very minimal distribution of these chemicals to the air. Predicted distribution of the chemicals in the environment was to water and sediment compartments based on the assumption that release of the chemicals to the environment is all via water. Extensive biodegradation testing across the Category indicated that the FND Amines




Category chemicals are biodegradable, often meeting the “readily biodegradable” criteria. No additional biodegradation studies are proposed since there is no observable pattern or structural properties of the chemicals within the Category and Subcategories to suggest that non-tested chemicals would behave differently. The substantial numbers of studies evaluating the aquatic toxicity of the FND Amine Category chemicals clearly indicate that these surfactants are highly toxic (LC50/EC50 values generally < 1 mg/L) to aquatic organisms when bioavailable. Furthermore, this high toxicity is consistent with the large numbers of tests conducted for other FND surfactants (amides, cationics) and for surfactants in general. Therefore, further testing of these chemicals for aquatic toxicity is considered of little or no value in a screening program such as the HPV Chemical Challenge. For the purpose of the program, all of the FND Amine Category chemicals can be considered highly toxic to aquatic species. Overall, the available data support the conclusion that the FND Amines Category chemicals possess similar environmental fate and ecotoxicity across the category.

Additional Testing – Environmental Fate and Ecotoxicity

No additional testing (Table 6) is proposed for the Category. The available model data are adequate for photodegradation, particularly in light of the very limited potential volatility of the FND Amines Category chemicals, as well as for fugacity. These chemicals are not expected to exhibit hydrolysis under normal conditions. Adequate biodegradation data are available to indicate the chemicals in the Category are readily or nearly readily biodegradable. As noted above, additional testing for aquatic toxicity is unwarranted since all of the FND Amine Category chemicals, similar to other surfactants, can be considered highly toxic to aquatic organisms. The available data are considered adequate for the screening purposes of the HPV Chemical Challenge Program.

Human Health-Related Data

The human health effects data for SIDS endpoints of the 23 FND Amines Category chemicals and 12 supporting chemicals are presented in Table 4. Robust summaries for the reliable studies are provided in Appendix A. The Test Plan for human health related studies is presented in Table 7.

Subcategory I – Primary Alkylamines and Alkyldiamines: The rat acute oral LD50 value for the HPV chemical, CAS RN 124-22-1, in two separate studies was 1020 and >2000 mg/kg indicating that the chemical possesses slight acute toxicity by the oral route. The value for mice was similar (1160 mg/kg). The LD50 value for the alkyldiamine HPV chemical (CAS RN 61791-55-7) in this Subcategory was >5000 mg/kg. Results were similar for six supporting chemicals with LD50 values ranging from approximately 1000 to >6000 mg/kg. Three studies evaluating rabbit acute dermal toxicity for CAS RN 61788-46-3* gave LD50 values >2000 mg/kg. One acute inhalation study (CAS RN 61788-46-3*) indicated this chemical caused irritation but no lethality at 0.099 mg/L from a one-hour exposure.

Repeated dose toxicity studies were available for four supporting chemicals. In two chronic two-year dietary studies in rats for CAS RN 124-30-1*, the NOAEL was approximately 25 mg/kg/day. In a one-year chronic dietary study in dogs for this chemical, the reported NOAEL was 3.0 mg/kg/day. In this latter study, the occurrence of “foamy” histiocytes in the mesenteric lymph nodes and abnormal appearance of the intestines was recorded. For CAS RN




61790-33-8*, a 4-week gavage study had an NOAEL of 12.5 mg/kg/day. A 14-day repeated dose skin study in rats with minimal observations was reported with CAS RN 112-90-3*. The chemical was irritating at all doses after several days of dosing with the lowest dose of 0.5% showing minimal irritation. No necropsies were performed so this study is considered of supplemental value to establishing the irritant properties of the test chemical. For the mixture of hydrofluoride salts of hexadecylamine and octadecenamine (CAS RN 3151-59-5 + 36505-83-6), a 24-month rat study and a 2-year dog study were available. The NOAEL for both studies was 6.0 mg/kg/day. Non-specific effects on body weight, food consumption, clinical chemistry measurements and organ weights were observed at 30 mg/kg/day in the rat study. Enlarged intestinal lymph nodes with histological evidence of sinusoidal dilation with congestion and fibroplasia were observed at the high dose. Dogs could not tolerate a dose of 30 mg/kg/day and the high dose was reduced to 12 mg/kg/day after five weeks. Effects at the high dose were minimal, primarily related to decreased serum protein throughout the study.

Adequate Salmonella Reverse Mutation (Ames) assays for one of the FND Amines Category chemicals (CAS RN 143-27-1) and four of the supporting chemicals (CAS RN 124-30-1*, 61788-46-3*, 61790-33-8*, and 112-90-3*) were identified. All of the assays were negative. In two cases (CAS RN 124-30-1* and 61788-46-3*), toxicity was observed for the higher concentrations used in these studies thus limiting the number of concentrations available for evaluation. However, since the criteria for a positive test includes dose response and the concentrations that could be evaluated were as high as could have been tested, these studies are considered adequate. An in vivo rat micronucleus assay for CAS RN 61790-33-8* was negative. A CHO/HGPRT gene mutation assay, a mouse lymphoma assay, a chromosome aberration assay and an in vivo cytogenetics assay were negative for CAS RN 112-90-3*.

Evaluations of potential reproductive effects were available for three supporting chemicals. For CAS RN 124-30-1*, reproductive organs were examined in both two-year toxicity studies with rats and the one-year toxicity study with dogs. No effects were seen in the reproductive organs at the highest doses tested (approximately 25 mg/kg/day for rats and 15 mg/kg/day for dogs). Reproductive and developmental screening for CAS RN 61790-33-8* was conducted in a study that followed OECD 421 guidelines. The parental and offspring NOAEL was 12.5 mg/kg based on body weight effects at the mid dose of 50 mg/kg/day. The high dose of 120 mg/kg/day was lethal. No effects on reproduction or developmental toxicity were observed. For the mixture of hydrofluoride salts of hexadecylamine and octadecenamine (CAS RN 3151-59-5 + 36505-83-6), in a Segment I, reproductive screening assay, male body weights were decreased at the highest dose (30 mg/kg/day) while no effects on offspring were noted. Results for two developmental toxicity studies were available for the supporting chemical, CAS RN 112-90-3*. The NOAEL for maternal toxicity in rats was 10 mg/kg/day and the corresponding value for rabbits was 3.0 mg/kg/day. No teratogenic or developmental toxicity was observed in either study at the highest doses tested. For the mixture (CAS RN 3151-59-5 + 36505-83-6), Segment II (teratology) studies in rats and rabbits and a Segment III (perinatal) study in rats were identified. Maternal body weights were decreased in the Segment II study for rats (NOAEL = 6.0 mg/kg/day) and rabbits (NOAEL not established). No developmental toxicity was observed in these studies and no effects on offspring or mothers were observed in the Segment III study (NOAELs = 30 mg/kg/day).




Subcategory II – Dimethylalkylamines: Rat acute oral toxicity LD50 data were available for the five HPV chemicals and two of three supporting chemicals in this Subcategory. Values ranged from approximately 800 to >2000 mg/kg indicating that the chemicals possess slight acute toxicity by the oral route. Acute dermal studies for the HPV chemicals (CAS RN 112-69-6, 124-28-7, and 61788-91-8) and supporting chemicals (CAS RN 112-18-5 and 61788-93-0) yielded LD50 values ranging from approximately 3000 to 5000 mg/kg. These values indicate that these chemicals possess slight toxicity via the dermal route with doses of 3000 to 8000 mg/kg being lethal to some animals for the tested chemicals.

Salmonella Reverse Mutation (Ames) assays were conducted on three HPV chemicals (CAS RN 112-75-4, 112-69-6 and 124-28-7). These studies were conducted using only two strains of bacteria and do not adequately fulfill the HPV Chemical Challenge Program requirements. However, the results were negative adding support to the large weight of evidence that the FND Amines Category chemicals are unlikely to be mutagenic. An in vivo mouse micronucleus assay for supporting chemical, CAS RN 112-18-5, was negative.

No reproductive or developmental toxicity studies were identified for the chemicals in this Subcategory.

Subcategory III – Dialkylmethylamines and Dialkylamines: Two HPV (CAS RN 4088-22-6 and 61788-63-4) and two supporting (CAS RN 61788-62-3 and 61789-79-5) chemicals had reported acute oral LD50 values of >2000, >5000, > 10000 or > 15000 mg/kg. An acute dermal study with CAS RN 4088-22-6 indicated the dermal LD50 is greater than 2000 mg/kg.

A series of repeated dose toxicity studies was reported for CAS RN 4088-22-6. In a limited gavage range finding study in rabbits at doses of 100 to 1000 mg/kg/day, the LOAEL was determined to be 100 mg/kg/day based on altered body weights and reduced food consumption. In a 13-week dietary toxicity study in rats at concentrations of 0.15, 0.5, and 1.5% (approximately 130, 375 and 1000 mg/kg/day), the LOAEL was 130 mg/kg/day. This study reported extensive findings of ‘foamy macrophages’ in the intestinal mucosa and other organs including ovaries. This finding was dose-related and occurred at all doses. The lymph nodes in the intestines were enlarged at all doses as well. No NOAEL was, therefore, established. In three studies with repeated dermal exposure of 7 days or 13 weeks duration, no systemic toxicity was observed but skin irritation was prominent at doses of approximately 5 mg/kg/day and above.

An adequate Salmonella Reverse Mutation (Ames) assay for CAS RN 4088-22-6 was negative. A series of genetic toxicity screening studies with CAS RN 61788-63-4, including the Salmonella Reverse Mutation assay, mouse lymphoma, in vitro UDS, and in vivo cytogenetics, were all negative.

Reproductive organs were examined in the 13-week dietary study with CAS RN 4088-22-6. The identification of ‘foamy macrophages’ in the ovaries of this study precludes a definition of a NOAEL. This finding is not considered related to reproductive toxicity per se and is likely related to clearance of the test material. However, finding these macrophages in the ovaries is not common for chemicals that have this type of lesion due to clearance. No effect on reproductive organs was observed in a 13-week dermal study with rabbits at 5 or 50 mg/kg/day. A developmental toxicity study for CAS RN 4088-22-6 with rabbits at doses of 50, 250 and




1000 mg/kg/day provided a maternal NOAEL of 50 mg/kg/day without showing fetal effects at 250 mg/kg/day. Fetal body weight effects were minimal at in the high dose group. No teratogenicity was observed.

Subcategory IV – Trialkylamines: Rat acute oral toxicity LD50 data were available for the two diethanolamines (CAS RN 61791-31-9 and 61791-44-4) in this Subcategory. Values ranged from 630 to >15,000 mg/kg. The wide range of lethal doses for CAS RN 61791-44-4 is not clearly explainable. However, the lower LD50 values were obtained from studies in which the test chemical was dosed neat while the higher values (> 2000 and > 15,000 mg/kg) were dosed with suspensions of the test chemical. It is possible that the corrosive effects of neat test material in the stomach resulted in the lower doses required to cause toxicity and death. Overall, these chemicals exhibit acute toxicity similar to the other chemicals in the category.

One acute inhalation study for this Subcategory (CAS RN 61791-44-4) was conducted. The study had an unusual design, using heated test material with and without polypropylene aerosol. The study design and untoward results prohibited a clear definition of an LC50 since 100% of the animals with the polypropylene in the aerosol died while none died without the inert polymer. The authors speculate that the actual concentration of the test material may have been much higher than the nominal value in the polypropylene plus test material group. Therefore, the LC50

of > 0.08 mg/L (no deaths) for the group exposed to the test chemical only, is considered to be uncertain (FND Amines Task Group).

Three acute dermal studies produced no deaths at 2000 mg/kg. However, in a fourth study, 4 of 6 animals died following a 2000 mg/kg dose. The reason for the difference in this latter study with three studies showing no mortality at 1500 or 2000 mg/kg or 2000 ml/kg is not clearly explainable.

A number of repeated dose studies have been reported for CAS RN 61791-44-4. The NOAELs for a 90-day dietary study in rats and dogs were approximately 50 mg/kg/day and 13 mg/kg/day, respectively. In the dog study, the higher doses of 40 and 120 mg/kg/day were poorly tolerated with extensive emesis reported. Both of these studies reported the finding of “foamy macrophages” in the intestines of the animals at the higher doses, similar to that reported for the Subcategories I and III chemicals discussed above. In a second 90-day study with rats, the NOAEL was 12 mg/kg/day based on slightly lower body weights and the presence of “foamy macrophages” at the highest dose of 400 mg/kg/day. In dermal studies of approximately three or four weeks duration and limited numbers of doses, no systemic toxicity was observed but skin irritation was prominent at doses as low as 2 mg/kg/day.

In vitro genetic assays for CAS RN 61791-44-4, including three Salmonella Reverse Mutation assays, a mouse lymphoma study, and a UDS assay were negative for mutagenic effects. An in vitro chromosomal aberration assay was negative without metabolic activation but was considered positive with metabolic activation. However, in vivo mouse micronucleus and cytogenetics studies were negative indicating the finding in the in vitro assay was aberrant. Overall these studies are consistent with the lack of mutagenicity for the chemicals in the FND Amines category as well as the other FND Category chemicals (amides, cationics, nitriles).

Evaluations of reproductive organs were made for the animals in the two 90-day rat studies and the 90-day dog study (CAS RN 61791-44-4) meeting the requirements for the HPV screening for




reproductive effects. No effects were observed at the highest doses tested (approximately 450, 400 and 120 mg/kg/day, respectively). No developmental toxicity data were available for chemicals in this Subcategory.

Summary – Human Health-Related Data

Adequate acute oral LD50 studies were available throughout the category. They indicate slight to minimal acute toxicity for the FND Amines Category chemicals. Acute dermal studies indicate these chemicals can be classified as minimally toxic. Acute inhalation studies did not result in deaths under normal exposure conditions for two chemicals. Repeated dose toxicity studies in Subcategories I, III, and IV had similar NOAELs (12.5 to 50 mg/kg/day for rats and 3 or 13 mg/kg/day for dogs). Importantly because the highest exposure potential for some of the FND Amines Category chemicals is via skin contact, a number of repeat dose dermal studies indicate the chemicals are highly irritating. This irritation helps provide added assurance that human exposure will be limited due to avoidance of the irritant effects. No clear organ-specific toxicity occurred in any of the repeat dose studies with the chemicals in the FND Amines Category. Interestingly, one dog study for a chemical in Subcategory I (CAS RN 124-30-1*) and the rat and dog studies from Subcategories III and IV all reported ‘foamy macrophages’ in the intestines, this finding being associated with effects by which the NOAELs were established. These types of findings have been reported following oral consumption of white oils (Firriolo et al., 1995; Shoda et al., 1997). These lesions are thought to be related to clearance of high molecular weight oils but are not associated with long-term effects. Enlargement and lesions in the intestinal lymph nodes in the chronic rat study with the hydrofluoride salt mixture (CAS RN 3151-59-5 + 36505-83-6) in Subcategory I were also observed. The occurrence of these lesions following exposure to the FND Amines Category chemicals suggests that clearance may be similar to that of the high molecular weight oils. Available data indicate that the FND Amines Category chemicals are unlikely to be mutagenic and that they are not reproductive or developmental toxins.

Additional Testing – Human Health-Related Studies

In evaluating potential further testing of the FND Amines Category chemicals, it is useful to review the available data for the related FND Cationic and FND Amides Category chemicals. Acute oral toxicity studies (approximately 80 studies for 40 chemicals in the three categories) provide LD50 values from approximately 400 to 10,000 mg/kg with no apparent organ specific toxicity. Similarly, repeated dose toxicity studies (approximately 35 studies for 15 chemicals) provide NOAELs between 10 and 100 mg/kg/day for rats and slightly lower for dogs. More than 60 genetic toxicity studies (in vitro bacterial and mammalian cells as well as in vivo studies) indicated only one equivocally positive Salmonella Reverse Mutation assay and one positive chromosomal aberration assay that was ultimately shown to be aberrant, among more than 30 chemicals tested. For reproductive evaluations, 14 studies evaluated reproductive endpoints and/or reproductive organs for 11 chemicals and 15 studies evaluated developmental toxicity for 13 chemicals indicating no reproductive or developmental effects for the FND group as a whole.

These comparisons clearly provide a strong weight of evidence that the FND Amines Category chemicals will not pose significant toxicity to humans. As noted previously, it is not appropriate to consider the FND Amines Category chemicals to represent a continuum of alkyl chain substitution. As outlined in Text Table C, the minimal difference among the alkyl substituents




and the large database for the FND Categories indicates that the structural differences in these large alkyl chains do not result in differences in toxicity or mutagenicity. Thus, there is no current scientifically justifiable expectation that any of the alkylamines in the Category will result in significant toxicity not already established by tests with the HPV and supporting chemicals. The primary alkylamines and alkyldiamines are well represented by the available data. Additional substitutions, as with the chemicals in the other Subcategories, serve to decrease bioavailability while providing no additional structural alerts to warrant selection for additional testing. Based on the consistent pattern of toxicity within and among the FND Categories, no additional testing is proposed for the FND Amines Category chemicals. Table 7 provides the Test Plan for the human health related endpoints.

References

Firriolo, J.M., C.F. Morris, G.W. Trimmer, L.D. Twitty, J.H. Smith and J.J. Freeman. 1995. Comparative 90-day feeding study with low-viscosity white mineral oil in Fischer-344 and Sprague-Dawley-derived CRL:CD rats. Toxicologic Pathol 23: 26-33.

Klimisch, H.J., M. Andreae and U. Tillmann. 1997. A Systematic Approach for Evaluating the Quality of Experimental Toxicological and Ecotoxicological Data. Reg. Toxicol. Pharmacol. 25:1 – 5.

Mackay, D., A. Di Guardo, S. Paterson, G. Kicsi and C. E. Cowan. 1996a. Assessing the Fate of New and Existing Chemicals: A Five-stage Process. Environ. Toxicol. Chem. 15(9): 1618 – 1626.

Mackay, D., A. Di Guardo, S. Paterson and C. E. Cowan. 1996b. Evaluating the Environmental Fate of a Variety of Types of Chemicals Using the EQC Model. Environ. Toxicol. Chem. 15(9): 1627 – 1637.

Meylan, W. and P. H. Howard. 1998. User’s Guide for the ECOSAR Class Program, Version 0.99d. Syracuse Research Corporation, North Syracuse, NY.

Meylan, W. and P. H. Howard. 1999a. User’s Guide for MPBPVP, Version 1.4. Syracuse Research Corporation, North Syracuse, NY.

Meylan, W. and P. H. Howard. 1999b. User’s Guide for KOWWIN, Version 1.6. Syracuse Research Corporation, North Syracuse, NY.

Meylan, W. and P. H. Howard. 1999c. User’s Guide for WSKOWWIN, Version 1.3. Syracuse Research Corporation, North Syracuse, NY.

Meylan, W. and P. H. Howard. 2000a. User’s Guide for AOPWIN, Version 1.9. Syracuse Research Corporation, North Syracuse, NY.

Shoda T., K. Toyoda, C. Uneyama, K. Takada and M. Takahashi. 1997. Lack of carcinogenicity of medium-viscosity liquid paraffin given in the diet to F344 rats. Food Chem Toxicol 35: 1181-1190.




Syracuse Research Corporation. 2000. Users Guide for Estimation Programs Interface for Windows, Version 3. Syracuse Research Corporation, North Syracuse, NY.

U. S. EPA. 1999a. Draft Guidance on Developing Robust Summaries. http://www.epa.gov/chemrtk/robsumgd.htm.

U. S. EPA. 1999b. The Use of Structure-activity Relationships (SAR) in the High Production Volume Chemicals Challenge Program. http://www.epa.gov/chemrtk/sarfinl1.htm.

U. S. EPA. 2000. ECOSAR Program, Risk Assessment Division (7403). U. S. Environmental Protection Agency, Washington, DC.




Table 1

Structures of FND Amines Category Chemicals

Subcategory I: Primary Alkylamines and Alkyldiamines

H2N (CH2)11 CH3

Dodecylamine 124-22-1

H2N (CH2)15 CH3

Hexadecylamine 143-27-1

H2N R

R = C14 – C18 alkyl

Amines, C14-18 -alkyl 68037-91-2

H2N R

R = hydrogenated tallow alkyl

Amines, hydrogenated tallow alkyl 61788-45-2*

H2N CH3(CH2)17

Octadecylamine 124-30-1*

H2N R

R = coco alkyl

Amines, coco alkyl 61788-46-3*

H2N R

R = C14 – C18- and C16 – C18-unsaturated alkyl

Amines, C14-18 and C16-18 -unsatd. alkyl

68155-38-4

H2N R

R = tallow alkyl

Amines, tallow alkyl 61790-33-8*

H2N R

R = soya alkyl

Amines, soya alkyl 61790-18-9

H2N R

R = C16 – C18- and C18-unsaturated alkyl

Amines, C16-18 and C18-unsaturated alkyl 68037-95-6

Shaded cells with name and CAS RN in italics are for supporting chemicals [non-HPV]




Table 1


H2N CH3

(CH2)7(CH2)8

Cis-9-Octadecenylamine 112-90-3 *

H N NH2

R (CH2)3

R = tallow alkyl

Amines, N-tallow alkyltrimethylenedi-61791-55-7

(H2C)7 (CH2)3(CH2)7 H2N (CH2)15

N H

NH2

1,3-Propanediamine, N-(9Z)-octadecenyl-7173-62-8

CH3

Hexadecylamine hydrofluoride (Hetaflur)3

3151-59-5

CH3H2N

(CH2)8 (CH2)7 9-Octadecen-1-amine hydrofluoride3

36505-83-6

Subcategory II: Dimethylalkylamines

H3C CH3 H3C CH3

N N

(CH2)11 (CH2)13

H3C H3C

1-Dodecanamine, N,N-dimethyl 1-Tetradecanamine, N,N-dimethyl 112-18-5 112-75-4


* These chemicals were removed from the original FND Amines Category because they are sponsored by APAG under the ICCA program.3 Hydrofluoride salt not shown in structure.




Table 1


H3C

N

H3C CH3

(CH2)15

1-Hexadecanamine, N,N-dimethyl 112-69-6

H3C

N

H3C CH3

(CH2)17

1-Octadecanamine, N,N-dimethyl 124-28-7

N RCH3

CH3

R = coco alkyl

Amines, coco alkyl dimethyl 61788-93-0

N RCH3

CH3


Amines, (hydrogenated tallow alkyl)dimethyl 61788-95-2

N RCH3

CH3

R = soya alkyl

Amines, dimethyl soya alkyl 61788-91-8

N CH3

CH3

H3C (CH2)15

Octadecen-1-amine, N,N-dimethyl 28061-69-0

Subcategory III: Dialkylmethylamines and Dialkylamines

N

CH3

CH3H3C

(CH2)9(CH2)9

1-Decanamine, N-decyl-N-methyl 7396-58-9

N

CH3

R R


Amines, di-C14-18 -alkylmethyl 67700-99-6





Table 1


NH RR


Amines, di-C12-18 -alkyl 68153-95-7

N

CH3

CH3H3C (CH2)17 (CH2)17

1-Octadecanamine, N-methyl-N-octadecyl 4088-22-6

N

CH3

R R N

CH3

R R

R = coco alkyl R = hydrogenated tallow alkyl

Amines, dicoco alkylmethyl Dihydrogenated tallow methylamine 61788-62-3 61788-63-4

NR R NR R H H

R = hydrogenated tallow alkyl R = coco alkyl

Amines, bis(hydrogenated tallow alkyl) Amines, dicoco alkyl 61789-79-5 61789-76-2

NR R H

R = tallow alkyl

Amines, ditallow alkyl 68783-24-4





Table 1


Subcategory IV: Trialkylamines

NR

R

R


Amines, tri-C8-10 -alkyl-68814-95-9

NR

R

R


Amines, tris (hydrogenated tallow alkyl) 61790-42-9

N OHHO

R

R = coco alkyl derivs.

Ethanol, 2,2’-iminobis-, N-coco alkyl derivs. 61791-31-9

N OHHO

R

R = tallow alkyl derivs.

Ethanol, 2,2’-iminobis-, N-tallow alkyl derivs. 61791-44-4



FND

Am

ines

Cat

egor

y H

PV C

hem

ical

Cha

lleng

e D

ecem

ber 2

9, 2

003

Page

29

of 4

7

Tab

le 2

Phy

sica

l/Che

mic

al P

rope

rtie

s D

ata

for

FN

D A

min

es C

ateg

ory

Che

mic

als

CA

S R

N

Mel

ting

Poi

nt

(��C

) B

oilin

g P

oint

(��

C)

Vap

or P

ress

ure

(hP

a)

Par

titi

on

Coe

ffic

ient

(l

og K

ow)

Wat

er S

olub

ility

(m

g/L

)

Subc

ateg

ory

I: P

rim

ary

Alk

ylam

ines

and

Alk

yldi

amin

es

124-

22-1

28

.3

28.3

259

259

0.00

81

4.76

2000

45.1

14

3-27

-1

47

323

0.00

013

6.73

0.

48

6803

7-91

-2

6178

8-45

-2*

52.9

52.9

348

347

0.00

0012

0.00

0087

7.

71

0.04

9 12

4-30

-1*

52.9

52.9

347

349

347

0.00

0012

0.00

0087

7.

71

1000

no

t sol

uble

0.04

9 61

788-

46-3

* 68

155-

38-4

61

790-

33-8

* 34

– 4

0 25

– 3

0 20

0 –

230

< 1.

3 7.

5 in

solu

ble

6179

0-18

-9

6803

7-95

-6

112-

90-3

* ~

21

21

93

275-

344

335

346

< 1.

3 0.

0001

3 4

0.00

0037

7.5

4 and

8.1

4

7.5

4

>3.1

1

7.50

(0.5

x 1

0-3) 4 a

nd

(0.7

x 1

0-5) 4

inso

lubl

e ve

ry in

solu

ble

0.07

6 61

791-

55-7

71

73-6

2-8

142

402

4.9

x 10

-7

7.47

0.

037

4 Est

imat

ed v

alue

.



FND

Am

ines

Cat

egor

y H

PV C

hem

ical

Cha

lleng

e D

ecem

ber 2

9, 2

003

Page

30

of 4

7

Tab

le 2

Phy

sica

l/Che

mic

al P

rope

rtie

s D

ata

for

FN

D A

min

es C

ateg

ory

Che

mic

als

Par

titi

on

Mel

ting

Poi

nt

Boi

ling

Poi

nt

Vap

or P

ress

ure

Coe

ffic

ient

W

ater

Sol

ubili

ty

CA

S R

N

(��C

) (��

C)

(hP

a)

(log

Kow

) (m

g/L

) 31

51-5

9-5

+ 3

6505

-83-

6

Subc

ateg

ory

II:

Dim

ethy

lalk

ylam

ines

112-

18-5

-1

5 to

-20

22

26

0 0.

0159

5.

44

8.58

11

2-75

-4

43

292

0.00

20

6.42

0.

88

112-

69-6

63

32

1 0.

0002

9 7.

41

0.08

9

124-

28-7

22

.9

19.6

-22

.4

22.9

34

6 0.

0001

7 8.

39

not

solu

ble

0.00

89

6178

8-93

-0

6178

8-95

-2

6178

8-91

-8

2806

1-69

-0

80

345

0.00

0052

8.

25

0.01

2

Subc

ateg

ory

III:

Dia

lkyl

met

hyla

min

es a

nd D

ialk

ylam

ines

73

96-5

8-9

6770

0-99

-6

6815

3-95

-7

4088

-22-

6 21

6 54

3 2.

0 x

10-1

1 17

2

x 10

-11

6178

8-62

-3

6178

8-63

-4

3.15

0.

288

6178

9-79

-5

6178

9-76

-2

6878

3-24

-4

Not

e: B

old

font

ind

icat

es r

elia

ble

data

for

whi

ch a

Rob

ust

Sum

mar

y is

pro

vide

d in

App

endi

x A

R

egul

ar f

ont

indi

cate

s da

ta o

btai

ned

from

app

ropr

iate

mod

els

as d

escr

ibed

in

the

text

and

App

endi

x B

. S

hade

d ce

lls

wit

h C

AS

RN

and

dat

a in

ita

lics

are

for

sup

port

ing

chem

ical

s [n

on-H

PV].

E

mpt

y bl

ock

deno

tes

data

eit

her

are

not

ava

ilab

le o

r ar

e av

aila

ble

and

judg

ed i

nade

quat

e.

* T

hese

che

mic

als

wer

e re

mov

ed f

rom

the

ori

gina

l F

ND

Am

ines

Cat

egor

y be

caus

e th

ey a

re s

pons

ored

by

AP

AG

und

er t

he I

CC

A p

rogr

am.

Sub

cate

gory

IV

, Tri

alky

lam

ines

, is

not s

how

n; n

o da

ta a

vail

able



FND

Am

ines

Cat

egor

y H

PV C

hem

ical

Cha

lleng

e D

ecem

ber 2

9, 2

003

Page

31

of 4

7

Tab

le 3

Env

iron

men

tal F

ate

and

Eco

toxi

city

Dat

a fo

r F

ND

Am

ines

Cat

egor

y C

hem

ical

s

CA

S R

N

Pho

tode

grad

atio

n (c

m3 /m

olec

ule

-sec

fo

r k p

hot

)

Stab

ility

in

W

ater

T

rans

port

&

Dis

trib

utio

n 5

Bio

degr

adat

ion

Acu

te/P

rolo

nged

T

oxic

ity

to F

ish

96

-hou

r L

C50

(mg/

L)

Acu

te/C

hron

ic

Tox

icit

y to

In

vert

ebra

tes

EC

50 (

mg/

L)

Tox

icit

y to

A

quat

ic P

lant

s 72

-hr.

EC

50

(mg/

L)

Subc

ateg

ory

I: P

rim

ary

Alk

ylam

ines

and

Alk

yldi

amin

es

124-

22-1

46

E-1

2 t 1

/2 =

2.8

hr

not

calc

ulab

le

Air:

<1%

W

ater

: 75%

So

il: <

1%

Sedi

men

t: 25

%

> 6

0% T

hOD

in 2

8 d

0.

42

9.77

(0

.87)

6

3.2

(0.0

9) 6

not c

alcu

labl

e (0

.45)

6

143-

27-1

51

E-1

2 t 1

/2 =

2.5

hr

not

calc

ulab

le

Air:

<1%

W

ater

: 13%

So

il: <

1%

Sedi

men

t: 87

%

not t

oxic

at

solu

bilit

y

not t

oxic

at

solu

bil it

y (0

.008

) 6

not c

alcu

labl

e (n

ot to

xic

at

solu

bilit

y) 6

6803

7-91

-2

6178

8-45

-2*

54 E

-12

t 1/2

= 2

.4 h

r no

t ca

lcul

able

Air

: <

1%

Wat

er:

10%

So

il: <

1%

Sedi

men

t: 9

0%

75%

ThO

D in

28

d 64

% C

O2 i

n 28

d

0.88

not t

oxic

at

solu

bilit

y

0.16

<1

.0

not t

oxic

at

solu

bilit

y

96-h

our:

E

bC50

7 = 0

.012

E

rC50

7 ~ 0

.016

not c

alcu

labl

e (n

ot to

xic

at

solu

bilit

y) 6

124-

30-1

* 54

E-1

2 t 1

/2 =

2.4

hr

not

calc

ulab

le

Air

: <

1%

Wat

er:

10%

So

il: <

1%

Sedi

men

t: 9

0%

>60

% T

hOD

in 1

2 d

70%

ThO

D in

28

d no

t tox

ic a

t so

lubi

lity

0.13

not t

oxic

at

solu

bilit

y

EbC

50 =

0.0

62

ErC

50 =

0.12

not c

alcu

labl

e (n

ot to

xic

at

solu

bilit

y) 6

5 W

ater

was

ass

umed

to

be t

he e

xclu

sive

rou

te o

f en

try

into

the

env

iron

men

t.

6 Ori

gina

l mod

el c

alcu

lati

ons

wer

e m

ade

spec

ifyi

ng th

e ch

emic

als

as “

Cat

ioni

c S

urfa

ctan

ts”;

a s

econ

d ca

lcul

atio

n w

as m

ade

assu

min

g th

e ch

emic

als

are

Alip

hatic

Am

ines

– th

e va

lues

for t

his s

econ

d ca

lcul

atio

n ar

e in

clud

ed in

( )

if d

iffe

rent

than

for

Cat

ioni

c S

urfa

ctan

ts.

7 EbC

50 is

the

EC

50 b

ased

on

grow

th (

biom

ass)

; E

rC50

is th

e E

C50

bas

ed o

n gr

owth

rat

e.



FND

Am

ines

Cat

egor

y H

PV C

hem

ical

Cha

lleng

e D

ecem

ber 2

9, 2

003

Page

32

of 4

7

Tab

le 3

Env

iron

men

tal F

ate

and

Eco

toxi

city

Dat

a fo

r F

ND

Am

ines

Cat

egor

y C

hem

ical

s

CA

S R

N

Pho

tode

grad

atio

n (c

m3 /m

olec

ule

-sec

fo

r k p

hot

)

Stab

ility

in

W

ater

T

rans

port

&

Dis

trib

utio

n 5

Bio

degr

adat

ion

Acu

te/P

rolo

nged

T

oxic

ity

to F

ish

96

-hou

r L

C50

(mg/

L)

Acu

te/C

hron

ic

Tox

icit

y to

In

vert

ebra

tes

EC

50 (

mg/

L)

Tox

icit

y to

A

quat

ic P

lant

s 72

-hr.

EC

50

(mg/

L)

6178

8-46

-3*

56%

ThO

D in

28

d (7

4% in

42

d)

58%

ThC

0 2 in

28

d 91

.1%

ThC

0 2 in

28

d

0.16

0.

24

0.04

5 0.

09

Lar

vae

= 2.

0 –

3.0

8

Pup

ae =

3.

5 –

13.0

8

EbC

50 =

0.1

4 E

rC50

=0.

17

96-h

our:

E

bC50

=0.

0007

5 E

rC50

=0.

0011

6815

5-38

-4

6179

0-33

-8*

56%

TC

O2

in 2

8 d

>51%

BO

D in

28

d (~

70%

in 4

2 d)

73

% in

28

d

9.3

>0.1

8 an

d <0

.25

0.09

3 0.

09

<0.2

5

EbC

50 =

0.0

52

ErC

50 =

0.05

9

EbC

50 =

0.0

68

ErC

50 =

0.08

3 61

790-

18-9

68

037-

95-6

112-

90-3

* 11

0 E

-12

t 1/2

= 1

.2 h

r no

t ca

lcul

able

Air

: <

1%

Wat

er:

11%

So

il: <

1%

Sedi

men

t: 8

9%

> 60

% T

hOD

in 1

2 d

44%

ThO

D in

28

d (7

2% in

42

d)

66%

ThC

0 2 in

28

d 69

% T

hOD

in 2

8 d

0.11

not t

oxic

at

solu

bilit

y

0.01

1

not t

oxic

at

solu

bilit

y

96-h

our:

E

bC50

=0.

03

ErC

50 =

0.04

not t

oxic

at

solu

bilit

y

6179

1-55

-7

90%

D

OC

elim

inat

ion

in 3

hrs

; 87

%

adso

rpti

on in

slu

dge

8 Val

ues

are

ppm

. T

est p

erfo

rmed

on

4 st

ra in

s of

mos

quit

o la

rvae

and

pup

ae; C

.p. q

uinq

uefa

scia

tus,

A. a

lbim

anus

, A. a

egyp

ti, a

nd A

. nig

rom

acul

is.



FND

Am

ines

Cat

egor

y H

PV C

hem

ical

Cha

lleng

e D

ecem

ber 2

9, 2

003

Page

33

of 4

7

Tab

le 3

Env

iron

men

tal F

ate

and

Eco

toxi

city

Dat

a fo

r F

ND

Am

ines

Cat

egor

y C

hem

ical

s

CA

S R

N

Pho

tode

grad

atio

n (c

m3 /m

olec

ule

-sec

fo

r k p

hot

)

Stab

ility

in

W

ater

T

rans

port

&

Dis

trib

utio

n 5

Bio

degr

adat

ion

Acu

te/P

rolo

nged

T

oxic

ity

to F

ish

96

-hou

r L

C50

(mg/

L)

Acu

te/C

hron

ic

Tox

icit

y to

In

vert

ebra

tes

EC

50 (

mg/

L)

Tox

icit

y to

A

quat

ic P

lant

s 72

-hr.

EC

50

(mg/

L)

7173

-62-

8 19

3 E

-12

t 1/2

= 0

.7 h

r no

t ca

lcul

able

Air:

<1%

W

ater

: 11%

So

il: <

1%

Sedi

men

t: 89

%

not t

oxic

at

solu

bilit

y no

t tox

ic a

t so

lubi

lity

not c

alcu

labl

e (n

ot to

xic

at

solu

bilit

y) 9

3151

-59-

5 +

365

05-8

3-6

Subc

ateg

ory

II:

Dim

ethy

lalk

ylam

ines

112-

18-5

93

E-1

2 t 1

/2 =

1.4

hr

not

calc

ulab

le

Air

: <

1%

Wat

er:

42%

So

il: <

1%

Sedi

men

t: 5

8%

67%

ThO

D in

28

d 72

% T

CO

2 in

29

d 67

% T

hN-B

OD

in

28 d

0.57

not t

oxic

at

solu

bili t

y

0.08

3

3.24

(0

.04)

10

EbC

50.=

0.0

56 11

ErC

50.=

0. 0

92

EbC

50.=

0.0

34

ErC

50.=

0.05

6

EbC

50 �

0.0

133

ErC

50 �

0.0

235

not c

alcu

labl

e (0

.26)

10

112-

75-4

96

E-1

2 t 1

/2 =

1.3

hr

not

calc

ulab

le

Air:

<1%

W

ater

: 7%

So

il: <

1%

Sedi

men

t: 93

%

< 2

% C

OD

in 2

8 d

12

0.18

>

0.0

1 an

d <

1.0

>

0.01

an

d <

0.1

0.

35

not t

oxic

at

solu

bilit

y

not t

oxic

at

solu

bilit

y (0

.01)

10

not c

alcu

labl

e (n

ot to

xic

at

solu

bilit

y) 10

9 O

rigi

nal m

odel

cal

cula

tion

s w

ere

mad

e sp

ecif

ying

the

chem

ical

s as

“C

atio

nic

Sur

fact

ants

”; a

sec

ond

calc

ulat

ion

was

mad

e as

sum

ing

the

chem

ical

s ar

e A

lipha

tic A

min

es –

the

valu

es fo

r thi

s sec

ond

ca

lcul

atio

n ar

e in

clud

ed in

( )

if d

iffe

rent

than

for

Cat

ioni

c S

urfa

ctan

ts.

10 O

rigi

nal

mod

el c

alcu

lati

ons

wer

e m

ade

spec

ifyi

ng t

he c

hem

ical

s as

“C

atio

nic

Sur

fact

ants

”; a

sec

ond

calc

ulat

ion

was

mad

e as

sum

ing

the

chem

ical

s are

Alip

hatic

Am

ines

– th

e va

lues

for t

his

seco

nd c

alcu

lati

on a

re in

clud

ed in

( )

if d

iffe

rent

than

for

Cat

ioni

c S

urfa

ctan

ts.

11 F

irst

fou

r va

lues

are

fro

m a

sin

gle

stud

y us

ing

two

natu

ral

wat

er s

ourc

es.

12 T

he s

cien

tifi

c va

lidi

ty o

f th

is v

alue

is u

njus

tifi

able

bas

ed o

n al

l ot

her

test

s of

sim

ilar

che

mic

als.

The

ass

ay i

s pr

esum

ed t

o be

inv

alid

.



FND

Am

ines

Cat

egor

y H

PV C

hem

ical

Cha

lleng

e D

ecem

ber 2

9, 2

003

Page

34

of 4

7

Tab

le 3

Env

iron

men

tal F

ate

and

Eco

toxi

city

Dat

a fo

r F

ND

Am

ines

Cat

egor

y C

hem

ical

s

CA

S R

N

Pho

tode

grad

atio

n (c

m3 /m

olec

ule

-sec

fo

r k p

hot

)

Stab

ility

in

W

ater

T

rans

port

&

Dis

trib

utio

n 5

Bio

degr

adat

ion

Acu

te/P

rolo

nged

T

oxic

ity

to F

ish

96

-hou

r L

C50

(mg/

L)

Acu

te/C

hron

ic

Tox

icit

y to

In

vert

ebra

tes

EC

50 (

mg/

L)

Tox

icit

y to

A

quat

ic P

lant

s 72

-hr.

EC

50

(mg/

L)

112-

69-6

99 E

-12

t 1/2

= 1

.3 h

r no

t ca

lcul

able

Air:

<1%

W

ater

: 5%

So

il: <

1%

Sedi

men

t: 95

%

59%

ThO

D in

28

d (7

0% in

42

d)

107%

TC

O2

in 2

9 d

0.18

>

0.1

and

<1.

0

not t

oxic

at

solu

bilit

y

not t

oxic

at

solu

bilit

y

not c

alcu

labl

e (n

ot to

xic

at

solu

bilit

y) 10

124-

28-7

10

2 E

-12

t 1/2

= 1

.3 h

r no

t ca

lcul

able

Air:

<1%

W

ater

: 5%

So

il: <

1%

Sedi

men

t: 95

%

91%

TC

O2

at

0.2

mg/

L in

7 d

(79

%

at 2

.0 m

g/L

in 7

d);

11

8% T

CO

2 at

10

mg/

L in

40

d; a

nd

51%

TC

O2

at 2

0 m

g/L

in 4

0 d

49%

TC

O2

in 2

8 d

0.18

>

0.1

an

d <

1.0

not t

oxic

at

solu

bilit

y

LC

50 =

0.0

74 13

not t

oxic

at

solu

bilit

y

0.02

9; 0

.11

> 0

.032

; 0.

16 14

not c

alcu

labl

e (n

ot to

xic

at

solu

bilit

y) 15

6178

8-93

-0

81%

ThO

D in

28

d 69

% T

hOD

in 2

8 d

>0.1

and

<1.

0

6178

8-95

-2

58%

ThO

D in

28d

(6

6% in

42

d)

6178

8-91

-8

98%

ThO

D in

28

d >

0.1

and

< 1

.0

2806

1-69

-0

126

E-1

2 t 1

/2 =

1.0

hr

not

calc

ulab

le

Air

: <

1%

Wat

er:

5%

Soil:

<1%

Se

dim

ent:

95%

50%

ThO

D in

28

d (5

9% in

70

d)

not t

oxic

at

solu

bilit

y no

t tox

ic a

t so

lubi

lity

not c

alcu

labl

e (n

ot to

xic

at

solu

bilit

y) 15

13 9

6-ho

ur L

C50

val

ue f

or M

ysid

opsi

s ba

hia

14 T

he

stu

dy

was

co

nd

uct

ed o

n S

elen

astr

um c

apri

corn

utum

an

d M

icro

cyst

is a

erug

inos

a w

ith

a 5-

day

expo

sure

and

a 9

-day

reco

very

per

iod.

Fir

st tw

o va

lues

are

the

algi

stat

ic c

once

ntra

tions

for e

ach

spec

ies,

res

pect

ivel

y. S

econ

d tw

o va

lues

are

the

alg

icid

al c

once

ntra

tion

s fo

r ea

ch s

peci

es.

An

EC

50 w

as n

ot d

eter

min

ed.

Ori

gina

l mod

el c

alcu

lati

ons

wer

e m

ade

spec

ifyi

ng t

he c

hem

ical

s as

“C

atio

nic

Sur

fact

ants

”; a

sec

ond

calc

ulat

ion

was

mad

e as

sum

ing

the

chem

ical

s ar

e A

liph

atic

Am

ines

– th

e va

lues

for t

his

seco

nd c

alcu

lati

on a

re in

clud

ed in

( )

if d

iffe

rent

than

for

Cat

ioni

c S

urfa

ctan

ts.

15



FND

Am

ines

Cat

egor

y H

PV C

hem

ical

Cha

lleng

e D

ecem

ber 2

9, 2

003

Page

35

of 4

7

Tab

le 3

Env

iron

men

tal F

ate

and

Eco

toxi

city

Dat

a fo

r F

ND

Am

ines

Cat

egor

y C

hem

ical

s

CA

S R

N

Pho

tode

grad

atio

n (c

m3 /m

olec

ule

-sec

fo

r k p

hot

)

Stab

ility

in

W

ater

T

rans

port

&

Dis

trib

utio

n 5

Bio

degr

adat

ion

Acu

te/P

rolo

nged

T

oxic

ity

to F

ish

96

-hou

r L

C50

(mg/

L)

Acu

te/C

hron

ic

Tox

icit

y to

In

vert

ebra

tes

EC

50 (

mg/

L)

Tox

icit

y to

A

quat

ic P

lant

s 72

-hr.

EC

50

(mg/

L)

Subc

ateg

ory

III:

Dia

lkyl

met

hyla

min

es a

nd D

ialk

ylam

ines

73

96-5

8-9

6770

0-99

-6

6815

3-95

-7

4088

-22-

6 13

4 E

-12

t 1/2

= 1

.0 h

r no

t ca

lcul

able

Air:

<1%

W

ater

: 5%

So

il: <

1%

Sedi

men

t: 95

%

>10

0 an

d <

500

16

not t

oxic

at

solu

bilit

y

not t

oxic

at

solu

bilit

y

not c

alcu

labl

e (n

ot to

xic

at

solu

bilit

y) 17

6178

8-62

-3

82%

ThO

D in

28

d 6.

15

6178

8-63

-4

75%

ThO

D in

28

d (8

5% in

40

d);

100%

CO

D in

28

d;

48.3

or

63.5

%

in 5

3 d;

78

.5 o

r 73

.0%

in

55

d;

70.4

7% in

28

d

(acc

lim

ated

slu

dge)

; 91

.2%

SC

AS

Rem

oval

>10

00 16

23

180

35.2

(4

8 -hr

acu

te)

16

790

(48-

hr a

cute

) 16

3.1

(48-

hr a

cute

) 21

(48

-hr

acut

e)

2.0

(48-

hr a

cute

)

6.5;

22;

60

(48

hour

acu

te)

18

EbC

50=

0.0

5 E

rC50

=0.

12

AC

d5 =

0.0

52

AC

d5 =

0.9

6 A

Cd5

= 4

.6

AC

d5 =

1.1

4 19

16 T

he v

alue

(s)

is(a

re)

ques

tion

able

due

to

the

bioa

vail

abil

ity

of t

he t

est

subs

tanc

e in

thi

s st

udy.

O

rigi

nal m

odel

cal

cula

tion

s w

ere

mad

e sp

ecif

ying

the

chem

ical

s as

“C

atio

nic

Sur

fact

ants

”; a

sec

ond

calc

ulat

ion

was

mad

e as

sum

ing

the

chem

ical

s ar

e A

liph

atic

Am

ines

– th

e va

lues

for t

his

s eco

nd c

alcu

lati

on a

re in

clud

ed in

( )

if d

iffe

rent

than

for

Cat

ioni

c S

urfa

ctan

ts.

18 T

hree

stu

dies

wit

h a

mix

ture

or

a pr

ill c

onta

inin

g th

e te

st s

ubst

ance

wer

e co

nduc

ted

in d

iffe

rent

sou

rce

wat

ers –

EC

50 v

alue

s ar

e as

the

mix

ture

/pri

ll co

ncen

trat

ion;

wel

l wat

er

with

mix

ture

EC

50 =

6.5

mg/

L (8

3.5%

dita

llow

met

hyla

min

e);

wel

l wat

er w

ith p

rill

EC

50 =

22

mg/

L (6

3% d

itallo

wm

ethy

lam

ine)

; ri

ver w

ater

with

pri

ll E

C50

= 6

0 m

g/L

(63%

di

tallo

wm

ethy

lam

ine)

;19

AC

d5 =

Alg

ista

tic

conc

entr

atio

n af

ter

5 da

ys e

xpos

ure.

Fou

r se

para

te s

tudi

es w

ere

cond

ucte

d on

fou

r st

rain

s of

alg

ae; S

elen

astr

um c

apri

corn

utum

, Mic

rocy

stis

aer

ugin

osa,

N

avic

ula

sem

inul

um, a

nd N

avic

ula

pelli

culo

sa.

17



FND

Am

ines

Cat

egor

y H

PV C

hem

ical

Cha

lleng

e D

ecem

ber 2

9, 2

003

Page

36

of 4

7

Tab

le 3

Env

iron

men

tal F

ate

and

Eco

toxi

city

Dat

a fo

r F

ND

Am

ines

Cat

egor

y C

hem

ical

s

CA

S R

N

Pho

tode

grad

atio

n (c

m3 /m

olec

ule

-sec

fo

r k p

hot

)

Stab

ility

in

W

ater

T

rans

port

&

Dis

trib

utio

n 5

Bio

degr

adat

ion

Acu

te/P

rolo

nged

T

oxic

ity

to F

ish

96

-hou

r L

C50

(mg/

L)

Acu

te/C

hron

ic

Tox

icit

y to

In

vert

ebra

tes

EC

50 (

mg/

L)

Tox

icit

y to

A

quat

ic P

lant

s 72

-hr.

EC

50

(mg/

L)

6178

9-79

-5

16%

O2

in 2

8 d

16

� 2

20 a

nd �

500

16

6178

9-76

-2

20%

ThO

D in

28

d 20

(18%

in 4

2 d)

20

6878

3-24

-4

Subc

ateg

ory

IV:

Tri

alky

lam

ines

68

814-

95-9

61

790-

42-9

6179

1-31

-9

61%

CO

D in

28

d (6

2% in

42

d);

Up

to

85%

TC

O2 i

n 28

d –

Act

ivat

ed

Slu

dge

; >

97%

SC

AS

Rem

oval

; 10

0% (

Riv

er D

ie

Aw

ay)

0.47

(48

-hou

r)

0.01

79 (

30-d

ay)

0.38

(48

-hou

r)

0.15

(21

-day

gr

owth

)

0.14

(21

-day

gr

owth

)

6179

1-44

-4

52%

ThO

D i

n 28

d

(62%

in 3

5 d)

N

ote:

Bol

d fo

nt in

dica

tes

reli

able

dat

a fo

r w

hich

a R

obus

t S

umm

ary

is p

rovi

ded

in A

ppen

dix

A

Reg

ular

fon

t in

dica

tes

data

obt

aine

d fr

om a

ppro

pria

te m

odel

s as

des

crib

ed i

n th

e te

xt a

nd A

ppen

dix

B.

Sha

ded

cell

s w

ith

CA

S R

N a

nd d

ata

in i

tali

cs a

re f

or s

uppo

rtin

g ch

emic

als

[non

-HPV

].

Em

pty

bloc

k de

note

s da

ta e

ithe

r ar

e no

t av

aila

ble

or a

re a

vail

able

and

jud

ged

inad

equa

te.

* T

hese

che

mic

als

wer

e re

mov

ed f

rom

the

ori

gina

l F

ND

Am

ines

Cat

egor

y be

caus

e th

ey a

re s

pons

ored

by

AP

AG

und

er t

he I

CC

A p

rogr

am.

20 T

he v

alue

(s)

is(a

re)

ques

tion

able

due

to

the

bioa

vail

abil

ity

of t

he t

est

subs

tanc

e in

thi

s st

udy

.



FND

Am

ines

Cat

egor

y H

PV C

hem

ical

Cha

lleng

e D

ecem

ber 2

9, 2

003

Page

37

of 4

7

Tab

le 4

Hum

an H

ealt

h-R

elat

ed D

ata

for

FN

D A

min

es C

ateg

ory

Che

mic

als

Acu

te

Acu

te

Rep

eate

d D

ose

Tox

icit

y to

A

cute

Ora

l In

hala

tion

D

erm

al

Tox

icit

y R

epro

duct

ion

Dev

elop

men

tal

CA

S R

N

Tox

icit

y (g

/kg)

T

oxic

ity

(mg/

L)

Tox

icit

y (g

/kg)

N

OA

EL

(m

g/kg

/day

) G

enet

ic T

oxic

ity

In v

itro/

In

vivo

N

OA

EL

(m

g/kg

/day

) T

oxic

ity

NO

AE

L

(mg/

kg/d

ay)

Subc

ateg

ory

I: P

rim

ary

Alk

ylam

ines

and

Alk

yldi

amin

es

124-

22-1

1.

02

1.16

(m

ouse

) >2

.0

143-

27-1

N

egat

ive

(Am

es)

Neg

ativ

e (A

mes

) 68

037-

91-2

>

5.0

6178

8-45

-2*

4.8

>2.

0

124-

30-1

*

~1.0

(r

at a

nd m

ouse

) >

2.0

>2.

0

~25

21

~25

22

3.0

23

Neg

ativ

e (A

mes

) N

egat

ive

(Am

es)

Neg

ativ

e (A

mes

)

~25

21

~25

22

15 23

1.24

(m

ale)

6178

8-46

-3*

1.39

(fem

ale)

>

2.0

(mal

e)

2.82

(fe

mal

e)

2.04

>0.

099

24

>2.

0 >

2.0

ml/

kg

>2.

0 m

l/kg

N

egat

ive

(Am

es)

>6.

0 68

155-

38-4

21 C

hron

ic (

two

-yea

r) d

ieta

ry to

xici

ty s

tudy

in ra

ts.

The

NO

AE

L w

as 5

00 p

pm (h

ighe

st d

ose

test

ed) e

stim

ated

to b

e ap

prox

imat

ely

25 m

g/kg

/day

. R

epro

duct

ive

orga

ns w

ere

exam

ined

, mee

ting

the

requ

irem

ents

for

SID

S/H

PV

rep

rodu

ctiv

e sc

reen

ing.

22

Chr

onic

(tw

o-y

ear)

die

tary

toxi

city

stu

dy in

rat

s. R

epro

duct

ive

orga

ns w

ere

exam

ined

, mee

ting

the

requ

irem

ents

for

SID

S/H

PV

rep

rodu

ctiv

e sc

reen

ing.

23

Chr

onic

(on

e-ye

ar)

oral

(ca

psul

e) to

xici

ty s

tudy

in d

ogs.

Rep

rodu

ctiv

e or

gans

wer

e ex

amin

ed, m

eeti

ng th

e re

quir

eme

nts

for

SID

S/H

PV

rep

rodu

ctiv

e sc

reen

ing.

24

Exp

osur

e pe

riod

= 1

hou

r



FND

Am

ines

Cat

egor

y H

PV C

hem

ical

Cha

lleng

e D

ecem

ber 2

9, 2

003

Page

38

of 4

7

Tab

le 4

Hum

an H

ealt

h-R

elat

ed D

ata

for

FN

D A

min

es C

ateg

ory

Che

mic

als

Acu

te

Acu

te

Rep

eate

d D

ose

Tox

icit

y to

A

cute

Ora

l In

hala

tion

D

erm

al

Tox

icit

y R

epro

duct

ion

Dev

elop

men

tal

CA

S R

N

Tox

icit

y (g

/kg)

T

oxic

ity

(mg/

L)

Tox

icit

y (g

/kg)

N

OA

EL

(m

g/kg

/day

) G

enet

ic T

oxic

ity

In v

itro/

In

vivo

N

OA

EL

(m

g/kg

/day

) T

oxic

ity

NO

AE

L

(mg/

kg/d

ay)

6179

0-33

-8*

>2.

50 (m

ale)

>

2.00

(fem

ale)

; 2.

23 m

l/kg

(mal

e)

2.61

ml/k

g (fe

mal

e)

12.5

25

Neg

ativ

e (A

mes

) N

egat

ive

(In

vivo

rat

m

icro

nucl

eus)

Pare

nts

=

12.5

O

ffspr

ing

= 1

2.5

26

Pare

nts =

12.

5 O

ffspr

ing

= 1

2.5

26

6179

0-18

-9

6803

7-95

-6

112-

90-3

* N

egat

ive

(Am

es)

Neg

ativ

e (g

ene

~2.0

(fem

ales

) ~

1.18

(mal

es)

See

Robu

st Su

mm

ary

27

mut

atio

n)

Neg

ativ

e (m

ouse

ly

mph

oma)

N

egat

ive

(chr

om.

aber

ratio

n)

Mat

erna

l = 1

0;

Dev

elop

men

tal =

80

28

Mat

erna

l =3.

0 ;

Dev

elop

men

tal =

30 29

Neg

ativ

e (I

n vi

vo

cyto

gene

tic)

6179

1-55

-7

>5.0

71

73-6

2-8

3151

-59-

5

+ 3

6505

-83-

6 6.

0 30

6.0

31

Par

ents

=6.

0 O

ffspr

ing

=

30.0

32

Mat

erna

l = 6

.0

Dev

elop

men

tal =

30.

0 33

Mat

erna

l LO

AE

L =

1.2

D

evel

opm

enta

l = 3

0.0

34

Mat

erna

l and

O

ffspr

ing

= 3

0.0

35

25 F

our-

wee

k or

al (

gava

ge)

toxi

city

stu

dy in

rat

s.

26 O

EC

D 4

21 o

ral

gava

ge s

tudy

in

rats

.27

A 1

4-da

y de

rmal

tox

icit

y st

udy

in r

ats

wit

h li

mit

ed e

valu

atio

ns;

not

adeq

uate

for

SID

S/H

PV

tes

ting

but

prov

ides

dat

a on

the

irr

itat

ion

of t

he c

hem

ical

fol

low

ing

repe

ated

exp

osur

e.

28 D

evel

opm

enta

l to

xici

ty s

tudy

in

rats

dos

ed v

ia o

ral

gava

ge a

t do

ses

of 0

, 10,

40

and

80 m

g/kg

.29

Dev

elop

men

tal

toxi

city

stu

dy i

n ra

bbit

s do

sed

via

oral

gav

age

at d

oses

o f

0, 3

, 10

and

30 m

g/kg

/day

.30

24-

Mon

th f

eedi

ng s

tudy

in

rats

at

dose

s of

1.2

, 6.0

and

30.

0 m

g/kg

/day

.31

Tw

o-y

ear

stud

y in

dog

s vi

a or

al g

avag

e at

dos

es o

f 1.

2, 6

.0 a

nd 1

2.0

mg/

kg/d

ay.

32 S

egm

ent I

(F

erti

lity

and

Gen

eral

Rep

rodu

ctiv

e P

erfo

rman

ce)

stud

y in

rat

s vi

a or

al g

avag

e at

dos

es o

f 1.

2, 6

.0 a

nd 3

0.0

mg/

kg/d

ay.

33 T

wo

Seg

men

t II

(Ter

atol

ogy)

stu

dies

in r

ats

wer

e co

nduc

ted

at d

oses

of

1.2,

6.0

and

30.

0 m

g/kg

/day

. D

ecre

ases

in m

ater

nal b

ody

wei

ght g

ains

at 3

0.0

mg/

kg/d

ay in

the

conf

irm

ator

y st

udy.

34

Seg

men

t II

(T

erat

olog

y) s

tudy

in

rabb

its

at d

oses

of

1.2,

6.0

and

30.

0 m

g/kg

/day

. M

ater

nal

body

wei

ght

decr

ease

d at

the

low

dos

e.

35 S

egm

ent I

II (

Per

inat

al a

nd P

ostn

atal

) st

udy

in r

ats

at d

oses

of

1.2,

6.0

and

30.

0 m

g/kg

/day

.



FND

Am

ines

Cat

egor

y H

PV C

hem

ical

Cha

lleng

e D

ecem

ber 2

9, 2

003

Page

39

of 4

7

Tab

le 4

Hum

an H

ealt

h-R

elat

ed D

ata

for

FN

D A

min

es C

ateg

ory

Che

mic

als

Acu

te

Acu

te

Rep

eate

d D

ose

Tox

icit

y to

A

cute

Ora

l In

hala

tion

D

erm

al

Tox

icit

y R

epro

duct

ion

Dev

elop

men

tal

CA

S R

N

Tox

icit

y (g

/kg)

T

oxic

ity

(mg/

L)

Tox

icit

y (g

/kg)

N

OA

EL

(m

g/kg

/day

) G

enet

ic T

oxic

ity

In v

itro/

In

vivo

N

OA

EL

(m

g/kg

/day

) T

oxic

ity

NO

AE

L

(mg/

kg/d

ay)

Subc

ateg

ory

II:

Dim

ethy

lalk

ylam

ines

1.

22

Neg

ativ

e (I

n vi

vo

112-

18-5

0.

79

~5.0

m

ouse

>

1.26

and

<2.

52

mic

ronu

cleu

s)

112-

75-4

2.

116

1.32

N

egat

ive

(Am

es)

36

112-

69-6

0.

80 37

>2.0

4.

29 37

N

egat

ive

(Am

es)

36

1.01

5

124-

28-7

0.

78 37

2.11

6 4.

29 37

N

egat

ive

(Am

es)

36

6178

8-93

-0

1.50

(m

ale)

1.

30 (

fem

ale)

; >

1.0

and

<1.

25

1.58

37

4.29

37

6178

8-95

-2

>2.0

61

788-

91-8

0.

835

37

3.0

37

2806

1-69

-0

4088

-22-

6 >2

.0

>5.0

>2

.0

LO

AE

L =

130

38

LO

AE

L =

100

39

LO

AE

L =

50

40

LO

AE

L =

50

41

Neg

ativ

e (A

mes

) L

OA

EL

= 1

30 38

LO

AE

L =

50

41

Mat

erna

l = 5

0 D

evel

opm

enta

l = 2

50

6178

8-62

-3

>2.

0

36 E

valu

atio

n w

ith

only

tw

o te

ster

s tr

ains

.37

Val

ue is

ml/

kg.

38 1

3-w

eek

diet

ary

toxi

city

stu

dy in

rat

s. R

epro

duct

ive

orga

ns w

ere

exam

ined

, mee

ting

the

requ

irem

ents

for

SID

S/H

PV

rep

rodu

ctiv

e sc

reen

ing.

39

4-w

eek

gava

ge r

ange

-fin

ding

stu

dy (

deve

lopm

enta

l tox

icit

y) in

rab

bits

40

7-d

ay d

erm

al r

ange

fin

ding

stu

dy in

rab

bits

; L

OA

EL

det

erm

ined

by

skin

irri

tati

on

41 1

3-w

eek

derm

al s

tudy

in r

abbi

ts (

5 an

d 50

mg/

kg/d

ay).

LO

AE

L f

or r

epea

ted

dose

toxi

city

det

erm

ined

by

skin

irri

tati

on R

epro

duct

ive

orga

ns w

ere

exam

ined

, mee

ting

the

requ

irem

ents

for

S

IDS

/HP

V r

epro

duct

ive

scre

enin

g.



FND

Am

ines

Cat

egor

y H

PV C

hem

ical

Cha

lleng

e D

ecem

ber 2

9, 2

003

Page

40

of 4

7

Tab

le 4

Hum

an H

ealt

h-R

elat

ed D

ata

for

FN

D A

min

es C

ateg

ory

Che

mic

als

CA

S R

N

Acu

te O

ral

Tox

icit

y (g

/kg)

Acu

te

Inha

lati

on

Tox

icit

y (m

g/L

)

Acu

te

Der

ma l

T

oxic

ity

(g/k

g)

Rep

eate

d D

ose

Tox

icit

y N

OA

EL

(m

g/kg

/day

) G

enet

ic T

oxic

ity

In v

itro/

In

vivo

Tox

icit

y to

R

epro

duct

ion

NO

AE

L

(mg/

kg/d

ay)

Dev

elop

men

tal

Tox

icit

y N

OA

EL

(m

g/kg

/day

) Su

bcat

egor

y II

I: D

ialk

ylm

ethy

lam

ines

and

Dia

lkyl

amin

es

7396

-58-

9 67

700-

99-6

68

153-

95-7

6178

8-63

-4

>5.0

>1

5.0

Neg

ativ

e (A

mes

) N

egat

ive

(Mou

se

Lym

phom

a)

Neg

ativ

e ( i

n vi

tro

UD

S)

Neg

ativ

e (i

n vi

vo

Cyt

ogen

etic

s)

6178

9-79

-5

>10

.0 (

mal

es)

6178

9-76

-2

6878

3-24

-4



FND

Am

ines

Cat

egor

y H

PV C

hem

ical

Cha

lleng

e D

ecem

ber 2

9, 2

003

Page

41

of 4

7

Tab

le 4

H

uman

Hea

lth-

Rel

ated

Dat

a fo

r F

ND

Am

ines

Cat

egor

y C

hem

ical

s

Subc

ateg

ory

IV:

Tri

alky

lam

ines

68

814-

95-9

61

790-

42-9

61

791-

31-9

>5

.0

Neg

ativ

e (A

mes

) –

3 t

ests

; N

egat

ive

(Mou

se

6179

1-44

-4

1.50

(m

ale)

1.

20 (

fem

ale)

>2.0

0.

89

0.63

1.

15

>15.

0

See

Rob

ust

Sum

mar

y 42

>2.0

ml/k

g >2

.0

<2.

0 m

l/kg

43

>1.

5

~50

44

13 45

12 46

40 47

10 48

10 49

40/2

00 50

Lym

phom

a)

Neg

ativ

e w

itho

ut

met

abol

ic a

ctiv

atio

n,

Pos

itiv

e w

ith

met

abol

ic

acti

vati

on (

in v

itro

Chr

omos

omal

A

berr

atio

n);

Neg

ativ

e (i

n vi

tro

UD

S);

Neg

ativ

e (i

n vi

vo M

ouse

~450

44

120

45

400

46

Mic

ronu

cleu

s);

Neg

ativ

e (i

n vi

vo

Cyt

ogen

etic

s)

42 A

4-h

our

expo

sure

stu

dy w

as c

ondu

cted

tha

t do

es n

ot a

dequ

atel

y de

fine

the

LC

50 f

or t

he c

hem

ical

. T

he s

tudy

pro

vide

s ad

diti

onal

dat

a on

the

pot

enti

al i

nhal

atio

n ha

zard

.43

Fou

r of

6 a

nim

als

died

fol

low

ing

a 24

-hou

r ex

posu

re to

2.0

ml/

kg

44 9

0-da

y di

etar

y to

xici

ty s

tudy

in r

ats.

NO

AE

L f

or r

epea

ted

dose

toxi

city

was

500

ppm

in th

e di

et e

stim

ated

to b

e ap

prox

imat

ely

50 m

g/kg

/day

. R

epro

duct

ive

orga

ns w

ere

exam

ined

, mee

ting

the

re

quir

emen

ts f

or S

IDS

/HP

V r

epro

duct

ive

scre

enin

g. N

OE

L f

or r

epro

duct

ive

toxi

city

was

450

0 pp

m in

the

diet

est

imat

ed to

be

appr

oxim

atel

y 45

0 m

g/kg

/day

. 45

90-

day

diet

ary

toxi

city

stu

dy in

dog

s. D

oses

of

40 a

nd 1

20 m

g/kg

/day

wer

e po

orly

tole

rate

d w

ith

exte

nsiv

e em

esis

. R

epro

duct

ive

orga

ns w

ere

exam

ined

, mee

ting

the r

equi

rem

ents

for S

IDS/

HPV

re

prod

ucti

ve s

cree

ning

. 46

13-

wee

k di

etar

y st

udy

in r

ats.

Rep

rodu

ctiv

e or

gans

wer

e ex

amin

ed, m

eeti

ng t

he r

equi

rem

ents

for

SID

S/H

PV

rep

rodu

ctiv

e sc

reen

ing.

47

28-

day

derm

al s

tudy

in

rabb

its

(onl

y on

e do

se t

este

d; n

o sy

stem

ic to

xici

ty;

skin

irri

tati

on o

bser

ved)

48 4

-wee

k de

rmal

stu

dy i

n ra

bbit

s (t

wo

dose

s te

sted

; n

o sy

stem

ic t

oxic

ity;

ski

n ir

rita

tion

obs

erve

d fo

r bo

th t

he 2

and

10

mg/

kg/d

ay g

roup

s)

49 1

7-da

y de

rmal

exp

osur

e fo

llow

ed b

y ap

prox

imat

ely

10 w

eeks

of

exam

inat

ion

(stu

dy t

erm

inat

ed d

ue t

o ir

rita

tion

of

the

2 an

d 10

mg/

kg/d

ay d

oses

) 50

28-

day

derm

al s

tudy

in r

abbi

ts (

200

mg/

kg/d

ay f

or tw

o da

ys r

educ

ed to

40

mg/

kg/d

ay).

Onl

y sk

in ir

rita

tion

con

side

red

to b

e tr

eatm

ent r

elat

ed.

Not

e:

Sha

ded

cell

s w

ith

CA

S R

N a

nd d

ata

in it

alic

s ar

e fo

r su

ppor

ting

che

mic

als

[non

-HPV

]. E

mpt

y bl

ock

deno

tes d

ata

eith

er a

re n

ot a

vaila

ble

or a

re a

vaila

ble

and

judg

ed in

adeq

uate

. *

The

se c

hem

ical

s w

ere

rem

oved

fro

m t

he o

rigi

nal

FN

D A

min

es C

ateg

ory

beca

use

they

are

spo

nsor

ed b

y A

PA

G u

nder

the

ICC

A p

rogr

am.



FND

Am

ines

Cat

egor

y H

PV C

hem

ical

Cha

lleng

e D

ecem

ber 2

9, 2

003

Page

42

of 4

7

Tab

le 5

Pro

pose

d T

est P

lan

for

Am

eric

an C

hem

istr

y C

ounc

il F

ND

Am

ines

Cat

egor

y P

hysi

cal/C

hem

ical

Pro

pert

ies

CA

S R

N

Mel

ting

Poi

nt

(��C

) B

oilin

g P

oint

(��

C)

Vap

or P

ress

ure

(hP

a)

Par

titi

on

Coe

ffic

ient

(l

og K

ow)

Wat

er S

olub

ility

(m

g/L

)

Subc

ateg

ory

I: P

rim

ary

Alk

ylam

ines

and

Alk

yldi

amin

es

124-

22-1

A

(M

) A

(M

) M

M

A

(M

) 14

3-27

-1

M

M

M

M

M

6803

7-91

-2

R

R

R

R

R

6178

8-45

-2*

A (

M)

A (

M)

A (

M)

M

M

124-

30-1

* A

(M

) A

(M

) A

(M

) M

A

(M

) 61

788-

46-3

* R

R

R

R

R

68

155-

38-4

R

R

R

R

R

61

790-

33-8

* A

A

A

A

A

61

790-

18-9

R

R

R

R

R

68

037-

95-6

R

R

R

R

R

11

2-90

-3*

A (

M)

A (

M)

A (

M)

A (

M)

A (

M)

6179

1-55

-7

R

R

R

R

R

7173

-62-

8 M

M

M

M

M

31

51-5

9-5

+ 3

6505

-83-

6 R

R

R

R

R

Subc

ateg

ory

II:

Dim

ethy

lalk

ylam

ines

11

2-18

-5

A (

M)

M

M

M

M

112-

75-4

M

M

M

M

M

11

2-69

-6

M

M

M

M

M

124-

28-7

A

(M

) M

M

M

A

(M

) 61

788-

93-0

R

R

R

R

R

61

788-

95-2

R

R

R

R

R

61

788-

91-8

R

R

R

R

R

28

061-

69-0

M

M

M

M

M



FND

Am

ines

Cat

egor

y H

PV C

hem

ical

Cha

lleng

e D

ecem

ber 2

9, 2

003

Page

43

of 4

7

Tab

le 5

Pro

pose

d T

est P

lan

for

Am

eric

an C

hem

istr

y C

ounc

il F

ND

Am

ines

Cat

egor

y P

hysi

cal/C

hem

ical

Pro

pert

ies

CA

S R

N

Mel

ting

Poi

nt

(��C

) B

oilin

g P

oint

(��

C)

Vap

or P

ress

ure

(hP

a)

Par

titi

on

Coe

ffic

ient

(l

og K

ow)

Wat

er S

olub

ility

(m

g/L

)

Subc

ateg

ory

III:

Dia

lkyl

met

hyla

min

es a

nd D

ialk

ylam

ines

73

96-5

8-9

R

R

R

R

R

6770

0-99

-6

R

R

R

R

R

6815

3-95

-7

R

R

R

R

R

4088

-22-

6 M

M

M

M

M

61

788-

62-3

R

R

R

R

R

61

788-

63-4

R

R

R

A

A

61

789-

79-5

R

R

R

R

R

61

789-

76-2

R

R

R

R

R

68

783-

24-4

R

R

R

R

R

Subc

ateg

ory

IV:

Tri

alky

lam

ines

68

814-

95-9

R

R

R

R

R

61

790-

42-9

R

R

R

R

R

61

791-

31-9

R

R

R

R

R

61

791-

44-4

R

R

R

R

R

N

ote:

Sha

ded

cell

s w

ith

CA

S R

N a

nd d

ata

in i

tali

cs a

re f

or s

uppo

rtin

g ch

emic

als

[non

-HPV

]. A

= A

dequ

ate

repo

rted

val

ues

M =

Ade

quat

e m

odel

dat

a av

aila

ble

R =

Rea

d ac

ross

fro

m a

vail

able

dat

a an

d/or

exp

erim

enta

l det

erm

inat

ion

is c

onsi

dere

d in

appr

opri

ate.

*

The

se c

hem

ical

s w

ere

rem

oved

fro

m t

he o

rigi

nal

FN

D A

min

es C

ateg

ory

beca

use

they

are

spo

nsor

ed b

y A

PA

G u

nder

the

IC

CA

pro

gram

.



FND

Am

ines

Cat

egor

y H

PV C

hem

ical

Cha

lleng

e D

ecem

ber 2

9, 2

003

Page

44

of 4

7

Tab

le 6

Pro

pose

d T

est P

lan

for

Am

eric

an C

hem

istr

y C

ounc

il F

ND

Am

ines

Cat

egor

y E

nvir

onm

enta

l Fat

e an

d E

coto

xici

ty

Acu

te/P

rolo

nged

A

cute

/Chr

onic

T

oxic

ity

to

Pho

tode

grad

atio

n (c

m3 /m

olec

ule

-sec

St

abili

ty

in

Tra

nspo

rt &

T

oxic

ity

to F

ish

96

-hou

r L

C50

Tox

icit

y to

In

vert

ebra

tes

Aqu

atic

Pla

nts

72-h

r. E

C50

CA

S R

N

for

k ph

ot)

Wat

er

Dis

trib

utio

n B

iode

grad

atio

n (m

g/L

) E

C50

(m

g/L

) (m

g/L

)

Subc

ateg

ory

I: P

rim

ary

Alk

ylam

ines

and

Alk

yldi

amin

es

124-

22-1

M

N

C

M

A

A (

M)

M

M

143-

27-1

M

N

C

M

R

M

M

M

6803

7-91

-2

R

R

R

R

R

R

R

6178

8-45

-2*

M

NC

M

A

A

(M

) A

(M

) A

(M

) 12

4-30

-1*

M

NC

M

A

M

A

(M

) A

(M

) 61

788-

46-3

* R

R

R

A

A

A

A

68

155-

38-4

R

R

R

R

R

R

R

61

790-

33-8

* R

R

R

A

A

A

A

61

790-

18-9

R

R

R

R

R

R

R

68

037-

95-6

R

R

R

R

R

R

R

11

2-90

-3*

M

NC

M

A

A

(M

) A

(M

) A

(M

) 61

791-

55-7

R

R

R

A

R

R

R

71

73-6

2-8

M

NC

M

R

M

M

M

31

51-5

9-5

+ 3

6505

-83-

6 R

R

R

R

R

R

R

Subc

ateg

ory

II:

Dim

ethy

lalk

ylam

ines

11

2-18

-5

M

NC

M

A

A

(M

) A

(M

) A

(M

) 11

2-75

-4

M

NC

M

A

A

(M

) M

M

11

2-69

-6

M

NC

M

A

A

(M

) M

M

12

4-28

-7

M

NC

M

A

A

(M

) A

(M

) A

(M

) 61

788-

93-0

R

R

R

A

A

R

R

61

788-

95-2

R

R

R

A

R

R

R

61

788-

91-8

R

R

R

A

A

R

R

28

061-

69-0

M

N

C

M

A

M

M

M



FND

Am

ines

Cat

egor

y H

PV C

hem

ical

Cha

lleng

e D

ecem

ber 2

9, 2

003

Page

45

of 4

7

Tab

le 6

Pro

pose

d T

est P

lan

for

Am

eric

an C

hem

istr

y C

ounc

il F

ND

Am

ines

Cat

egor

y E

nvir

onm

enta

l Fat

e an

d E

coto

xici

ty

CA

S R

N

Pho

tode

grad

atio

n (c

m3 /m

olec

ule

-sec

fo

r k p

hot

)

Stab

ility

in

W

ater

T

rans

port

&

Dis

trib

utio

n B

iode

grad

atio

n

Acu

te/P

rolo

nged

T

oxic

ity

to F

ish

96

-hou

r L

C50

(mg/

L)

Acu

te/C

hron

ic

Tox

icit

y to

In

vert

ebra

tes

EC

50 (

mg/

L)

Tox

icit

y to

A

quat

ic P

lant

s 72

-hr.

EC

50

(mg/

L)

Subc

ateg

ory

III:

Dia

lkyl

met

hyla

min

es a

nd D

ialk

ylam

ines

73

96-5

8-9

R

R

R

R

R

R

R

6770

0-99

-6

R

R

R

R

R

R

R

6815

3-95

-7

R

R

R

R

R

R

R

4088

-22-

6 M

N

C

M

R

A (

M)

M

M

6178

8-62

-3

R

R

R

A

A

R

R

6178

8-63

-4

R

R

R

A

A

A

A

6178

9-79

-5

R

R

R

A

A

R

R

6178

9-76

-2

R

R

R

A

R

R

R

6878

3-24

-4

R

R

R

R

R

R

R

Subc

ateg

ory

IV:

Tri

alky

lam

ines

68

814-

95-9

R

R

R

R

R

R

R

61

790-

42-9

R

R

R

R

R

R

R

61

791-

31-9

R

R

R

A

A

A

R

61

791-

44-4

R

R

R

A

R

R

R

N

ote:

Sha

ded

cell

s w

ith

CA

S R

N a

nd d

ata

in i

tali

cs a

re f

or s

uppo

rtin

g ch

emic

als

[non

-HPV

].

A =

Ade

quat

e re

port

ed v

alue

s M

= A

dequ

ate

mod

el d

ata

avai

labl

e R

= R

ead

acro

ss f

rom

ava

ilab

le d

ata

and/

or e

xper

imen

tal

dete

rmin

atio

n is

con

side

red

inap

prop

riat

e.

NC

= M

odel

cou

ld n

ot c

alcu

late

a v

alue

. *

The

se c

hem

ical

s w

ere

rem

oved

fro

m t

he o

rigi

nal

FN

D A

min

es C

ateg

ory

beca

use

they

are

spo

nsor

ed b

y A

PA

G u

nder

the

IC

CA

pro

gram

.



FND

Am

ines

Cat

egor

y H

PV C

hem

ical

Cha

lleng

e D

ecem

ber 2

9, 2

003

Page

46

of 4

7

Tab

le 7

P

ropo

sed

Tes

t Pla

n fo

r A

mer

ican

Che

mis

try

Cou

ncil

FN

D A

min

es C

ateg

ory

Hum

an H

ealt

h-R

elat

ed D

ata

Tox

icit

y to

D

evel

opm

enta

l A

cute

Ora

l A

cute

Inh

alat

ion

Acu

te D

erm

al

Rep

eate

d D

ose

Rep

rodu

ctio

n T

oxic

ity

CA

S R

N

Tox

icit

y (g

/kg)

T

oxic

ity

(mg/

L)

Tox

icit

y (g

/kg)

T

oxic

ity

NO

AE

L

(mg/

kg/d

ay)

Gen

etic

Tox

icit

y In

vitr

o/ I

n vi

vo

NO

AE

L

(mg/

kg/d

ay)

NO

AE

L

(mg/

kg/d

ay)

Subc

ateg

ory

I: P

rim

ary

Alk

ylam

ines

and

Alk

yldi

amin

es

124-

22-1

A

R

R

R

R

R

R

14

3-27

-1

R

R

R

R

A (

Am

es)

R

R

6803

7-91

-2

R

R

R

R

R

R

R

6178

8-45

-2*

A

R

R

R

R

R

R

124-

30-1

* A

R

R

A

A

(A

mes

) A

R

61

788-

46-3

* A

A

A

R

A

(A

mes

) R

R

68

155-

38-4

R

R

R

R

R

R

R

61

790-

33-8

* A

R

R

A

A

(Bot

h)

A

A

6179

0-18

-9

R

R

R

R

R

R

R

6803

7-95

-6

R

R

R

R

R

R

R

112-

90-3

* A

R

R

R

A

(Bot

h)

R

A

6179

1-55

-7

A

R

R

R

R

R

R

7173

-62-

8 R

R

R

R

R

R

R

31

51-5

9-5

+ 3

6505

-83-

6 R

R

R

A

R

A

A

Subc

ateg

ory

II:

Dim

ethy

lalk

ylam

ines

11

2-18

-5

A

R

A

R

A (C

yto)

R

R

11

2-75

-4

A

R

R

R

A 51

R

R

11

2-69

-6

A

R

A

R

A 5

1 R

R

12

4-28

-7

A

R

A

R

A 5

1 R

R

61

788-

93-0

A

R

A

R

R

R

R

61

788-

95-2

A

R

R

R

R

R

R

61

788-

91-8

A

R

A

R

R

R

R

28

061-

69-0

R

R

R

R

R

R

R

51 S

alm

onel

la R

ever

se M

utat

ion

Ass

ay i

n tw

o es

ters

str

ains

was

neg

ativ

e.



FND

Am

ines

Cat

egor

y H

PV C

hem

ical

Cha

lleng

e D

ecem

ber 2

9, 2

003

Page

47

of 4

7

Tab

le 7

P

ropo

sed

Tes

t Pla

n fo

r A

mer

ican

Che

mis

try

Cou

ncil

FN

D A

min

es C

ateg

ory

Hum

an H

ealt

h-R

elat

ed D

ata

CA

S R

N

Acu

te O

ral

Tox

icit

y (g

/kg)

Acu

te I

nhal

atio

n T

oxic

ity

(mg/

L)

Acu

te D

erm

al

Tox

icit

y (g

/kg)

Rep

eate

d D

ose

Tox

icit

y N

OA

EL

(m

g/kg

/day

) G

enet

ic T

oxic

ity

In v

itro/

In

vivo

Tox

icit

y to

R

epro

duct

ion

NO

AE

L

(mg/

kg/d

ay)

Dev

elop

men

tal

Tox

icit

y N

OA

EL

(m

g/kg

/day

)

Subc

ateg

ory

III:

Dia

lkyl

met

hyla

min

es a

nd D

ialk

ylam

ines

73

96-5

8-9

R

R

R

R

R

R

R

6770

0-99

-6

R

R

R

R

R

R

R

6815

3-95

-7

R

R

R

R

R

R

R

4088

-22-

6 A

R

A

A

A

(A

mes

) A

A

61

788-

62-3

A

R

R

R

R

R

R

61

788-

63-4

A

R

R

R

A

(B

oth

) R

R

61

789-

79-5

A

R

R

R

R

R

R

61

789-

76-2

R

R

R

R

R

R

R

68

783-

24-4

R

R

R

R

R

R

R

Subc

ateg

ory

IV:

Tri

alky

lam

ines

68

814-

95-9

R

R

R

R

R

R

R

61

790-

42-9

R

R

R

R

R

R

R

61

791-

31-9

A

R

R

R

R

R

R

61

791-

44-4

A

R

A

A

A

A

R

N

ote:

Sha

ded

cell

s w

ith

CA

S R

N a

nd d

ata

in i

tali

cs a

re f

or s

uppo

rtin

g ch

emic

als

[non

-HPV

].

Rel

iabl

e da

ta f

or a

cute

tox

icit

y by

any

of

the

thre

e ro

utes

of

expo

sure

are

con

side

red

adeq

uate

und

er t

he E

PA

HP

V C

hall

enge

Pro

gram

. A

= A

dequ

ate

reli

able

dat

a R

= E

ndpo

int f

ulfi

lled

by

cate

gory

rea

d-ac

ross

fro

m e

xist

ing

or p

ropo

sed

test

dat

a.

* T

hese

che

mic

als

wer

e re

mov

ed f

rom

the

ori

gina

l F

ND

Am

ines

Cat

egor

y be

caus

e th

ey a

re s

pons

ored

by

AP

AG

und

er t

he I

CC

A p

rogr

am.



Alky Amine Polyalkoxylates Human Health Risk Assessment

Page 2 of 94

Table of Contents

1.0 Executive Summary ................................................................................................ 4 Regulatory Recommendation.......................................................................................... 6

2.0 Background............................................................................................................. 7 3.0 Ingredient Profile .................................................................................................... 8

3.1 Summary of Proposed Uses ................................................................................ 8 3.2 Structural Information......................................................................................... 8 3.3 Physical and Chemical Properties....................................................................... 9

4.0 Hazard Characterization/Assessment.................................................................... 10

4.1 Hazard and Dose-Response Characterization................................................... 10 4.1.1 Database Summary ................................................................................... 10 4.1.2 Toxicological Effects and Metabolism ..................................................... 11

4.2 Dose Response Assessment .............................................................................. 12 4.2.1 Acute Reference Dose (aRfD) – All Populations ..................................... 13 4.2.2 Chronic Reference Dose (cRfD)............................................................... 13 4.2.3 Incidental Oral (Short-Term and Intermediate-Term), Dermal (All Durations) and Inhalation (All Durations)................................................................ 14 4.2.4 Dermal Absorption.................................................................................... 14

4.3 FQPA Considerations ....................................................................................... 14 4.4 Classification of Carcinogenic Potential........................................................... 15 4.5 Hazard Identification and Toxicity Endpoint Selection.................................... 16 4.6 Endocrine Disruption ........................................................................................ 17

5.0 Dietary Exposure/Risk Characterization............................................................... 17

5.1 Residues of Concern ......................................................................................... 17 5.2 Drinking Water Residue Profile........................................................................ 18 5.3 Food Residue Profile......................................................................................... 18 5.4 Analytical Methodology ................................................................................... 19 5.5 Dietary (Food and Water) Exposure and Risk.................................................. 19

5.5.1. Acute Dietary Exposure and Risk............................................................. 20 5.5.2 Chronic Dietary Exposure and Risk ......................................................... 21 5.5.3 Cancer Dietary Exposure and Risk ........................................................... 21 5.5.4. Summary of Dietary Exposure and Risk Assessment Results.................. 22

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ....................... 22

6.1 Residential Handler Exposure........................................................................... 22 6.2. Residential Postapplication Exposure............................................................... 26

7.0 Aggregate Risk Assessments and Risk Characterization...................................... 29

7.1 Acute Aggregate Risk ....................................................................................... 29 7.2 Short-Term/Intermediate-Term Aggregate Risk............................................... 29 7.3 Long-Term Aggregate Risk .............................................................................. 30




Page 3 of 94

7.4 Cancer Risk....................................................................................................... 31 8.0 Occupational Exposure/Risk Pathway.................................................................. 31

8.1 Handler Risk ..................................................................................................... 31 8.2 Occupational Postapplication Risk ................................................................... 45

9.0 Environmental Justice........................................................................................... 50 10.0 Human Studies ...................................................................................................... 51 APPENDIX A................................................................................................................... 52

A.1 Acute Toxicity Profile for Alkyl Amine Polyalkoxylates ................................ 52 A.2. Toxicity Profile for the Alkyl Amine Polyalkoxylates ..................................... 55 A.3. Toxicity Study Executive Summaries............................................................... 58

APPENDIX B ................................................................................................................... 68

B.1. Structure-Activity Relationship (SAR) Discussion .......................................... 68 APPENDIX C ................................................................................................................... 70

C.1. Drinking Water Surrogate Analysis.................................................................. 70 APPENDIX D................................................................................................................... 73

D.1. Listing of the Surrogate Active Ingredients...................................................... 73 APPENDIX E ................................................................................................................... 74

E.1. Residential Exposure Assessment Introduction................................................ 74 E2. Residential Handler/Applicator Exposures ...................................................... 75 E3. Residential Postapplication Exposures............................................................. 80

APPENDIX F.................................................................................................................... 85

F.1. Occupational Exposure Assessment Introduction ............................................ 85 F2. Occupational Handler/Applicator Exposures ................................................... 86 F3. Occupational Postapplication Exposures.......................................................... 93




Page 4 of 94

1.0 Executive Summary The Joint Inert Task Force (JITF) Cluster Support Team Number 4 (CST4) has submitted a petition proposing to establish exemptions from the requirement of a tolerance for the following clusters of compounds when used as inert ingredients in pesticide formulations.

N,N-Bis-[alpha]-ethyl-[omega]-hydroxypoly(oxy-1,2-ethanediyl) C8-C18 saturated and unsaturated alkylamines; the poly(oxy-1,2-ethanediyl) content is 2 – 60 moles.

N,N-Bis-[alpha]-ethyl-[omega]-hydroxypoly(oxy-1,2-ethanediyl/oxy(methyl-1,2-ethanediyl) C8-C18 saturated and unsaturated alkylamines; the poly(oxy-1,2-ethanediyl/oxy(methyl-1,2-ethanediyl) content is 2 – 60 moles.

The compounds, referred to as alkyl amine polyalkoxylates (AAPs), are not discrete compounds, but are a mixture of compounds formed from the reaction of fatty acid derived amines with either ethylene oxide or propylene oxide. The AAPs are used primarily as surfactants in pesticide formulations. The petitioner is proposing to limit the maximum amount of the inert in any end-use product to no more than 10% in fungicide and insecticide products and no more than 25% in herbicide formulations. The toxicology database is adequate to support the use of the alkyl amine polyalkoxylates when used as inert ingredients. The AAPs are not acutely toxic by the oral and dermal routes of exposure, or via inhalation under normal use conditions. Concentrated materials are generally corrosive, eye and skin irritants and may be dermal sensitizers. There is no evidence that the AAPs are neurotoxic, mutagenic, or clastogenic. There is no clear target organ identified across the AAPs. Following subchronic exposure to rats, some gastrointestinal irritation was observed, but no specific target organ toxicity or neurotoxicity was seen. In subchronic studies in rats and/or dogs, the most sensitive effects noted were increased mortality, clinical signs (salivation, wheezing, emesis, and/or soft feces), cataracts, cellular changes in the stomach, and liver effects characterized by enzyme induction, and pigment accumulation in Kupffer cells and bile canaliculi. There was no increased susceptibility to the offspring of rats following in utero exposure in two prenatal developmental toxicity studies. However, there is evidence of increased susceptibility in a reproductive screening study in rats. The points of departure (PoDs) selected for the dietary assessments are lower than the doses at which offspring toxicity occurred in the rat reproduction study and are protective of offspring toxicity occurring at higher doses. There were no residual concerns and the Food Quality Protection Act (FQPA) safety factor was reduced to 1X. Sufficient data were provided on the chemical identify of the AAPs, however, limited data are available on the metabolism and environmental degradation of the AAPs; further, no residue data were provided. The Agency relied collectively on information provided on the representative chemical structures, the generic cluster structures, the submitted physicochemical EPI Suite™ data, structure-activity relationship information,




Page 5 of 94

as well as information on other surfactants and chemicals of similar size and functionality to determine the residues of concern for this group of inert ingredients. In the absence of data, the Agency has developed an approach that uses surrogate information to derive upper bound exposure estimates for the subject inert ingredients. Acute and chronic dietary risk assessments, which assumed no more than 10% AAP in the final formulation for fungicides and insecticides and 25% for herbicides, resulted in dietary risks that were not of concern. The Agency evaluated residential handler and post application risks for high-end residential exposure scenarios. The combined margins of exposure (MOEs) for all the residential handler scenarios were above 100, and therefore, did not demonstrate a risk of concern to the Agency. Short-term and intermediate-term aggregate risks, which combined high end residential exposure with average food and drinking water exposures, were not of concern. Acute and long-term (chronic) aggregate risks that included food and water only, were not of concern. HED has completed an occupational exposure and risk assessment for the AAPs. Since they can be used in a wide range of applications, HED has selected scenarios that are likely to result in high-end exposure. HED traditionally considers a level of concern (LOC) for these risk assessments to be for an MOE of 100 based on the standard 10x inter and 10x intra species extrapolation safety factors. However, HED notes that for the AAPs, the primary toxic effect seen is related to the surfactants inherent function to disrupt cell membranes resulting in irritating properties to tissues. Given that HED does not expect to see a significant difference between species for this type of effect, an LOC lower than 100 may be appropriate for the non-dietary risk assessments. Occupational handler risks are not of concern for all scenarios except for workers using a low pressure handwand applying pesticides containing the AAPs to ornamentals in greenhouse settings. HED notes that the occupational handler assessment assumes that mixer/loader/applicators who are handling pesticides containing the AAPs for aerial and ground application on high acreage crops or turf will wear chemical-resistant gloves. HED believes this is a reasonable assumption given the volume of pesticide handled for these applications. Since MOEs for workers applying pesticides to ornamentals in greenhouses containing the AAPs in herbicides at 25%, the requested maximum allowable amount, and in herbicides and insecticides at 10%, do not exceed 100, HED has provided additional exposure and risk estimates reflecting lower percentages in final formulations. HED has provided risk estimates in this document for workers applying pesticides containing AAPs using a low pressure handwand to ornamentals in a green house setting assuming variable amounts of the AAP in herbicide formulations including 25%, 20%, 15%, 10% and 5%. For the insecticide and fungicide assessments, HED has provided estimates assuming variable amounts of the AAP in the formulations including 8%, 6% and 5%. Occupational post application handler risks exceed an MOE of 100 on the day of




Page 6 of 94

application for all scenarios except for postapplication activities involving herbicides and insecticides on corn, specifically the hand-harvesting / detassling scenario. Those scenarios resulted in MOE of 26 and 69, respectively on the day of application (Day 0). The Agency notes that it is not expected to be typical agricultural practice to apply herbicides or insecticides on the same day workers would be conducting hand harvesting and detassling activities. Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf). This assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide. These studies have received the appropriate ethical review for use in risk assessment. Regulatory Recommendation There are no human health exposure or risk issues that would preclude the approval of an exemption from the requirement of a tolerance for the inert ingredients generically referred to as alkyl amine polyalkoxylates (AAPs), provided the following limitations are addressed specifically in the exemption statement:

• The maximum percent by weight of the AAPs in fungicide and insecticide products should be limited to no more than 10% with the one exception noted below.

• The maximum percent by weight of the AAPs in herbicide formulations should be limited to no more than 25%, with the one exception noted below.

• The maximum percent by weight of the AAPs in herbicide, fungicide and insecticide formulations intended for application by low pressure handwands to ornamentals in a green house setting may need to be reduced from the petitioner requested caps based on a risk benefit assessment for this scenario.

• HED assumed no indoor uses exist. This should be validated by RD, and restrictions on use of these inerts for indoor-use products should be mandated.

HED has no objection to the expansion of this exemption to include not only AAPs derived from animal and plant sources, but also from AAPs derived from petrochemical sources. The specific limitations noted above should be applied to the two cluster classifications that the petitioner has proposed:

N,N-Bis-[alpha]-ethyl-[omega]-hydroxypoly(oxy-1,2-ethanediyl) C8-C18 saturated and unsaturated alkylamines; the poly(oxy-1,2-ethanediyl) content is 2 – 60 moles



http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf�


Page 7 of 94

N,N-Bis-[alpha]-ethyl-[omega]-hydroxypoly(oxy-1,2-ethanediyl/oxy(methyl-1,2-ethanediyl) C8-C18 saturated and unsaturated alkylamines; the poly(oxy-1,2-ethanediyl/oxy(methyl-1,2-ethanediyl) content is 2 – 60 moles

2.0 Background Inert ingredients are those ingredients that are added to end use products that are not active ingredients. The terms "active ingredient" and "inert ingredient" are defined under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). An active ingredient is one that prevents, destroys, repels or mitigates a pest, or is a plant regulator, defoliant, desiccant or nitrogen stabilizer. The statute defines the term "inert ingredient" as an ingredient that is not active. As mandated by the Food Quality Protection Act (FQPA) of 1996, EPA conducted a reassessment of inert ingredients used in pesticide products to determine if they met the Agency’s current standard of safety. As a result of that reassessment, the Agency published a final rule in the Federal Register (FR Notice Volume 71, No. 153, p. 45422) proposing revocation of specific exemptions from the requirement of a tolerance due to insufficient data. These tolerance exemptions are currently slated to be revoked on August 9, 2009 and included the following exemptions:

180.920 m. N,N-Bis-[alpha]-ethyl-[omega]-hydroxypoly(oxyethylene) alkylamine; the poly(oxyethylene) content averages 3 moles; the alkyl groups (C14-C18) are derived from tallow, or from soybean or cottonseed oil acids. 180.920 n. N,N-Bis (2-hydroxyethyl)alkylamine, where the alkyl groups (C8 – C18) are derived from coconut, cottonseed, soya, or tallow acids. 180.920 o. N,N-Bis 2-([omega]-hydroxypolyoxyethylene) ethyl) alkylamine; the reaction product of 1 mole N,N-bis(2-hydroxyethyl)alkylamine and 3-60 moles of ethylene oxide, where the alkyl group (C8-C18) is derived from coconut, cottonseed, soya or tallow acids. 180.920 p. N,N-Bis 2-([omega]-hydroxypolyoxyethylene/polyoxypropylene) ethyl) alkylamine; the reaction product of 1 mole N,N-bis(2-hydroxyethyl)alkylamine and 3-60 moles of ethylene oxide and propylene oxide, where the alkyl group (C8-C18) is derived from coconut, cottonseed, soya or tallow acids.

The Joint Inert Task Force (JITF) Cluster Support Team Number 4 (CST4) has submitted Petition #8E7382, proposing to consolidate and replace the four exemptions listed above with exemptions for the JITF CST4 inert ingredients known collectively as alkyl amine polyalkoxylates or “AAPs”. The JITF CST4 is proposing to establish the following tolerance exemptions:




Page 8 of 94

N,N-Bis-[alpha]-ethyl-[omega]-hydroxypoly(oxy-1,2-ethanediyl) C8-C18 saturated and unsaturated alkylamines; the poly(oxy-1,2-ethanediyl) content is 2 – 60 moles.

N,N-Bis-[alpha]-ethyl-[omega]-hydroxypoly(oxy-1,2-ethanediyl/oxy(methyl-1,2-ethanediyl) C8-C18 saturated and unsaturated alkylamines; the poly(oxy-1,2-ethanediyl/oxy(methyl-1,2-ethanediyl) content is 2 – 60 moles.

HED notes that while the proposed exemptions do represent a consolidation of the four exemptions slated for revocation, they also expand the previously approved exemptions to include alky amine polyalkoxylates manufactured from the reaction of ethylene oxide and propylene oxide with fatty acids derived from not only animal and plant sources, but also from petrochemical sources. 3.0 Ingredient Profile 3.1 Summary of Proposed Uses Alkyl amine polyalkoxylates are used primarily as surfactants in pesticide formulations. Additionally, the petitioner notes that these mixtures may also be used to a lesser extent as emulsifiers and wetting agents. While the AAPs are inert ingredients in all classes of pesticides, the majority of use reported by the petitioner is in herbicide and fungicide products. The petitioner indicates that currently the concentration of AAPs in formulated products generally does not exceed 25% by weight. The petitioner is proposing to limit the use of AAPs in herbicide formulations to no more than 25% by weight and 10% by weight in all other pesticide formulations. In addition to uses as inerts in pesticide formulations, AAPs have a variety of industrial applications. They appear to have very limited use in consumer or personal care products and the petitioner states that concentrations in potential consumer care products would be at lower concentrations than proposed in pesticide formulations.

3.2 Structural Information The “alkyl amine polyalkoxylates” refers not to a discrete compound, but to mixtures of compounds. Information on the generic structures of these compounds and the manufacturing process to derive these surfactants is summarized in Table 3.2, below.




Page 9 of 94

TABLE 3.2. Alky Amine Polyalkoxylate (AAP) Chemical Information Chemical Structure These surfactants are typically complex mixtures formed from the reaction of fatty

acid derived amines with either ethylene oxide or propylene oxide. The AAP carbon chain is defined in the exemption request as ranging from C8 – C18. The degree of polyalkoxylation is defined in the range of 2 to 60 moles. The generic structures for the alkylamine polyethoxylated compounds (AAP, POE) and alkylamine polypropoxylated (AAP POP) compounds are shown below.1

Common name Alkyl Amine Polyethoxylates (AAPs) Use Class Non ionic surfactants used as inert ingredients in pesticide formulations. May also

be used as emulsifiers and wetting agents. Discussion of Synthesis AAPs are synthesized by reacting fatty acids or petrochemical derived long carbon

chain acids with ammonia at high temperatures to generate long chain fatty acid type carbon amides which are dehydrated to the nitrile and then reduced to a primary fatty acid derived amine. The amine is then reacted with ethyl oxide or ethylene oxide and propylene oxide to form tertiary amine polyalkoxylates (POE or POE/POP). The alkyl amine precursors can be from plants, animals or petrochemicals. 2 The registrant has indicated (personal communication to K. Leifer) that branching consists of methyl groups and not longer branched chains.

1 Figure 1a and 1b excerpted directly from petition, page 8 dated June 19, 2008. 2 Manufacturing process description taken from petition, page 11 dated June 19, 2008. 3.3 Physical and Chemical Properties As noted previously, the AAPs are not discrete chemicals, but are complex mixtures of chemicals. To address the requirement to provide information on physical and chemical properties, the registrant selected four representative compounds and modeled physicochemical data using EPI Suite™ modeling (http://www.epa.gov/opptintr/expsoure/pubs/episuite.htm). Results of the EPI Suite™ modeling as reported by the registrant are summarized in Table 3.3, below.



http://www.epa.gov/opptintr/expsoure/pubs/episuite.htm�


Page 10 of 94

Table 3.3. Physicochemical Properties of Representative Alky Amine Polyalkoxylates1

CAS No. (Company Name)

Molecular Formula (MW) Log KOW

Water Solubility (mg/L)

Henry’s Law Constant

Melting Point (°C)

Vapor Pressure (mm Hg @ 25 °C)

61791-26-2

C48H97NO15 (928.31)

3.15 381.83 4.2 x 10-33 349.84 5.8 x 10-27

61791-31-9 (MON 8109)

C16H35NO2 (273.46)

3.90 299.47 1.94 x 10-9 131.43 1.76 x 10-8

70955-14-5 C18H39NO2 (301.52)

4.96 19.48 4.99 x 10-10 127.14 3.86 x 10-8

68213-26-3 (Armoblend 557)

C64H129NO17 (1184.74)

7.53 6.685 x 10-8 2.37 x 10-34 349.84 3.77 x 10-33

1 Table values taken directly from submission entitled Petition Proposing an Exemption from the Requirement of a Tolerance for Residues of Joint Inerts Task Force Cluster 4 “Alkyl Amines Polyalkoxylates” in or on Raw Agricultural Products and Food Products. Submitted by JITF Cluster Support Team Number 4, 6/19/2008, Table 7, pp 19 – 20. 4.0 Hazard Characterization/Assessment 4.1 Hazard and Dose-Response Characterization 4.1.1 Database Summary The available mammalian toxicology database includes acute, subchronic repeat dose oral, developmental, reproductive, and mutagenicity data for four representative compounds of the alkyl amine polyalkoxylate (AAP) group. The toxic effects seen in the submitted studies include gastrointestinal problems due to local irritation and corrosive effects. The chemicals for which toxicity data were submitted are listed below: ►MON 0818 [CAS 61791-26-2 (tallow); Ave POE n=15] acute oral and dermal, eye and skin irritation, dermal sensitization, Ames, in vivo mouse micronucleus assay, 4-week rat (diet), 3-month rat (diet), OECD 421 2-generation reproduction rat screening (diet), OECD 422 28-day rat reproductive/developmental (diet); ►MON 8109 [CAS 61791-31-9 (coco); Ave POE n=2] acute oral and inhalation, eye and skin irritation studies, OECD 422 28-day rat repeated oral dose (dietary) reproductive/developmental; ►ATMER® 163 [CAS 70955-14-5; C13-C15; ave POE n=2] acute oral, skin irritation, Ames, in vitro human peripheral lymphocyte cytogenic assay, in vitro mouse lymphoma mutation assay, 90 day rat oral (gavage), 90-day dog (capsule). ►Armoblen 557 [CAS 68213-26-3; Ave POE n=5/Ave POP n=12] acute oral and inhalation, eye and skin irritation, Ames, 28-day rat oral (gavage)




Page 11 of 94

The available toxicology data are adequate to support the requested exemption from the requirement of tolerance when used in pesticide formulations for these AAP inert compounds. In a joint meeting of the HED ToxSAC (Toxicology Science Advisory Committee) and the ROCKS (Residues of Concern Knowledge-based Subcommittee), the Agency concluded that the four surrogate chemicals (MON 0818, MON 8109, Atmer 163, and Armoblen 557) are representative of all the chemicals in the AAP cluster. Further, the ToxSAC members agreed that the currently available toxicity dataset is adequate to apply to the cluster and to characterize the potential toxic effects of these surfactants. The ROCKS members noted that there was sufficient bracketing of the range of molecular weights to represent the entire class of AAPs. The available mammalian toxicity database includes acute, subchronic, developmental, reproductive toxicity studies via the oral route as well as mutagenicity data for the four compounds. While there is no chronic toxicity study, the ToxSAC noted that the effects do not increase in severity over time (4 weeks to 13 weeks). Based on the lack of progression of severity of effects with time along with the considerable similarities of effects across the species tested and the observation that the vast majority of the effects observed were related to local irritation and corrosive effects, the ToxSAC concluded that chronic studies would not be required. Moreover, an additional uncertainty factor (UF) for extrapolation from subchronic toxicity study to a chronic exposure scenario would not be needed since the severity of effects did not increase with time and similar effects (related to local irritation) occurred at comparable dose levels across species. As a result, the committee concluded that the typical 100-fold uncertainty factor (10X interspecies and 10X intraspecies) would be adequately protective. The ToxSAC noted that use of the full 10X interspecies factor will actually provide an additional margin of safety because it is not expected that humans’ response to local irritation/corrosiveness effects would be markedly different from animals. 4.1.2 Toxicological Effects and Metabolism Toxicological Effects As previously noted, the AAPs in this inert class cover the range of C8-C18 carbon lengths and polyalkoxylation of n = 2-60. The majority of toxicology information is available for four AAPs, which is meant to represent the entire class of compounds. Details can be found in the JIFT Cluster Support Team Number 4 (2008) submission. Generally, lower molecular weight AAPs (lower carbon chain units and less alkoxylation) may potentially be more bioavailable because they may be more easily absorbed and distributed than higher molecular weight compounds. Thus overall, the longer chain carbon amine higher polyalkoxylates should be less bioavailable. The AAPs are not acutely toxic by the oral and dermal routes of exposure, or via inhalation under normal use conditions (i.e., maximum 25% in pesticide end-use products and non-respirable droplet sizes). Concentrated materials are generally corrosive, eye and skin irritants and may be dermal sensitizers. There is no evidence that the AAPs are mutagenic, or clastogenic.




Page 12 of 94

There is no clear target organ identified across the AAPs. Following subchronic exposure to rats, some gastrointestinal irritation was observed, but no specific target organ toxicity or neurotoxicity was seen. No effects were detected in a functional observational battery (FOB) or motor activity assessment. In a subchronic rat study, the most sensitive effects noted were increased mortality, salivation, wheezing, cataracts, and micro- and macroscopic changes in the non-glandular stomach at doses as low as 30 mg/kg/day. In a subchronic dog study, the most sensitive effects included clinical signs (increased incidence of salivation, emesis, and soft feces) and liver effects characterized by enzyme induction, and pigment accumulation in Kupffer cells and bile canaliculi. In rat developmental studies, no adverse fetal effects were seen, even at maternally toxic doses. No effects were observed on estrous cyclicity, spermatogenic endpoints, or testosterone and thyroid levels in a two-generation rat reproduction study. However, reproductive and offspring toxicity were noted for AAPs (specifically MON 0818 and MON 8109) based on litter loss, increase mean number of unaccounted-for implantation sites and decreased mean number of pups born, live litter size and postnatal survival from birth to LD 4. Surfactants are surface-active materials that can damage the structural integrity of cellular membranes at high dose levels. Thus, surfactants are often corrosive and irritating in concentrated solutions, as indicated by the acute toxicity studies for these inert materials. It is possible that some of the observed toxicity seen in the repeated studies, such as diarrhea or decreased body weight gain, can be attributed to the corrosive and irritating nature of these surfactants. Metabolism Very little metabolism information is available for the alkyl amine polyalkoxylates. However, it is possible to predict mammalian metabolism based on studies for the alkyl alcohol alkoxylates, which are another class of surfactants. It has been proposed that the primary metabolic pathway involves the excretion of the polyalkoxylate moiety and conversion of the alkyl amine group to a fatty acid that is then converted via oxidative degradation to carbon dioxide and water. In general, the gastrointestinal absorption of AAPs with relatively short alkoxylate chain lengths is expected to be rapid and extensive, while less absorption is likely for the more extensively polyalkoxylated AAPs with larger molecular weights. 4.2 Dose Response Assessment The Agency believes the dose-response assessment described herein and used for risk assessment purposes for the AAPs is conservative because the most health protective surrogate chemical was selected to represent the entire AAP class of inert ingredients.




Page 13 of 94

4.2.1 Acute Reference Dose (aRfD) – All Populations Study Selected: developmental toxicity – rat (OPPTS 870.3700) MRID No.: 46902005 Executive Summary: See Appendix A, Guideline §870.3700 Dose and Endpoint for Risk Assessment: NOAEL = 72 mg/kg/day, based on 2 deaths on gestation day (GD) 8 (after 2 doses) at the LOAEL of 216 mg/kg/day. Uncertainty Factor(s): 100X (10 interspecies; 10X intraspecies) Comments about Study/Endpoint/Uncertainty Factors: The rats in this study were administered a test material that contained 71.9% of the inert ingredient to be tested, therefore the doses in this study were adjusted accordingly. The executive summary for the rat developmental toxicity study may be found in Appendix A, Section A.3 of this document. 4.2.2 Chronic Reference Dose (cRfD) Study Selected: 90-day oral toxicity – rat (OPPTS 870.3100) MRID No.: 47041301 Executive Summary: See Appendix A, Guideline §870.3100 Dose and Endpoint for Risk Assessment: NOAEL = 15 mg/kg/day, based on increased mortality, salivation, and posterior subcapsular cataracts in males as well as wheezing, and micro- and macro-scopic changes in the non-glandular stomach of both sexes at the systemic LOAEL of 30 mg/kg/day. Uncertainty Factor(s): 100X (10 interspecies; 10X intraspecies) Comments about Study/Endpoint/Uncertainty Factors: The purity of the test material was not reported in the study, but the Agency confirmed via personal communication that this inert ingredient (ATMER 163) is a nominally 100% pure product. The study provides the lowest NOAEL. Two deaths occurred at 30 mg/kg/day (on days 36 and 78). Although the duration of exposure was 90 days, there is no need for an additional uncertainty factor because the effects do not seem to increase in severity over time (4 weeks to 13 weeks). Based on the lack of progression of severity of effects with time along with the considerable similarities of effects across the species tested and the observation that the vast majority of the effects observed were related to local irritation and corrosive effects, the ToxSAC concluded that an additional UF for extrapolation from subchronic toxicity study to a chronic exposure scenario would not be needed. As a result, the ToxSAC concluded that the typical 100-fold uncertainty factor would be sufficiently protective since it is not expected that humans’ response to local irritation/corrosiveness effects would be markedly different from animals. The executive summary of the subchronic oral toxicity study in rats may be found in Appendix A, Section A.3 of this document.




Page 14 of 94

4.2.3 Incidental Oral (Short-Term and Intermediate-Term), Dermal (All Durations) and Inhalation (All Durations) Study Selected: 90-day oral toxicity – rat (OPPTS 870.3100) MRID No.: 47041301 Executive Summary: See Appendix A, Guideline §870.3100 Dose and Endpoint for Risk Assessment: NOAEL = 15 mg/kg/day, based on increased mortality, salivation, and posterior subcapsular cataracts in males as well as wheezing, and micro- and macroscopic changes in the non-glandular stomach of both sexes at the systemic LOAEL of 30 mg/kg/day. Uncertainty Factor(s): 100X (10 interspecies; 10X intraspecies) Comments about Study/Endpoint/Uncertainty Factors: The study provides the lowest NOAEL. Two deaths occurred at 30 mg/kg/day (days 36 and 78). Although the duration of exposure was 90 days, there is no need for an additional uncertainty factor for risk assessments reflecting longer exposure durations because the effects do not seem to increase in severity over time (4 weeks to 13 weeks). The executive summary of the subchronic oral toxicity study in rats may be found in Appendix A, Section A.3 of this document. A dermal absorption factor of 5% is recommended (see section 4.2.5). Since no inhalation absorption data are available for the surrogate chemicals, toxicity by the inhalation route was considered to be equivalent to toxicity by the oral route of exposure. 4.2.4 Dermal Absorption There are no dermal absorption data on the AAPs. However, data on functionally and structurally similar surfactants suggest that dermal absorption of the AAPs is likely to be low. As referenced in Section B of the petition (JITF CST 4 2008), dermal absorption models commonly used in the cosmetic and detergent industries also suggest low systemic exposure for AAPs. Predicted dermal absorptions for the representative AAP chemicals using such models were said to range from negligible to 1.1% absorption. Based on the lack of data for the AAPs and the irritant properties of these surfactants, in order to be health protective, a conservative dermal absorption factor of 5% was selected. 4.3 FQPA Considerations The toxicity database, with respect to FQPA, consists of a rat developmental study (MON 0818) and one rat reproduction study (MON 0818) to cover the C8-C18 (coco and tallow) range of carbon chain length and polyalkoxylation from the lower, more bioavailable end n=2 to the higher end n=15. A summary of these studies is in Appendix A. There are no neurotoxicity studies available for the AAPs; however, there is no indication of neurotoxicity in the available toxicity studies. HED performed a Degree of Concern Analysis because the rat reproduction study provided evidence of increased susceptibility in the offspring relative to the parents. The purpose of the Degree of Concern analysis was (1) to determine the level of concern for




Page 15 of 94

the effects observed when considered in the context of all available toxicity data; and (2) identify any residual uncertainties after establishing toxicity endpoints and traditional uncertainty factors to be used in the risk assessment. In the case of the AAPs, there was no increased susceptibility to the offspring of rats following in utero exposure in the prenatal development toxicity study. However, there was evidence of increased susceptibility in the reproduction toxicity studies in rats. Offspring effects include litter loss, increased mean number of unaccounted-for implantation sites and decreased mean number of pups born, live litter size and postnatal survival from birth to LD 4 (F1) at 1000 ppm MON 0818 (41-48.6 mg/kg/day) and at 2000 ppm MON 8109 (134-148 mg/kg/day). However, the rat reproduction study identified a NOAEL of 300 ppm for both MON 0818 and MON 8109 (12-14 mg/kg/day and 23-26 mg/kg/day, respectively) for offspring effects, and the selected point of departure for the dietary, dermal and inhalation risk assessments is protective of these offspring effects, thus there are no residual concerns. There are no residual uncertainties identified in the exposure databases. The food exposure assessments are considered to be conservative. The food and drinking water assessment is not likely to underestimate exposure to any subpopulation, including those comprised of infants and children. The FQPA factor can be reduced to 1X. A 1X FQPA Safety Factor is appropriate for the following reasons:

• The toxicology database is adequate for assessing the sensitivity of infants and children to AAP exposure.

• No quantitative or qualitative increased susceptibility was demonstrated in the fetuses in the prenatal developmental toxicity study in rats following in utero exposure.

• Although there is some increased susceptibility in the rat reproductive toxicity study (where the offspring NOAEL of 300 ppm (12-14 mg/kg/day) was lower than the paternal NOAEL of 1000 ppm (41-48.6 mg/kg/day), the dose-response for this effect has been adequately characterized, and the point of departure for the chronic dietary, dermal and inhalation risk assessment which is based on a NOAEL of 15 mg/kg/day with a 100X uncertainty factor, is protective of the adverse offspring effects.

• Residue values used in the dietary risk assessment are unlikely to underestimate risk.

4.4 Classification of Carcinogenic Potential There is no evidence that the AAPs are carcinogenic. The Agency used a qualitative structure activity relationship (SAR) database, DEREK11, to determine if there were structural alerts for a representative large molecule, as well as a smaller molecule that had been extensively dealkylated, with the amine group intact. No structural alerts were identified. In addition, there was little concern by the Residues of Concern Knowledge-based Subcommittee (ROCKS) about any of the postulated metabolites having greater




Page 16 of 94

toxicity than the parent compounds. See Appendix B for a complete description of the SAR analysis conducted for the alkyl amine polyalkoxylates. 4.5 Hazard Identification and Toxicity Endpoint Selection

A summary of the points of departure selected may be found in Table 4.5. Points of Departure for risk assessment were selected at a Joint ToxSAC/ROCKS meeting and are documented in the meeting minutes entitled “CST4 Inerts – Joint ToxSAC/ROCKS Meeting on December 9, 2008” (J. Kidwell, 1/16/2009). The level of concern (LOC) is for MOEs which are less than 100 and is based on 10X for interspecies extrapolation from animals to humans and 10X for variation in sensitivity between humans. These LOCs are applicable to all populations, including individuals exposed in a residential setting and occupationally exposed workers. An aggregate risk assessment can be performed for the AAPs since common endpoints were selected for the oral, dermal and inhalation routes of exposure. Table 4.5. Summary of Toxicological Doses and Endpoints for AAPs for Use in Dietary, Non-Occupational, and Occupational Human Health Risk Assessments

Exposure/ Scenario

Point of Departure

Uncertainty Factors

RfD, PAD, Level of Concern for Risk Assessment Study and Toxicological Effects

Acute Dietary (all populations)

NOAEL = 72 mg/kg/day

UFA= 10x UFH=10x FQPA SF = 1x

aRfD = aPAD= 0.72 mg/kg/day

90-day oral toxicity study – rat MON 0818 [CAS 61791-26-2 (tallow); Ave POE n=15]

LOAEL = 216 mg/kg/day, based on mortality (2 deaths after 2 exposures; GD 2), with a total of 6/25 deaths during GD 6-15.

Chronic Dietary (All Populations)



cRfD =cPAD= 0.15 mg/kg/day

90-day oral (gavage) toxicity study – rat ATMER®163 (CAS 70955-14-5 (C13-C15, POE n=2) LOAEL = 30 mg/kg/day, based on increased mortality [2 deaths (days 36, 78)], salivation, and posterior subcapsular cataracts in males as well as wheezing, and macro- and microscopic changes in the nonglandular stomach of both sexes.

Incidental Oral Short-Term (1–30 days) and Intermediate-Term (1-6 months)



Residential LOC for MOE = 100





Page 17 of 94

Table 4.5. Summary of Toxicological Doses and Endpoints for AAPs for Use in Dietary, Non-Occupational, and Occupational Human Health Risk Assessments

Exposure/ Scenario

Point of Departure

Uncertainty Factors

RfD, PAD, Level of Concern for Risk Assessment Study and Toxicological Effects

Dermal and Inhalation (All Durations)

oral NOAEL = 15 mg/kg/day (5% dermal absorption) (inhalation absorption rate = 100%)


Residential/ Occupational LOC for MOE = 100


Cancer (oral, dermal, inhalation)

Classification: No animal toxicity data available for an assessment; Based on SAR analysis, AAPs are not expected to be carcinogenic.

Point of Departure (PoD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies). PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. 4.6 Endocrine Disruption EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) “may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” Following recommendations of its Endocrine Disruptor and Testing Advisory Committee (EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC’s recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program (EDSP). When additional appropriate screening and/or testing protocols being considered under the Agency’s EDSP have been developed, AAPs may be subjected to further screening and/or testing to better characterize effects related to endocrine disruption. 5.0 Dietary Exposure/Risk Characterization 5.1 Residues of Concern Very limited information is available for the alkyl amine polyalkoxylates with respect to plant and animal metabolism or environmental degradation. The ROCKS Subcommittee




Page 18 of 94

met in a joint meeting with the ToxSAC on December 9, 2008 to determine if the selected representative chemicals from the AAPs were representative of the entire cluster and to discuss residues of concern. The subcommittee considered the representative chemical structures, the generic cluster structures, the submitted physicochemical EPI Suite™ information as well as the structure-activity relationship analysis detailed in Appendix B of this review. Additionally, the ROCKS members considered information on other surfactants and chemicals of similar size and functionality. The committee concluded that the cluster grouping was appropriate and that there were not likely to be degradates of the alky amine polyalkoxylates that were likely to be of greater toxicological concern than the AAPs themselves. 5.2 Drinking Water Residue Profile No monitoring data or data reflecting the concentration of these inert ingredients in drinking water is available. For the purpose of the screening level dietary risk assessment to support this request for an exemption from the requirement of a tolerance for the AAPs, a value of 100 ppb based on screening level modeling was used for both the acute and chronic dietary risk assessments. EFED conducted modeling runs on four surrogate inert chemicals using a range of physical chemical properties which bracket those expected in for the AAPs (email from D. Young to M. Metzger dated 1/15/09). EFED selected a North Carolina cotton scenario with an application date of July 1st as the scenario that would likely provide high end drinking water values for use in risk assessment. Percent crop area (PCA) factors were not applied. Simulations were run assuming a rate of 1 lb inert ingredient/A. Since degradation information was not available, three degradation scenarios were investigated: 1) chemically stable in water and soil; 2) a 100-day half-life in water and soil; and 3) a 10-day half life in water and soil. Further, two possible scenarios were investigated, one where all of the inert was applied as a single application, and the second assuming that the inert was applied evenly over a growing season. Modeled acute drinking water values ranged from 0.001 ppb to 41 ppb. Modeled chronic drinking water values ranged from 0.0002 ppb to 19 ppb. Further details of the EFED analysis are contained in Appendix C of this document. HED considers the value of 100 ppb to be a high end, conservative assumption that is not likely to underestimate drinking water risks. 5.3 Food Residue Profile No residue data were submitted for the alkyl amine polyalkoxylate inert ingredients. In the absence of data, the Agency has developed an approach which uses surrogate information to derive upper bound exposure estimates for the subject inert ingredients. Upper bound exposure estimates are based on the highest tolerance for a given commodity from a list of 57 high use insecticides (22), herbicides (20), and fungicides (17). The 57 pesticides were selected based on an overall ranking scheme that included consideration of the 1999 data for active ingredients use. All herbicides at greater than 5




Page 19 of 94

million lbs/yr and all fungicides and insecticides at greater than 1 million lbs/yr were included as candidate surrogate chemicals. The 57 pesticide surrogate candidates are listed in Appendix D of this risk assessment. OPP assumed that the residue level of the inert ingredient would be no higher than the highest tolerance for a given commodity. Implicit in this assumption is that there would be similar rates of degradation between the active and inert ingredient (if any) and that the concentration of inert ingredient in the scenarios leading to these highest of tolerances would be no higher than the concentration of the active ingredient. To summarize, the Agency believes the assumptions used to estimate dietary exposures lead to a very conservative assessment of dietary risk for the following reasons:

• the highest tolerance level from the surrogate pesticides for every food is used; • 100% crop treated is assumed for all crops (every food eaten by a person each day

has tolerance-level residues); • many of these high tolerances are based on very short pre-harvest intervals where

there is little time for degradation, whereas actual pesticide applications occur throughout the growing season;

• no consideration was given to potential degradation between harvest and consumption (use of tolerance level residues which are typically one to two orders of magnitude higher than actual residues found in monitoring data);

• residue values were assigned to every commodity in DEEM™ with no consideration given to potential reduction in residues from washing or cooking.

Although sufficient information to quantify actual residue levels in food is not available, the compounding of these conservative assumptions will lead to a significant exaggeration of actual exposures. OPP does not believe that this approach underestimates exposure in the absence of residue data. 5.4 Analytical Methodology Since this request is for an exemption from the requirement of a tolerance, an analytical method for enforcement purposes is not required to support this action. 5.5 Dietary (Food and Water) Exposure and Risk The model and inputs used for the AAP dietary risk assessment are described briefly below. A complete description of the dietary exposure and risk assessment is provided in the memorandum entitled “Alkyl Amines Polyalkoxylates (Cluster 4): Acute and Chronic Aggregate (Food and Drinking Water) Dietary Exposure and Risk Assessments for the Inerts.” (D361707, S. Piper, 2/25/09). Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model DEEM-FCID™, Version 2.03 which uses food consumption data from the U.S. Department of




Page 20 of 94

Agriculture’s Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998. 5.5.1. Acute Dietary Exposure and Risk A screening level assessment for acute dietary (food and drinking water) exposure assessment was conducted for the alkyl amine polyalkoxylates. In the absence of actual exposure information HED assumed that the residues of the inert ingredients would be no higher than the highest exposure from 57 of the most significant active ingredients. Inherent in this assumption is the supposition that the inert ingredient will be in the final formulation at no higher percentage than the active ingredient (i.e. 50% active, 50% inert). RD has conducted a review of current formulations used in agricultural settings and has found that individual inert ingredients are not present at levels in excess of the active ingredient (personal communication K. Leifer). The highest tolerance level residue for all food forms, including meat, milk, poultry and eggs, default processing factors for dried commodities and 100% percent crop treated (%CT) were used. No monitoring data or data reflecting the concentration of these inert ingredients in drinking water is available. For the purpose of this screening level dietary risk assessment, a value of 100 ppb was used for drinking water residues for both the acute and chronic dietary risk assessments. The initial screening level acute dietary exposure estimates for food and drinking water, assuming that the inert ingredient would be in the formulation at a level equivalent to the active ingredient (50% active ingredient; 50% AAP), identified potential risks of concern. HED conducted a more refined assessment to reflect the actual use pattern of these inert ingredients in pesticide formulations. The petitioner has indicated that these inerts will not be used at more than 10% by weight in fungicide and insecticide formulations and at no more than 25% in herbicide formulations. In refining the dietary risk assessment, HED notes that it is the fungicide tolerances which are typically the highest and serve as the basis for the residue value used in the dietary risk assessment. This is consistent with expectation given that fungicides are often applied late in the season and herbicides and insecticides are typically used much earlier in the season, resulting in much lower residues. HED has not yet developed a dietary exposure model for inerts which would allow for inclusion of inert ingredients at different percentages in the final formulation based on class of pesticide. The current model uses predominantly fungicide residues to estimate a high end exposure. HED does not expect that allowing a maximum of 25% in the final formulation for herbicides only will have a significant impact on the dietary exposure. Across the board it appears that selecting the highest fungicide tolerance and correcting for its limitation to 10% by weight as a maximum in the final formulation, results in a higher residue input into the dietary risk assessment than selecting the highest herbicide tolerance and correcting for 25% by weight as a maximum in the final formulation. This assertion that herbicides at 25% of the final formulation will not significantly impact risk above that resulting from use of fungicides at 10% of the final formulation is




Page 21 of 94

supported by examining the major drivers in the AAP dietary risk assessment. The major drivers for the AAP dietary risk assessment are apples and grapes. For both of these commodities, the highest tolerances were from the fungicide, captan and were 25 ppm in both crops. The highest herbicide tolerance for apples and grapes was from diuron and was 1 ppm for both crops. To calculate the effective residue level to input into the refined assessment, HED has started with the assumption in the screening level that residues of the active ingredient and the inert are equivalent or that at a maximum, the inert is present in the formulation at 50%. Since the petitioner proposes to cap the use of the AAPs in fungicides to 10%, a 5-fold reduction factor is applied to the residue (25 ppm x 0.2 = 5 ppm). The proposed cap for herbicide use is 25%, so the initial residue value can be refined to account for a 2-fold reduction in the residue from the original herbicide tolerance (1 ppm x 0.5 = 0.5 ppm). Even allowing for a higher percent in the final herbicide formulation, the residue value resulting from the fungicide use is significantly higher than that of the herbicide. Based on the refined dietary risk assessment which allows for a reduction of residues based on a lower percentage in the final formulation, the AAP dietary exposure at the 95th percentile for food and drinking water is 16% of the aPAD for the U.S. population and 44% of the aPAD for children 1-2 yrs old, the most highly exposed population subgroup. The results for all regulated subgroups are shown in Table 5.5.4, below. 5.5.2 Chronic Dietary Exposure and Risk A conservative screening level assessment was conducted for chronic dietary (food and drinking water) exposure using the highest tolerance level residue for all food forms, including meat, milk, poultry and eggs, default processing factors for dried commodities and 100% CT. In addition, a default concentration of 100 ppb was assumed for inert ingredient residues in drinking water. The chronic dietary exposure estimates for food and drinking water, assuming that the inert ingredient would be in the formulation at a level equivalent to the active ingredient, resulted in a screening level assessment which identified potential risks of concern. Based on the results of the screening level assessment, HED conducted a more refined assessment to reflect the actual use pattern of these inert ingredients in pesticide formulations as described above for the acute dietary assessment. The chronic dietary (food and water) exposure estimates are 27% of the cPAD for the U.S. population and 85% of the cPAD for children 1-2 yrs old, the most highly exposed population subgroup when the assessment was refined based on the proposed maximum amounts these inerts are likely to be in final formulations. See Table 5.4.4, below for a summary of results. 5.5.3 Cancer Dietary Exposure and Risk HED has not identified any concerns for carcinogenicity relating to the AAPs; therefore, a cancer dietary exposure assessment was not performed.




Page 22 of 94

5.5.4. Summary of Dietary Exposure and Risk Assessment Results The results of the acute and chronic dietary risk assessment are shown in the summary table, below.

Table 5.5.4. Summary of Dietary (Food and Water) Exposure and Risk for AAPs

Acute Dietary (95 th Percentile) Chronic Dietary

Population Subgroup Dietary Exposure

(mg/kg/day) % aPAD

Dietary Exposure

(mg/kg/day) % cPAD

General U.S. Population 0.113767 16 0.039989 27

All Infants (< 1 year old) 0.252003 35 0.084945 57

Children 1-2 years old 0.315197 44 0.127307 85



Youth 13-19 years old 0.081379 11 0.030045 20

Adults 20-49 years old 0.079350 11 0.030455 20

Adults 50+ years old 0.079669 11 0.032072 21

Females 13-49 years old 0.081334 11 0.030647 20 The most highly exposed subgroup is bolded. 6.0 Residential (Non-Occupational) Exposure/Risk Characterization A screening level residential exposure and risk assessment was completed for products containing alkyl amine polyalkoxylates as inert ingredients. Details of the residential exposure and risk assessment can be found in Appendix E. A summary of the residential exposure and risk assessment is presented below. 6.1 Residential Handler Exposure Exposure Scenarios In this assessment, the Agency selected representative scenarios, based on end-use product application methods and labeled application rates. The residential products are typically formulated as liquids in concentrates or as wettable powders. The AAPs themselves have no pesticidal properties, and are added to pesticide formulations for their adjuvant properties. According the petition submitted by the JITF CST4, the AAPs are not added to any pesticides intended for indoor use (i.e., where the Agency would




Page 23 of 94

typically assess crack and crevice/pet uses)1. Therefore, HED assumed no indoor uses exist; but this should be validated by RD, and restrictions on use of these inerts for indoor-use products should be mandated. For each of the use scenarios, the Agency assessed residential handler (applicator) inhalation and dermal exposure for outdoor scenarios with high exposure potential (i.e., exposure scenarios with high end unit exposure values) to serve as a screening assessment for all potential residential pesticides containing the AAP inert ingredients. Mixer/Loader/Applicator High Exposure Outdoor Scenarios:

• Liquid products: Low Pressure Handwand; • Liquid products: Hose End Sprayer • Ready to Use (RTU): Trigger Pump Sprayer Applications;

Exposure Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the residential handler risk assessments for the AAPs. Each assumption and factor is detailed below. In addition to these factors, unit exposures were used to calculate risk estimates. These unit exposures were primarily taken from the Pesticide Handlers Exposure Database (PHED). Several of the assumptions and factors used for the assessment are similar to those used in the occupational assessment presented below. Some of the factors used in the residential scenarios are highlighted below. The Agency also used assumptions based on the Residential Exposure Assessment Standard Operating Procedures (SOPs). The duration of exposure was assumed to be short- and intermediate-term for all residential scenarios assessed. The following assumptions were used in this assessment:

• The maximum application rate per pesticide group (herbicide/pesticide/fungicide) has been assessed for the short-term exposure duration.

• The average application rate per pesticide group (herbicide/pesticide/fungicide) has been assessed for the intermediate-term exposure duration.

• Residential risk assessments are based on estimates of what homeowners would typically treat. Per HED’s Residential SOPs (1997 & 2001 revision), residential pesticide handlers are assumed to mix and use a volume of 5 gallons of product per day.

• For herbicide applications, residential handlers are assumed to use 1.125 lbs AAP per day.

This estimate is based on the following assumptions:

Five (5) gallons of formulated pesticide solution are assumed to be used per day by a residential handler (Revised Residential SOPs Area Treated, February, 2001). Consistent with the residential SOPs, the density of the formulated pesticide solution is assumed to be 9 lbs/gallon. For herbicides, 25% of the five

1 The Joint Inert Task Force (JITF) Cluster Support Team Number 4 (CST4) presented this information verbally at the January 14th, 2009 JITF/OPP Update meeting.




Page 24 of 94

5 gallons formulated pesticide solution*(9 lbs/gallon)*(25% AAP)*(1 part product concentrate/10 parts water) = 1.125 lbs AAP in herbicide formulated pesticide solutions per day

gallons of formulated pesticide solution can be AAPs and the product concentrate is assumed to be diluted at a 1 to 10 ratio with water.

• For insecticide/fungicide applications, residential handlers are assumed to use 0.45 lbs AAP per day.

This estimate is based on the following assumptions:

Five (5) gallons of formulated pesticide solution are assumed to be used per day by a residential handler (Revised Residential SOPs Area Treated, February, 2001). Consistent with the residential SOPs, the density of the formulated pesticide solution is assumed to be 9 lbs/gallon. For insecticides/fungicides, 10% of the five gallons of formulated pesticide solution can be AAPs and the product concentrate is assumed to be diluted at a 1 to 10 ratio with water.

• Residential exposure is assessed assuming clothing consisting of a short-sleeved

shirt, short pants and no gloves or respiratory protection.

5 gallons formulated pesticide solution*(9 lbs/gallon)*(10% AAP)*(1 part product concentrate/10 parts water) = 0.45 lbs AAP in insecticide or fungicide formulated pesticide solutions per day




Page 25 of 94

Risk Characterization For all residential handler scenarios, risk estimates are not of concern (i.e., MOEs are all greater than 100) for both the route-specific (dermal or inhalation) assessment and for the total MOE (dermal and inhalation combined). A summary of the results are provided below in Table 6.1. The Agency believes that the scenarios assessed in this document represent worse-case exposures and risks resulting from use of pesticide products containing the AAPs in residential environments.

1Application rates are based on high end application rates of products containing inerts in the AAPs multiplied by 25% to convert to application rate of just inert in an herbicides product (Herbicide products contain maximum of 25% inert from the AAPs according to Inerts Task Force). For insecticide and fungicide application rates, the AAPs multiplied by 10% to convert to application rate of just inert in an insecticide/fungicide products. Application rates for Short-Term exposure risk estimates are based on maximum product application rates. Application rates for Intermediate-Term exposure risk estimates arer based on average product application rates. 2Area treated daily values are back-calculated from 5 gallons of product used per day (Revised Residential SOPs 2001). 3Unit Exposure values are reported in PHED Surrogate Exposure Guide dated August 1998 except for liquids hose end sprayer scenario (See footnote 9). All exposure scenarios assess exposure reflecting applicators wearing short-sleeved shirts and shorts and no respiratory protection. 4Daily Dermal Dose = (Dermal Unit Exposure (mg inert /lb inert) * Application Rate (lb inert /A) * Area Treated (A /day))/ Body Weight (70 kg) * Dermal Absorption Factor of 5% (0.05)

Table 6.1. Short- and Intermediate-Term Exposure and Risks for Residential Handlers of the AAPs

Exposure Scenario (Formulation/ Application)

Application Rate1 (lb

inert/ day)

Area Treated Daily2

(units)

Dermal Unit

Exposure (mg/lb inert)3

Inhalation Unit

Exposure (mg/ lb inert)3

Dermal Dose

(mg/kg /day)4

Inhalation

Dose (mg/kg/

day)5

Baseline Dermal MOE6

Baseline Inhalation MOE7 Total MOE8

Herbicide Mixer/Loader/Applicator Scenarios Liquids/ Low Pressure Handwand 1.125 38 0.003 0.03054 4.82x10-5 490 310,000 490

Liquids/ Hose End Sprayer9 1.125 11 0.017 0.00884 0.000273 1,700 55,000 1,600

Liquids/ Trigger Sprayer/ Home Garden 1.125

1

54 0.0019 0.0434 3.05x10-5 350 490,000 350

Insecticide and Fungicide Mixer/Loader/Applicator Scenarios

Liquids/ Low Pressure Handwand 0.45 38 0.003 0.0122 1.93x10-5 1,200 780,000 1,200

Liquids/ Hose End Sprayer9 0.45 11 0.017 0.0035 1.09x10-4 4,200 140,000 4,100

Liquids/ Trigger Sprayer/ Home Garden 0.45

1

54 0.0019 0.017 1.22x10-5 860 1,200,000 860




Page 26 of 94

5 Daily Inhalation Dose = (Inhalation Unit Exposure (µg inert / lb inert) * Conversion Factor (1 mg /1000 µg) * Application Rate (lb inert /A) * Area Treated (A /day)) / Body Weight (70 kg) 6 Dermal MOE = PoD (NOAEL of 15 mg/kg/day)/ Daily dermal dose (mg/kg/day) 7ST Inhalation MOE = PoD (NOAEL of 15 mg/kg/day) / Daily inhalation dose (mg/kg/day) 8Total MOE = 1/ (1/Dermal MOE + 1/Inhalation MOE) 9Uses unit exposures from ORETF Homeowner Study (MRID 449722-01) 6.2. Residential Postapplication Exposure Exposure Scenarios Residential postapplication exposures result when bystanders, such as children come in contact with the AAPs in areas where end-use products have recently been applied (e.g., treated lawns or gardens). As noted above, the AAPs are not added to any pesticides intended for indoor use. Postapplication High End Outdoor Exposure Scenarios

• Dermal exposure to treated lawns (adults/children) • Hand-to-Mouth activity for toddlers on treated lawns (children) • Object-to-Mouth activity for toddlers on treated lawns (children) • Soil ingestion from treated soil (children)

The exposures from these routes and scenarios were considered individually and were also added together, where appropriate, to determine a total dose for children exposure to treated lawns. Residential postapplication exposure is assessed on the day of application, typically referred to as Day 0. Inhalation exposures are not typically calculated for residential post-application scenarios for the formulation types applicable to the AAPs because inhalation exposures generally account for a negligible percentage of the overall body burden for most pesticide chemicals. This is particularly true for chemicals with a low vapor pressure such as the AAPs. Exposure Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the residential postapplication risk assessments. The assumptions and factors used in the risk calculations are consistent with current HED policy for completing residential exposure assessments (i.e., SOPs for Residential Exposure Assessment [1997 and 2001 revision]). Exposures to adults/children after contact with treated lawns have been addressed using the latest approaches for this scenario including:

• The adverse effects for the short- and intermediate-term dermal and inhalation endpoints are based on studies where the effects were observed in both sexes. For adult exposure, the mean for US males and females was used to estimate exposure (70 kg). For child exposure, the mean of median values for male and female 3 year olds was used to estimate exposure (15 kg).

• HED has developed standard transfer coefficient (TC) values for residential postapplication scenarios to ensure consistency in exposure assessments. For the




Page 27 of 94

short-term assessment, TC values of 14,500 cm2/hr (adults) and 5,200 cm2/hr (children) were used. For intermediate-term risk assessment, TC values of 7,300 cm2/hr and 2,600 cm2/hr were used. These default transfer coefficients, found in the 2001 Residential SOPs were used to calculate postapplication exposures.

• Herbicides have a maximum of 25% by weight of AAPs in the end use product and insecticides and fungicides have a maximum of 10% by weight of the AAPs in the end use product.

• AAP application rates are derived above in Section 6.1 • Dermal absorption is assumed to be 5%.

Risks were calculated using the Margin of Exposure (MOE) approach, which is a ratio of the body burden to the toxicological PoD. Exposures were calculated by considering the potential sources of exposure (i.e., transferable residues on treated lawns), then calculating dermal and nondietary ingestion exposures. Risk Characterization A summary of the residential post application exposure and risk estimates are presented in Table 6.2, below. The risk estimates are expressed in terms of the MOE. In addition to estimating route specific MOEs, a total MOE was calculated for the AAPs because common toxicity endpoints were identified for the oral, dermal and inhalation routes of exposure. Additionally, the Agency has combined risk estimates resulting from separate postapplication exposure scenarios when it is likely that they can occur simultaneously based on the use-pattern and the behavior associated with the exposed population. The combined non-dietary risks from dermal exposure and hand-to-mouth exposure on treated lawns do not demonstrate risks of concern for toddlers. All assessed scenario risk estimates are not of concern (i.e., the MOEs for the assessed scenarios are greater than 100) for both the individual exposure scenario assessed and for the aggregate risk estimates.




Page 28 of 94

Table 6.2. Residential Postapplication Short- and Intermediate-term Exposures and Risks for the AAPs

Exposure Scenario

Application Rate (lb inert/day)1

Exposed Population &

Exposure Duration2

Daily Dose (mg/kg/day)3

MOE4

Herbicide Product Scenarios Adult ST 0.013 1,100

Adult IT 0.007 2,300

Child ST 0.022 690

Dermal Exposure to Treated Lawns

Child IT 0.011 1,400

Child ST 0.0168 900 Hand-to-Mouth from Treated Lawn Child IT 0.00799 1,900 Object-to-Mouth from Treated Lawn

Child 0.00421 3,600

Soil Ingestion Child 5.635x10-5 270,000

Child ST 0.0388 390 Total Aggregated Exposures*

1.125

Child IT 0.0190 790 Insecticide and Fungicide Product Scenarios

Adult ST 0.0052 2,900

Adult IT 0.003 5,000

Child ST 0.00875 1,700

Dermal Exposure to Treated Lawns

Child IT 0.004 3,800

Child ST 0.0067 2,200 Hand-to-Mouth from Treated Lawn Child IT 0.0032 4,700 Object-to-Mouth from Treated Lawn Child 0.00168 8,900

Soil Ingestion Child 2.254 x10-5 670,000

Child ST 0.0155 970 Total Aggregated Exposures5

0.45

Child IT 0.007 2,100 1 Application rates derived in Section 6.1 2 ST and IT indicate short- or intermediate-term exposure durations 3 Daily Dose = Daily Dose algorithms for various residential postapplication scenarios outlined in Appendix E. 4 MOE = PoD (NOAEL of 15 mg/kg/day for short- & intermediate-term exposure durations)/ Daily dose (mg/kg/day) 5 Aggregated exposures reflect the aggregation of dermal exposure to treated lawns and HTM exposure from treated lawns (for children). Total Aggregate Exposures = (NOAEL of 15 mg/kg/day for short-term exposure durations)/ [Daily dose dermal + Daily dose HTM (mg/kg/day)]




Page 29 of 94

7.0 Aggregate Risk Assessments and Risk Characterization As previously noted, the AAPs appear to have very limited use in consumer or personal care products. Given the high end dietary exposure and residential exposure screening level assessments used to address exposure and risk from the uses of the AAPs as inerts in pesticide products, and given their limited uses and low concentrations in consumer products, HED believes that the consumer care uses are unlikely to significantly impact aggregate risk. 7.1 Acute Aggregate Risk For the alkyl amine polyalkoxylates, the acute aggregate risk includes dietary exposures to food and drinking water. Dietary (food and water) exposures and risk are discussed in Section 5.5.1 of this memorandum. Acute aggregate risks for the AAPs are not of concern. 7.2 Short-Term/Intermediate-Term Aggregate Risk Short-term and intermediate-term aggregate risk assessments for the AAPs combine high end residential short- or intermediate-term exposures with average food and drinking water exposures, and compare this total to a short- or intermediate term PoD. Short- and intermediate-term aggregate risks are summarized in Table 7.2. Short- and intermediate-term aggregate risks are not of concern. While the MOE for short-term aggregate exposure for children is slightly below 100, HED does not consider this MOE to represent a risk of concern for the following reasons.

• The hazard assessment for the AAPs is conservative. o The PoDs used to calculate aggregate risks for AAPs were based on the

most toxic surrogate chemical. The AAPs are actually a mixture of compounds, so it is likely that the PoD is a conservative assessment of toxicity.

o HED traditionally considers a level of concern (LOC) for these risk assessments to be for an MOE of 100 based on the standard 10x inter and 10x intra species extrapolation safety factors. However, HED notes that for the AAPs, the primary toxic effect seen is related to the surfactants inherent function to disrupt cell membranes resulting in irritating properties to tissues. Given that HED does not expect to see a significant difference between species for this type of effect, an LOC lower than 100 may be appropriate for the non-dietary risk assessments.

• The dietary (food and water) portion of the aggregate risk assessment is a driver

in the aggregate assessment and is considered to be highly conservative. o The highest tolerance level from the surrogate pesticides for every food is

used. o 100% crop treated is assumed for all crops (every food eaten by a person

each day has tolerance-level residues).




Page 30 of 94

o Many of these high tolerances are based on very short pre-harvest intervals where there is little time for degradation.

o No consideration was given to potential degradation between harvest and consumption (use of tolerance level residues which are typically one to two orders of magnitude higher than actual residues found in monitoring data).

o Residue values were assigned to every commodity in DEEM™ with no consideration given to potential reduction in residues from washing or cooking.

• The residential portion of the assessment is based on high-end application rates

and assumes a dermal absorption of 5% which is a conservative, health protective value.

• Finally, the aggregate assessment assumes that a child would receive a high-end

dietary exposure with high-end dermal and hand-to-mouth exposures concurrently.

Table 7.2. Short- and Intermediate-Term Aggregate Risk Calculations for the AAPs

Short- and Intermediate-Term

Population

NOAEL mg/kg/day LOC1

Max Allowable Exposure2 mg/kg/day

Average Food & Water Exposure mg/kg/day

Residential Exposure3 mg/kg/day

Aggregate MOE (food and residential)4

Adult Male ST/IT 15 100 0.15 0.039989 0.056430 156

Adult Female ST/IT 15 100 0.15 0.030647 0.056430 172

Child - ST 15 100 0.15 0.127307 0.0388 90

Child - IT 15 100 0.15 0.127307 0.0190 102 1 The LOC (Level of Concern) is based on the standard inter- and intra-species uncertainty factors totaling 100. 2 Maximum Allowable Exposure (mg/kg/day) = PoD/LOC 3 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure]. Adult residential exposure combines high end dermal and inhalation handler exposure (Table 6.1) with high end post application dermal exposure (Table 6.2). Children’s residential exposure combines turf dermal exposure with HTM exposures (Table 6.2). 4 Aggregate MOE = [PoD/ (Avg Food & Water Exposure + Residential Exposure)] 7.3 Long-Term Aggregate Risk For the alkyl amine polyalkoxylates, the long-term aggregate risk includes dietary exposures to food and drinking water. Dietary (food and water) exposures and risk are discussed in Section 5.5.2 of this memorandum. Long-Term (chronic) aggregate risks for the AAPs are not of concern.




Page 31 of 94

7.4 Cancer Risk HED has not identified any concerns for carcinogenicity; therefore, an aggregate cancer dietary exposure assessment was not performed. 8.0 Occupational Exposure/Risk Pathway Based on examination of product labels which might potentially contain the AAPs as inert ingredients, HED has determined that exposure to handlers can occur in a variety of occupational environments. Details of the occupational exposure assessment for the alkyl amine polyalkoxylates can be found in Appendix F. The representative occupational scenarios selected by the Agency for assessment were evaluated based on likely maximum application rates for products which may contain the AAPs as inert ingredients for the short-term exposure assessment, and average application rates for products likely to contain the AAPs as inerts for the intermediate- and long-term exposure durations. Active ingredient application rates were corrected for the maximum amount of AAPs likely to be in the final formulations to determine exposure and risk from exposure to the AAPs grouped by fungicide/insecticide or herbicide. A summary of the occupational assessment is presented below. HED traditionally considers a level of concern (LOC) for these risk assessments to be an MOE of 100 based on the standard 10X inter and 10X intra species extrapolation safety factors. However, HED notes that for the AAPs, the primary toxic effect seen is related to the surfactants’ inherent function to disrupt cell membranes resulting in irritating properties to tissues. Given that HED does not expect to see a significant difference between species for this type of effect, an LOC lower than 100 may be appropriate for the non-dietary risk assessments. 8.1 Handler Risk Exposure Scenarios Exposure to pesticide handlers is likely during the occupational use of pesticides containing the AAPs as inert ingredients. Dermal and inhalation exposure was estimated using the Pesticide Handlers Exposure Database (PHED) and Outdoor Residential Exposure Task Force (ORETF) data. Appendix F contains additional description about the data sources and methodology used to assess occupational exposure. The quantitative exposure/risk assessment developed for occupational handlers to support the requested exemption for the AAPs is based on the following scenarios. HED notes that these scenarios were selected to represent the scenarios with the highest potential exposure.

Mixer/Loader/Applicators: 1) Mixer/Loader for aerial application- high acreage field crops (liquids) 2) Mixer/Loader for airblast application- tree nuts crops (both liquid and

wettable powder)




Page 32 of 94

3) Mixer/Loader for groundboom application- high acreage field crops and turf (liquids and wettable powder)

4) Applicators for aerial application- high acreage field crops (liquid) 5) Applicators for airblast- tree nut crops 6) Applicators for groundboom- high acreage field crops and turf 7) Mixer/Loader/Applicator- low pressure handwand (liquids and wettable

powders)* 8) High pressure handwand- greenhouse (wettable powders) 9) Flagging- high acreage field crops (liquids)

* Uses ORETF unit exposure data. All others use PHED data. Risk estimates were calculated using the Margin of Exposure (MOE) which is a ratio of the toxicological PoD to the daily dose. Daily dose values are calculated by first calculating exposures by considering application parameters (i.e., rate and area treated) along with unit exposures. Exposures are then normalized by body weight to calculate dose levels. Dermal and inhalation short-term exposure is compared to the dermal and inhalation PoD of 30 mg/kg/day. Dermal and inhalation intermediate-term exposure is compared to the intermediate term dermal and inhalation PoD of 15 mg/kg/day. For the scenarios where applicable, dermal and inhalation intermediate-term exposure is compared to the long-term dermal and inhalation PoD of 15 mg/kg/day. For both short- and intermediate-term dermal assessments, exposures were adjusted for 5% dermal absorption for comparison to the POD from an oral toxicity study, and inhalation toxicity was assumed to be equivalent to oral toxicity. A combined dermal and inhalation MOE was also calculated for each exposure duration for the AAPs since common toxicity endpoints were identified for both the dermal and inhalation routes of exposure. To assess handler risks, the Agency used surrogate unit exposure data from the Pesticide Handlers Exposure Database (PHED), and ORETF data. Occupational handler exposure assessments are completed by the Agency using different levels of personal protection. The Agency typically evaluates all exposures with a tiered approach. The lowest tier is represented by the baseline exposure scenario followed by increasing the levels of personal protection represented by personal protective equipment or PPE (e.g., gloves, extra clothing, and respirators) and engineering controls (e.g., closed cabs and closed loading systems). This approach is always used by the Agency in order to be able to define label language using a risk-based approach and not based on generic requirements for label language. In addition, the minimal level of adequate protection for a chemical is generally considered by the Agency to be the most practical option for risk reduction. The levels of protection that form the basis for the calculations in this assessment include:

• Baseline Exposure Scenario: Represents typical work clothing; a long-sleeved shirt, long pants, socks, and shoes. Chemical-resistant gloves or respiratory protection are not included in this scenario.

• Baseline Plus Gloves: Represents the baseline exposure scenario with the use of

chemical-resistant gloves. No respiratory protection is included in this scenario.




Page 33 of 94

• Engineering Controls: Represents the use of an appropriate engineering control

such as a closed cockpit. Engineering controls are not applicable to handheld application methods which have no known devices that can be used to routinely lower the exposures for these methods.

The following assumptions and factors were used in order to complete the exposure and risk assessment for occupational handlers/applicators:

• All worker scenarios were assumed to be short- and intermediate-term in exposure durations (i.e., 1-30 days and 1-6 months) with the exception of greenhouse/hothouse applications.

• For scenarios where greenhouse/hothouse applications are possible, a long-term exposure duration (6+ months) has also been calculated.

• The exposure assessment assumes an 8 hour work day. • The maximum application rate per pesticide group (herbicide/pesticide/fungicide)

has been assessed for the short-term exposure duration. • The average application rate per pesticide group (herbicide/pesticide/fungicide)

has been assessed for the intermediate-term exposure duration. • A body weight of 70 kg was assumed because the relevant toxicological PoDs

were not gender specific. • All exposures were assessed at the baseline exposure scenario. • For high acreage crops (e.g. corn, soybeans) where applicators can mix/load large

quantities of pesticide, exposure assessments have also been completed for the baseline exposure scenario plus chemical-resistant gloves (described in the previous paragraph), and no respiratory protection.

Risk Characterization: HED initially assessed handler exposure and risks for AAPs in fungicides, herbicides and insecticides at baseline PPE (long pants, a long-sleeved shirt, shoes, socks, no chemical-resistant gloves, and no respiratory protection) which HED considers to be the typical minimal worker clothing. When these assessments indicated that there were potential risks of concern for scenarios where workers would be handling large quantities of pesticide for high volume operations typically involving aerial applications to high acreage crops, HED repeated the assessments and included additional PPE (i.e., chemical-resistant gloves for pesticide handlers). The Agency believes workers handling large volumes of pesticides will be wearing chemical-resistant gloves. When handlers are wearing typical worker clothing (i.e., baseline PPE) the majority of occupational handler scenarios do not indicate risks of concern. For the occupational handler scenarios which involve the handling of large volumes of pesticides, those which EPA believes that handlers will be wearing chemical-resistant gloves, occupational handler scenarios do not indicate risks of concern with the addition of chemical-resistant gloves to baseline PPE (i.e., baseline plus gloves). For the occupational scenarios that involve mixer loader applicators applying pesticides containing an AAP formulated as a wettable powder with a low pressure handwand to ornamentals in a greenhouse




Page 34 of 94

environment, calculated risks resulted in MOEs below 100 when only traditional work clothes were assumed. Since the Agency does not believe that it is routine for these workers to wear gloves for these scenarios, an assessment was provided showing MOEs when the percent of AAP in the final formulation was reduced. For herbicides the assessments were provided reducing the cap from the proposed maximum of 25% to 20%, 15%, 10% and 5%. For insecticides and fungicides containing the AAPs, assessments were provided showing the impact on MOEs of reducing the maximum allowed amount in the final formulation from the proposed maximum of 10% to 8%, 6% and 5%.

Table 8.1.1. Exposure and Risks for Occupational Handlers of the AAPs in Herbicide Products (All

Exposure Durations) at Baseline Exposure Scenario

Exposure Scenario (Formulation/

Application/ Crop)

Application Rate1 (lb inert/ A)

Area Treated Daily2

(acres)

Dermal Unit


Inhalation Unit

Exposure (ug/ lb inert)3

Baseline Dermal Dose

(mg/kg /day)4

Baseline

Inhalation Dose

(mg/kg/ day)5


Baseline Inhalation

MOE7 Total MOE8

Mixer/Loader Scenarios Liquids/ Aerial

Application/ High Acreage Crops (ST)

2.6 6.46 0.0535 2 280 2 Liquids/ Aerial

Application/ High Acreage Crops (IT)

0.5 1200

1.24 0.0103 12 1,500 12 Liquids/ Airblast/ Nut Tree

(ST) 1.8 0.15 0.00123 100 12,000 100 Liquids/ Airblast/ Nut Tree

(IT) 0.8 40

0.0663 0.00055 230 27,000 220 Liquids/ Groundboom/

High Acreage Crops (ST) 2.6 1.077 0.0089 14 1,700 14 Liquids/ Groundboom/

High Acreage Crops (IT) 0.5 200

0.207 0.001714 72 8,800 72 Liquids/ Groundboom/ Turf

(ST) 2.6 0.215 0.00178 70 8,500 69 Liquids/ Groundboom/ Turf

(IT) 0.5 40

0.0414 0.00034 360 44,000 360 Liquids/ Low Pressure Handwand/ Turf (ST) 1.8 0.0186 0.000154 800 95,000 800 Liquids/ Low Pressure Handwand/ Turf (IT) 1.8

5

2.9 1.2

0.0186 0.000154 800 97,000 800 Wettable Powder/ Airblast/

Nut Tree (ST) 0.4 0.0423 0.0098 350 1,500 290 Wettable Powder/ Airblast/

Nut Tree (IT) 0.4 40

0.0423 0.0098 350 1,500 290 Wettable Powder/

Groundboom/ High Acreage Crops (ST)

0.4 0.2114 0.05 70 300 60 Wettable Powder/

Groundboom/ High Acreage Crops (IT)

0.25 200

0.1321 0.031 110 490 92

Wettable Powder/ Groundboom/ Turf (ST) 0.4 0.0423 0.0098 350 1,500 290

Wettable Powder/ Groundboom/ Turf (IT) 0.25

40 0.026 0.00614 570 2,400 460

Wettable powder/ Low Pressure Handwand/ Turf

(ST) 1.8 0.0238 0.0055 630 2,700 510


(IT) 1.8

5

3.7 43

0.0238 0.0055 630 2,700 510

Applicator Scenarios




Page 35 of 94

Table 8.1.1. Exposure and Risks for Occupational Handlers of the AAPs in Herbicide Products (All Exposure Durations) at Baseline Exposure Scenario


Application/ Crop)


Area Treated Daily2

(acres)

Dermal Unit


Inhalation Unit



(mg/kg /day)4

Baseline

Inhalation Dose

(mg/kg/ day)5


Baseline Inhalation

MOE7 Total MOE8

Liquid/ Aerial Application/ High Acreage Crops (ST)9 2.6 0.0123 0.003 1,200 5,000 1,000 Liquid/ Aerial Application/ High Acreage Crops (IT)9 0.5

1200 Eng

control only:

0.0055

Eng control only:

0.068 0.0024 0.0006 6,400 26,000 5,100 Airblast/ Nut Tree (ST) 0.4 0.00411 0.00103 3,600 15,000 2,900 Airblast/ Nut Tree (IT) 0.4 40 0.36 4.5 0.00411 0.00103 3,600 15,000 2,900

Groundboom/ High Acreage Crops (ST) 2.6 0.0052 0.0055 2,900 2,700 1,400 Groundboom/ High Acreage Crops (IT) 0.5

200 0.001 0.0011 15,000 14,000 7,300

Groundboom/ Turf (ST) 2.6 0.00104 0.0011 14,000 14,000 7,000 Groundboom/ Turf (IT) 0.5 40

0.014 0.74

0.0002 0.0002 75,000 71,000 36,000 Mixer/Loader/Applicator Scenarios

Low Pressure Handwand/ Turf (ORETF data) (ST)10 1.8 NA 0.00085 NA 18,000 NA Low Pressure Handwand/ Turf (ORETF data) (IT)10 1.8

5 no data 6.6

NA 0.00085 NA 18,000 NA Wettable Powder/ Low

Pressure Handwand/ Ornamentals (ST)10

1.8 NA 0.1414 NA 110 NA Wettable Powder/ Low

Pressure Handwand/ Ornamentals (IT)10


Pressure Handwand/ Ornamentals (LT)10

1.8

5 no data 1100

NA 0.1414 NA 110 NA Liquid/ Low Pressure

Handwand/ Ornamentals (ST)

1.8 0.6429 0.0039 23 3,900 23 Liquid/ Low Pressure

Handwand/ Ornamentals (IT)


Handwand/ Ornamentals (LT)

1.8

5 100 30

0.6429 0.0039 23 3,900 23

Flagger Scenarios Liquid/ Flagger/ High Acreage Crops (ST) 2.6 0.0245 0.0156 600 960 380

Liquid/ Flagger/ High Acreage Crops (IT) 0.5

1200 0.011 0.35 0.0047 0.003 3,200 5,000 1,900

1Application rates are based on maximum application rates of products containing inerts in the AAPs multiplied by 25% to convert to application rate of just inert in an herbicides product (Herbicide products contain a maximum of 25% inert AAPs according to Inerts Task Force). Application rates for Short-term (ST) exposure risk estimates are based on maximum application rates. Application rates for Intermediate-term (IT) and long-term (LT) exposures are based on average application rates. Baseline Exposure Scenario represents typical work clothing, no gloves. 2Area treated daily values are from the EPA HED estimates of acreage treated in a single day for each exposure scenario of concern. 3Unit Exposure values are reported in PHED Surrogate Exposure Guide dated August 1998 or from ORETF data. All exposure scenarios assess baseline exposure scenario and baseline inhalation exposure except for aerial applicator scenarios, which assess inhalation and dermal exposures with engineering controls. 4Daily Dermal Dose = (Dermal Unit Exposure (mg inert /lb inert) * Application Rate (lb inert /A) * Area Treated (A /day))/ Body Weight (70 kg) * Dermal Absorption Factor of 5% (0.05) 5 Daily Inhalation Dose = (Inhalation Unit Exposure (µg inert / lb inert) * Conversion Factor (1 mg /1000 µg) * Application Rate (lb inert /A) * Area Treated (A /day)) / Body Weight (70 kg) 6 Dermal MOE = PoD (NOAEL of 15 mg/kg/day)/ Daily dermal dose (mg/kg/day) 7ST Inhalation MOE = PoD (NOAEL of 15 mg/kg/day) / Daily inhalation dose (mg/kg/day) 8Total MOE = 1/ (1/Dermal MOE + 1/Inhalation MOE)




Page 36 of 94

9Aerial applicators do not have baseline exposure: only engineering control exposure can be assessed. All other exposure scenarios assess the baseline exposure scenario and baseline inhalation exposure. 10These scenarios have baseline inhalation unit exposures, but not baseline dermal unit exposures. The M/L/A scenario assessed in Table 8.1.1. results in a higher exposure (and therefore is health protective) than either of the two “NA” scenarios shown at baseline plus gloves dermal exposure.

1Application rates are based on maximum application rates of products containing inerts in the AAPs multiplied by 25% to convert to application rate of just inert in an herbicides product (Herbicide products contain maximum of 25% inert from the AAPs according to Inerts Task Force). Application rates for Short-term (ST) exposure risk estimates are based on maximum application rates. Application rates for Intermediate-term (IT) and long-term (LT) exposures are based on average application rates. 2Area treated daily values are from the EPA HED estimates of acreage treated in a single day for each exposure scenario of concern. 3Unit Exposure values are reported in PHED Surrogate Exposure Guide dated August 1998 or from ORETF data. All exposure scenarios assess baseline plus gloves plus baseline inhalation exposure except for aerial applicator scenarios, which assess inhalation and dermal exposures with engineering controls. 4Daily Dermal Dose = (Dermal Unit Exposure (mg inert /lb inert) * Application Rate (lb inert /A) * Area Treated (A /day))/ Body Weight (70 kg) * Dermal Absorption Factor of 5% (0.05) 5 Daily Inhalation Dose = (Inhalation Unit Exposure (µg inert / lb inert) * Conversion Factor (1 mg /1000 µg) * Application Rate (lb inert /A) * Area Treated (A /day)) / Body Weight (70 kg) 6 Dermal MOE = PoD (NOAEL of 15 mg/kg/day)/ Daily dermal dose (mg/kg/day) 7ST Inhalation MOE = PoD (NOAEL of 15 mg/kg/day) / Daily inhalation dose (mg/kg/day) 8Total MOE = 1/ (1/Dermal MOE + 1/Inhalation MOE) *Aerial applicators do not have baseline exposure: only engineering control exposure can be assessed. All other exposure scenarios assess baseline plus gloves and baseline inhalation exposure.

Table 8.1.2. Exposure and Risks for Occupational Handlers of AAPs in Herbicide Products (All Exposure Durations) with Baseline Plus Gloves for High Acreage Mixer/ Loader Scenarios and Turf


Application/ Crop)


Area Treated Daily2

(acres)

Dermal Unit


Inhalation Unit


Baseline +

Gloves Dermal Dose

(mg/kg /day)4

Baseline

Inhalation Dose

(mg/kg/ day)5

Baseline + Gloves Dermal MOE6

Baseline Inhalation

MOE7 Total MOE8



2.6 0.0513 0.0535 290 280 150 Liquids/ Aerial


0.5 1200

0.0099 0.0103 1,500 1,500 750 Liquids/ Groundboom/

High Acreage Crops (ST) 2.6 0.00854 0.0089 1,800 1,700 850 Liquids/ Groundboom/

High Acreage Crops (IT) 0.5 200

0.00164 0.001714 9,100 8,800 4,500 Liquids/ Groundboom/

Turf (ST) 2.6 0.0017 0.0018 8,800 8,400 4,300 Liquids/ Groundboom/

Turf (IT) 0.5 40

0.023 1.2

0.00033 0.00034 47,000 44,000 22,000 Wettable Powder/ Groundboom/ High Acreage Crops (ST)

0.4 0.00971 0.05 1,500 300 250 Wettable Powder/ Groundboom/ High Acreage Crops (IT)

0.25 200 0.17 43

0.00610 0.031 2,500 490 410




Page 37 of 94

1Application rates are based on maximum application rates of products containing inerts in the AAPs multiplied by variable % AAP in formulation to convert to application rate of just inert in an herbicide product. Application rates for Short-term (ST) exposure risk estimates are based on maximum application rates. Application rates for Intermediate-term (IT) and long-term (LT) exposures are based on average application rates. 2Area treated daily values are from the EPA HED estimates of acreage treated in a single day for each exposure scenario of concern. 3Unit Exposure values are reported in PHED Surrogate Exposure Guide dated August 1998 or from ORETF data. All exposure scenarios assess baseline exposure scenario plus baseline inhalation exposure 4Daily Dermal Dose = (Dermal Unit Exposure (mg inert /lb inert) * Application Rate (lb inert /A) * Area Treated (A /day))/ Body Weight (70 kg) * Dermal Absorption Factor of 5% (0.05) 5 Daily Inhalation Dose = (Inhalation Unit Exposure (µg inert / lb inert) * Conversion Factor (1 mg /1000 µg) * Application Rate (lb inert /A) * Area Treated (A /day)) / Body Weight (70 kg) 6 Dermal MOE = PoD (NOAEL of 15 mg/kg/day)/ Daily dermal dose (mg/kg/day) 7 Inhalation MOE = PoD (NOAEL of 15 mg/kg/day) / Daily inhalation dose (mg/kg/day) 8Total MOE = 1/ (1/Dermal MOE + 1/Inhalation MOE)

Table 8.1.4. Exposure and Risks for Occupational Handlers of AAPs in Insecticide Products (All Exposure Durations) at Baseline Exposure Scenario


Application/ Crop)


Area Treated Daily2

(acres)

Dermal Unit


Inhalation Unit



(mg/kg /day)4

Baseline

Inhalation Dose

(mg/kg/ day)5


Baseline Inhalation

MOE7 Total MOE8



0.2 0.497 0.00411 30 3,600 30 Liquids/ Aerial


0.07 1200

2.9 1.2

0.174 0.00144 86 10,400 86

Table 8.1.3: Exposure and Risks for Occupational Handlers of AAPs in Herbicide Products Used in Low Pressure Handwand Applications to Ornamentals in Greenhouses (All Exposure Durations) at Baseline Exposure Scenario


Application/ Crop)


Area Treated Daily2

(acres)

Dermal Unit


Inhalation Unit



(mg/kg /day)4

Baseline

Inhalation Dose

(mg/kg/ day)5


Baseline Inhalation

MOE7 Total MOE8

Mixer/Loader/Applicator for Herbicide Products with 20% AAP in formulation Liquids/ Low Pressure Handwand/ Ornamentals 1.44 5 100 30 0.514 0.0031 29 4,900 29

Mixer/Loader/Applicator for Herbicide Products with 15% AAP in formulation

Liquids/ Low Pressure Handwand/ Ornamentals 1.08 5 100 30 0.386 0.0023 39 6,500 39






Page 38 of 94



Application/ Crop)


Area Treated Daily2

(acres)

Dermal Unit


Inhalation Unit



(mg/kg /day)4

Baseline

Inhalation Dose

(mg/kg/ day)5


Baseline Inhalation

MOE7 Total MOE8

Liquids/ Airblast/ Nut Tree (ST) 0.9 0.075 0.00062 200 24,000 200

Liquids/ Airblast/ Nut Tree (IT) 0.25

40 0.0207 0.00017 720 88,000 720

Liquids/ Groundboom/ High Acreage Crops (ST) 0.2 0.0829 0.00069 180 22,000 180

Liquids/ Groundboom/ High Acreage Crops (IT) 0.07

200 0.029 0.00024 520 63,000 520

Liquids/ Groundboom/ Turf (ST) 0.2 0.0166 0.000137 900 110,000 900

Liquids/ Groundboom/ Turf (IT) 0.07

40 0.0058 0.000048 2,600 310,000 2,600

Liquids/ Low Pressure Handwand/ Turf (ST) 0.72 0.0075 0.00006 2,000 240,000 2,000

Liquids/ Low Pressure Handwand/ Turf (IT) 0.72

5 0.0075 0.00006 2,000 240,000 2,000

Wettable Powder/ Airblast/ Nut Tree (ST) 0.6 0.0634 0.01474 240 1,000 190

Wettable Powder/ Airblast/ Nut Tree (IT) 0.3

40 0.0317 0.00737 470 2,000 380

Wettable Powder/ Groundboom/ High Acreage Crops (ST)

0.2 0.1057 0.025 140 600 120 Wettable Powder/

Groundboom/ High Acreage Crops (IT)

0.07 200

0.037 0.0086 410 1,700 330

Wettable Powder/ Groundboom/ Turf (ST) 0.2 0.02 0.0049 700 3,100 600


40 0.0074 0.00172 2,000 8,700 1,600


(ST) 0.72 0.0095 0.0022 1,600 7,000 1,300


(IT) 0.72

5

3.7 43

0.0095 0.0022 1,600 6,800 1,300


Liquid/ Aerial Application/ High Acreage Crops (ST)9 0.2 0.0009 0.0002 16,000 65,000 13,000

Liquid/ Aerial Application/ High Acreage Crops (IT)9 0.07

1200 Eng

control only:

0.0055

Eng control only:

0.068 0.0003 0.0001 45,000 180,000 36,000

Airblast/ Nut Tree (ST) 0.9 40 0.36 4.5 0.0093 0.002314 1,600 6,500 1,300




Page 39 of 94



Application/ Crop)


Area Treated Daily2

(acres)

Dermal Unit


Inhalation Unit



(mg/kg /day)4

Baseline

Inhalation Dose

(mg/kg/ day)5


Baseline Inhalation

MOE7 Total MOE8

Airblast/ Nut Tree (IT) 0.25 0.0026 0.000643 5,800 23,000 4,700

Groundboom/ High Acreage Crops (ST) 0.2 0.0004 0.000423 38,000 35,000 18,000

Groundboom/ High Acreage Crops (IT) 0.07

200 0.00014 0.000148 110,000 100,000 52,000

Groundboom/ Turf (ST) 0.2 0.00008 0.000085 190,000 180,000 90,000

Groundboom/ Turf (IT) 0.07 40

0.014 0.74

0.00003 0.00003 540,000 510,000 260,000

Mixer/Loader/ Applicator Scenarios

Low Pressure Handwand/ Turf (ORETF data) (ST)10 0.72 NA 0.00034 NA 44,000 NA

Low Pressure Handwand/ Turf (ORETF data) (IT) 10 0.72

no data 6.6

NA 0.00034 NA 44,000 NA Wettable Powder/ Low

Pressure Handwand/ Ornamentals (ST) 10


Pressure Handwand/ Ornamentals (IT) 10


Pressure Handwand/ Ornamentals (LT) 10

0.72

5

no data 1100

NA 0.05657 NA 270 NA Liquid/ Low Pressure

Handwand/ Ornamentals (ST)


Handwand/ Ornamentals (IT)


Handwand/ Ornamentals (LT)

0.72

5 100 30

0.257 0.00154 58 9,700 58

Flagger Scenarios

Liquid/ Flagger/ High Acreage Crops (ST) 0.2 0.0019 0.0012 7,900 13,000 4,800


1200 0.011 0.35 0.00066 0.00042 23,000 36,000 14,000




Page 40 of 94

1Application rates are based on maximum application rates of products containing inerts in the AAPs multiplied by 10% to convert to application rate of just inert in an insecticide product (Insecticide products contain maximum of 10% inert from the AAPs according to Inerts Task Force). Application rates for Short-term (ST) exposure risk estimates are based on maximum application rates. Application rates for Intermediate- (IT) and long-term (LT) exposures are based on average application rates. 2Area treated daily values are from the EPA HED estimates of acreage treated in a single day for each exposure scenario. 3Unit Exposure values are reported in PHED Surrogate Exposure Guide dated August 1998 or from ORETF data. All exposure scenarios assess baseline exposure scenario and baseline inhalation exposure except for aerial applicator scenarios, which assess inhalation and dermal exposures with engineering controls. 4Daily Dermal Dose = (Dermal Unit Exposure (mg inert /lb inert) * Application Rate (lb inert /A) * Area Treated (A /day))/ Body Weight (70 kg) * Dermal Absorption Factor of 5% (0.05) 5 Daily Inhalation Dose = (Inhalation Unit Exposure (µg inert / lb inert) * Conversion Factor (1 mg /1000 µg) * Application Rate (lb inert /A) * Area Treated (A /day)) / Body Weight (70 kg) 6 Dermal MOE = PoD (NOAEL of 15 mg/kg/day)/ Daily dermal dose (mg/kg/day) 7ST Inhalation MOE = PoD (NOAEL of 15 mg/kg/day) / Daily inhalation dose (mg/kg/day) 8Total MOE = 1/ (1/Dermal MOE + 1/Inhalation MOE) 9Aerial applicators do not have baseline exposure: only engineering control exposure can be assessed. All other exposure scenarios assess the baseline exposure scenario and baseline inhalation exposure. 10These scenarios have baseline inhalation unit exposures, but not baseline dermal unit exposures. The M/L/A scenario assessed in Table 8.1.4. results in a higher exposure (and therefore is health protective) than either of the two “NA” scenarios shown at baseline plus gloves dermal exposure.

1Application rates are based on maximum application rates of products containing inerts in the AAPs multiplied by 10% to convert to application rate of just inert in an insecticide product (Insecticide products contain maximum of 10% inert from the AAPs according to Inerts Task Force). Application rates for Short-term (ST) exposure risk estimates are based on maximum application rates. Application rates for Intermediate-term (IT) and long-term (LT) exposures are based on average application rates. 2Area treated daily values are from the EPA HED estimates of acreage treated in a single day for each exposure scenario of concern. 3Unit Exposure values are reported in PHED Surrogate Exposure Guide dated August 1998 or from ORETF data. All exposure scenarios assess baseline plus gloves and baseline inhalation exposure except for aerial applicator scenarios, which assess inhalation and dermal exposures with engineering controls. 4Daily Dermal Dose = (Dermal Unit Exposure (mg inert /lb inert) * Application Rate (lb inert /A) * Area Treated (A /day))/ Body Weight (70 kg) * Dermal Absorption Factor of 5% (0.05) 5 Daily Inhalation Dose = (Inhalation Unit Exposure (µg inert / lb inert) * Conversion Factor (1 mg /1000 µg) * Application Rate (lb inert /A) * Area Treated (A /day)) / Body Weight (70 kg) 6 Dermal MOE = PoD (NOAEL of 15 mg/kg/day)/ Daily dermal dose (mg/kg/day) 7ST Inhalation MOE = PoD (NOAEL of 30 15 mg/kg/day) / Daily inhalation dose (mg/kg/day) 8Total MOE = 1/ (1/Dermal MOE + 1/Inhalation MOE) *Aerial applicators do not have baseline exposure: only engineering control exposure can be assessed. All other exposure scenarios assess baseline plus gloves and baseline inhalation exposure.

Table 8.1.5. Exposure and Risks for Occupational Handlers of AAPs in Insecticide Products (All Exposure Durations) with Baseline Plus Gloves for High Acreage Mixer/ Loader Scenarios


Application/ Crop)


Area Treated Daily2

(acres)

Dermal Unit


Inhalation Unit


Baseline +

Gloves Dose

(mg/kg /day)4

Baseline

Inhalation Dose

(mg/kg/ day)5


Baseline Inhalation

MOE7 Total MOE8



0.2 0.00394 0.00411 3,800 3,600 1,900 Liquids/ Aerial


0.07 1200 0.023 1.2

0.00138 0.00144 11,000 10,400 5,300




Page 41 of 94

1Application rates are based on maximum application rates of products containing inerts in the AAPs multiplied by variable % AAP in formulation to convert to application rate of just inert in an insecticide product. Application rates for Short-term (ST) exposure risk estimates are based on maximum application rates. Application rates for Intermediate-term (IT) and long-term (LT) exposures are based on average application rates. 2Area treated daily values are from the EPA HED estimates of acreage treated in a single day for each exposure scenario of concern. 3Unit Exposure values are reported in PHED Surrogate Exposure Guide dated August 1998 or from ORETF data. All exposure scenarios assess baseline exposure scenario and baseline inhalation exposure 4Daily Dermal Dose = (Dermal Unit Exposure (mg inert /lb inert) * Application Rate (lb inert /A) * Area Treated (A /day))/ Body Weight (70 kg) * Dermal Absorption Factor of 5% (0.05) 5 Daily Inhalation Dose = (Inhalation Unit Exposure (µg inert / lb inert) * Conversion Factor (1 mg /1000 µg) * Application Rate (lb inert /A) * Area Treated (A /day)) / Body Weight (70 kg) 6 Dermal MOE = PoD (NOAEL of 15 mg/kg/day)/ Daily dermal dose (mg/kg/day) 7ST Inhalation MOE = PoD (NOAEL of 15 mg/kg/day) / Daily inhalation dose (mg/kg/day) 8Total MOE = 1/ (1/Dermal MOE + 1/Inhalation MOE)

Table 8.1.7. Exposure and Risks for Occupational Handlers of AAPs in Fungicide Products (All Exposure Durations) with Baseline Exposure Scenario


Application/ Crop)


Area Treated Daily2

(acres)

Dermal Unit


Inhalation Unit



(mg/kg /day)4

Baseline

Inhalation Dose

(mg/kg/ day)5


Baseline Inhalation

MOE7 Total MOE8

Mixer/Loader Scenarios Liquids/ Aerial Application/ High Acreage Crops (ST)

0.5 1.243 0.010286 12 1,500 12 Liquids/ Aerial Application/ High Acreage Crops (IT)

0.07 1200

0.174 0.00144 86 10,000 86

Liquids/ Airblast/ Nut Tree (ST) 1.1 40

2.9 1.2

0.09114 0.000754 160 20,000 160

Table 8.1.6: Exposure and Risks for Occupational Handlers of AAPs in Insecticides Products Used in Low Pressure Handwand Applications to Ornamentals in Greenhouses (All Exposure Durations) at Baseline Exposure Scenario


Application/ Crop)


Area Treated Daily2

(acres)

Dermal Unit


Inhalation Unit



(mg/kg /day)4

Baseline

Inhalation Dose

(mg/kg/ day)5


Baseline Inhalation

MOE7 Total MOE8

Mixer/Loader/Applicator for Insecticides Products with 8% AAP in formulation Liquids/ Low Pressure Handwand/ Ornamentals 0.576 5 100 30 0.2057 0.0012 73 12,000 72

Mixer/Loader/Applicator for Insecticides Products with 6% AAP in formulation


Mixer/Loader/Applicator for Insecticides Products with 5% AAP in formulation





Page 42 of 94



Application/ Crop)


Area Treated Daily2

(acres)

Dermal Unit


Inhalation Unit



(mg/kg /day)4

Baseline

Inhalation Dose

(mg/kg/ day)5


Baseline Inhalation

MOE7 Total MOE8

Liquids/ Airblast/ Nut Tree (IT) 0.3 0.0249 0.000206 600 73,000 600

Liquids/ Groundboom/ High Acreage Crops (ST) 0.5 0.207 0.001714 70 9,000 70

Liquids/ Groundboom/ High Acreage Crops (IT) 0.07

200 0.029 0.00024 520 63,000 510

Liquids/ Groundboom/ Turf (ST) 0.5 0.0414 0.000343 360 44,000 360

Liquids/ Groundboom/ Turf (IT) 0.07

40 0.0058 0.000048 2,600 310,000 2,600

Liquids/ Low Pressure Handwand/ Turf (ST) 0.72 0.0075 0.000062 2,000 240,000 2,000

Liquids/ Low Pressure Handwand/ Turf (IT) 0.72

5 0.0075 0.000062 2,000 240,000 2,000

Wettable Powder/ Airblast/ Nut Tree (ST) 0.7 0.074 0.0172 200 870 170

Wettable Powder/ Airblast/ Nut Tree (IT) 0.2

40 0.02114 0.004914 710 3,100 580

Wettable Powder/ Groundboom/ High Acreage Crops (ST)

0.1 0.0529 0.012286 280 1,200 230 Wettable Powder/ Groundboom/ High Acreage Crops (IT)

0.06 200

0.03171 0.00737 470 2,000 380

Wettable Powder/ Groundboom/ Turf (ST) 0.1 0.0106 0.002457 1,400 6,000 1,200


40 0.0063 0.00147 2,400 10,000 1,900

Wettable powder/ Low Pressure Handwand/ Turf (ST)

0.72 0.00951 0.002211 1,600 6,800 1,300 Wettable powder/ Low Pressure Handwand/ Turf (IT)

0.72 5

3.7 43

0.00951 0.002211 1,600 6,800 1,300


Liquid/ Aerial Application/ High Acreage Crops (ST)9 0.5 0.0024 0.0006 6,500 25,000 5,000

Liquid/ Aerial Application/ High Acreage Crops (IT)9 0.07

1200 Eng

control only:

0.0055

Eng control only:

0.068 0.0003 0.0001 45,000 180,000 36,000

Airblast/ Nut Tree (ST) 0.7 0.0072 0.0018 2,100 8,500 1,700

Airblast/ Nut Tree (IT) 0.3 40 0.36 4.5

0.0031 0.000771 4,900 19,000 3,900




Page 43 of 94



Application/ Crop)


Area Treated Daily2

(acres)

Dermal Unit


Inhalation Unit



(mg/kg /day)4

Baseline

Inhalation Dose

(mg/kg/ day)5


Baseline Inhalation

MOE7 Total MOE8

Groundboom/ High Acreage Crops (ST) 0.5 0.001 0.001057 15,000 14,000 7,500

Groundboom/ High Acreage Crops (IT) 0.07

200 0.00014 0.000148 110,000 100,000 52,000

Groundboom/ Turf (ST) 0.5 0.0002 0.000211 75,000 70,000 37,000

Groundboom/ Turf (IT) 0.07 40

0.014 0.74

0.00003 0.000029 540,000 510,000 260,000

Mixer/Loader/ Applicator Scenarios

Low Pressure Handwand/ Turf (ORETF data) (ST) 10 0.72 NA 0.000339 NA 44,000 NA

Low Pressure Handwand/ Turf (ORETF data) (IT) 10 0.72

NA 6.6 NA 0.000339 NA 44,000 NA

Wettable Powder/ Low Pressure Handwand/ Ornamentals (ST) 10

0.72 NA 0.05657 NA 270 NA Wettable Powder/ Low Pressure Handwand/ Ornamentals (IT) 10

0.72 NA 0.05657 NA 270 NA Wettable Powder/ Low Pressure Handwand/ Ornamentals (LT) 10

0.72

5

NA 1100

NA 0.05657 NA 270 NA Liquid/ Low Pressure Handwand/ Ornamentals (ST)

0.72 0.257 0.001543 58 9,700 58 Liquid/ Low Pressure Handwand/ Ornamentals (IT)

0.72 0.257 0.001543 58 9,700 58 Liquid/ Low Pressure Handwand/ Ornamentals (LT)

0.72

5 100 30

0.257 0.001543 58 9,700 58

Flagger Scenarios

Liquid/ Flagger/ High Acreage Crops (ST) 0.5 0.0047 0.003 3,200 5,000 1,900


1200 0.011 0.35 0.00066 0.00042 23,000 36,000 14,000 1Application rates are based on maximum application rates of products containing inerts in the AAPs multiplied by 10% to convert to application rate of just inert in an fungicide product (Fungicide products contain maximum of 10% inert from the AAPs according to the Inerts Task Force). Application rates for Short-term (ST) exposure risk estimates are based on maximum application rates. Application rates for Intermediate-term (IT) exposures are based on average application rates. 2Area treated daily values are from the EPA HED estimates of acreage treated in a single day for each exposure scenario of concern. 3Unit Exposure values are reported in PHED Surrogate Exposure Guide dated August 1998 or from ORETF data. All exposure scenarios assess baseline exposure scenario and baseline inhalation exposure except for aerial applicator scenarios, which assess inhalation and dermal exposures with engineering controls. 4Daily Dermal Dose = (Dermal Unit Exposure (mg inert /lb inert) * Application Rate (lb inert /A) * Area Treated (A /day))/ Body Weight (70 kg) * Dermal Absorption Factor of 5% (0.05)




Page 44 of 94

5 Daily Inhalation Dose = (Inhalation Unit Exposure (µg inert / lb inert) * Conversion Factor (1 mg /1000 µg) * Application Rate (lb inert /A) * Area Treated (A /day)) / Body Weight (70 kg) 6 Dermal MOE = PoD (NOAEL of 15 mg/kg/day)/ Daily dermal dose (mg/kg/day) 7ST Inhalation MOE = PoD (a NOAEL of 15 mg/kg/day) / Daily inhalation dose (mg/kg/day) 8Total MOE = 1/ (1/Dermal MOE + 1/Inhalation MOE) 9Aerial applicators do not have baseline exposure: only engineering control exposure can be assessed. All other exposure scenarios assess the baseline exposure scenario and baseline inhalation exposure. 10These scenarios have baseline inhalation unit exposures, but not baseline dermal unit exposures. The M/L/A scenario assessed in Table 8.1.7. results in a higher exposure (and therefore is health protective) than either of the two “NA” scenarios shown at baseline plus gloves dermal exposure.

Table 8.1.8. Exposure and Risks for Occupational Handlers of AAPs in Fungicide Products (All Exposure Durations) with Baseline Plus Gloves for High Acreage Mixer/ Loader Scenarios


Application/ Crop)


Area Treated Daily2

(acres)

Dermal Unit


Inhalation Unit


Baseline +

Gloves Dermal Dose

(mg/kg /day)4

Baseline

Inhalation Dose

(mg/kg/ day)5


Baseline Inhalation

MOE7 Total MOE8



0.5 0.00986 0.010286 1,500 1,500 750 Liquids/ Aerial


0.07 1200

0.00138 0.00144 11,000 10,000 5,300 Liquids/ Groundboom/ High Acreage Crops (ST) 0.5 0.00164 0.0017 9,100 8,800 4,500 Liquids/ Groundboom/ High Acreage Crops (IT) 0.07

200

0.023 1.2

0.00023 0.00024 65,000 63,000 32,000 1Application rates are based on maximum application rates of products containing inerts in the AAPs multiplied by 10% to convert to application rate of just inert in an fungicide product (Fungicide products contain maximum of 10% inert from the AAPs according to the Inerts Task Force). Application rates for Short-term (ST) exposure risk estimates are based on maximum application rates. Application rates for Intermediate-term (IT) exposures are based on average application rates. 2Area treated daily values are from the EPA HED estimates of acreage treated in a single day for each exposure scenario of concern. 3Unit Exposure values are reported in PHED Surrogate Exposure Guide dated August 1998 or from ORETF data. All exposure scenarios assess baseline plus gloves and baseline inhalation exposure except for aerial applicator scenarios, which assess inhalation and dermal exposures with engineering controls. 4Daily Dermal Dose = (Dermal Unit Exposure (mg inert /lb inert) * Application Rate (lb inert /A) * Area Treated (A /day))/ Body Weight (70 kg) * Dermal Absorption Factor of 5% (0.05) 5 Daily Inhalation Dose = (Inhalation Unit Exposure (µg inert / lb inert) * Conversion Factor (1 mg /1000 µg) * Application Rate (lb inert /A) * Area Treated (A /day)) / Body Weight (70 kg) 6 Dermal MOE = PoD (NOAEL of 15 mg/kg/day)/ Daily dermal dose (mg/kg/day) 7ST Inhalation MOE = PoD (a NOAEL of 15 mg/kg/day) / Daily inhalation dose (mg/kg/day) 8Total MOE = 1/ (1/Dermal MOE + 1/Inhalation MOE)




Page 45 of 94

1Application rates are based on maximum application rates of products containing inerts in the AAPs multiplied by variable % AAP in formulation to convert to application rate of just inert in a fungicides product. Application rates for Short-term (ST) exposure risk estimates are based on maximum application rates. Application rates for Intermediate-term (IT) and long-term (LT) exposures are based on average application rates. 2Area treated daily values are from the EPA HED estimates of acreage treated in a single day for each exposure scenario of concern. 3Unit Exposure values are reported in PHED Surrogate Exposure Guide dated August 1998 or from ORETF data. All exposure scenarios assess baseline exposure scenario and baseline inhalation exposure 4Daily Dermal Dose = (Dermal Unit Exposure (mg inert /lb inert) * Application Rate (lb inert /A) * Area Treated (A /day))/ Body Weight (70 kg) * Dermal Absorption Factor of 5% (0.05) 5 Daily Inhalation Dose = (Inhalation Unit Exposure (µg inert / lb inert) * Conversion Factor (1 mg /1000 µg) * Application Rate (lb inert /A) * Area Treated (A /day)) / Body Weight (70 kg) 6 Dermal MOE = PoD (NOAEL of 15 mg/kg/day)/ Daily dermal dose (mg/kg/day) 7ST Inhalation MOE = PoD (NOAEL of 15 mg/kg/day) / Daily inhalation dose (mg/kg/day) 8Total MOE = 1/ (1/Dermal MOE + 1/Inhalation MOE)

8.2 Occupational Postapplication Risk HED uses the term postapplication to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re-entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Postapplication exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for postapplication exposure. Inhalation exposures are not typically calculated for occupational post-application scenarios because inhalation exposures generally account for a negligible percentage of the overall body burden for most pesticide chemicals. This is particularly true for chemicals with a low vapor pressure such as the AAPs.

Table 8.1.9: Exposure and Risks for Occupational Handlers of AAPs in Fungicides Products Used in Low Pressure Handwand Applications to Ornamentals in Greenhouses (All Exposure Durations) at Baseline Exposure Scenario (14% AAP in Formulation)


Application/ Crop)


Area Treated Daily2

(acres)

Dermal Unit


Inhalation Unit



(mg/kg /day)4

Baseline

Inhalation Dose

(mg/kg/ day)5


Baseline Inhalation

MOE7 Total MOE8

Mixer/Loader/Applicator for Fungicide Products with 8% AAP in Formulation Liquids/ Low Pressure Handwand/ Ornamentals 0.576 5 100 30 0.2057 0.0012 73 12,000 72

Mixer/Loader/Applicator for Fungicide Products with 6% AAP in formulation


Mixer/Loader/Applicator for Fungicide Products with 5% AAP in formulation Liquids/ Low Pressure Handwand/ Ornamentals 0.36 5 100 30 0.129 0.00077 120 19,000 120




Page 46 of 94

Exposure Scenarios This assessment is considered to be a screening level estimate, demonstrating that there are minimal potential risks to workers re-entering fields treated with pesticides containing the AAPs as inert ingredients. While the AAPs are present in formulations designated for crops besides those assessed in this document, risk estimates for those occupational postapplication scenarios are expected to be less than those scenarios assessed in this document (i.e., calculated MOEs will be higher). The three occupational postapplication scenarios assessed are for postapplication activities associated with:

• Tall field/row crops (including scouting, weeding, hand harvesting sweet corn) • Turf (golf course/sod farm) (including mowing, transplanting, hand weeding) • Vine/Trellis crops (including scouting, training, tying, thinning, and grape girding

and cane turning)

Exposure Data and Assumptions The assumptions used in the postapplication risk assessment calculations are detailed as follows:

• The average occupational workday is assumed to be 8 hours. • The adverse effects for the short- and intermediate-term dermal PoD’s are based

on studies where the effects were observed in both sexes; therefore, the body weight of 70 kg was used to estimate exposure.

• HED has developed standard transfer coefficient values for occupational postapplication scenarios to ensure consistency in exposure assessments. These standard values were used to calculate postapplication exposures.

• Anticipated post-application activities and their respective dermal transfer coefficients (TCs) are summarized in Table 8.2.1. The TC information is based on the Science Advisory Council for Exposure Policy Number 3.1.

• The transfer coefficient for sod transplanting, and hand weeding used to represent dermal exposure is from Agriculture Reentry Task Force (ARTF) data; study ARF-035 (MRID 45432303).

• Calculations of postapplication exposures are completed using maximum application rates of the products of that type of pesticide (herbicide, insecticide, or fungicide) for short-term exposures and average application rates of products for intermediate-term exposures.

• Herbicides assessed can contain a maximum of 25% AAP in any product formulation; insecticides and fungicides contain a maximum of 10% in any product formulation.

• No postapplication data were submitted for the AAPs; a default 20% of the application rate (for agricultural crops) and 5% (for turf) is considered available as a transferrable residue with a 10% default daily dissipation rate.

• Dermal absorption is assumed to be 5%. Risks were calculated using the Margin of Exposure (MOE) approach, which is a ratio of the exposure to the toxicological PoD.




Page 47 of 94

Risk Characterization A variety of pesticide formulations contain AAPs. PPE is usually not required for worker re-entry, and therefore these postapplication risk estimates are based on the baseline exposure scenario (i.e., typical work clothing but no gloves). Typically, HED characterizes the risk estimate in relation to the restricted entry interval (REI) for a particular active ingredient. While REIs for specific products are not discussed in this risk assessment, occupational post-application scenarios assessed generally result in MOEs that do not indicate risks of concern on Day 0 (the day of application) except for two postapplication scenarios. Occupational postapplication risk estimates are presented in Table 8.2.1. The risk estimates for the three exposure scenarios assessed resulted in MOEs do not demonstrate risks of concern (i.e., MOEs > 100) on Day 0, except for two scenarios:

1) the short-term worker postapplication activities involving herbicides on corn, specifically the hand-harvesting harvesting/ detassling scenario. That scenario resulted in an MOE of 53 on the day of application (Day 0). Assuming an herbicide application at the maximum application rate, the MOE would exceed 100 for this scenario at day 13 after application. The Agency notes that it is not expected to be typical agricultural practice to apply herbicides on the same day workers would be conducting hand harvesting and detassling activities. As noted earlier in this assessment, herbicides and insecticides are typically applied relatively early in a growing season. All other postapplication scenarios result in MOEs that do not demonstrate risks of concern on the day of application (Day 0).

2) the short-term worker postapplication activities involving insecticides on corn, specifically the hand-harvesting harvesting/ detassling scenario. That scenario resulted in an MOE of 69 on the day of application (Day 0). Assuming an insecticide application at the maximum application rate, the MOE would exceed 100 for this scenario at day 4 after application. The Agency notes that it is not expected to be typical agricultural practice to apply insecticides on the same day workers would be conducting hand harvesting and detassling activities. As noted earlier in this assessment, herbicides and insecticides are typically applied relatively early in a growing season. All other postapplication scenarios result in MOEs that do not demonstrate risks of concern on the day of application (Day 0).

Table 8.2.1. Short- and Intermediate-Term Occupational Postapplication Dermal Exposures and Risks for the AAPs Crop &

Exposure Duration

Application Rate

(lb inert /A) Work Activity

Transfer Coefficient1

(cm2/hr) Day after

Treatment2 DFRt

(µg/cm2)3 Daily Dose

(mg/kg/day)4 MOE5 Herbicide Product Scenarios

Scout, weed low foliage 100 0 0.0033 4,500

Scout, weed high foliage 400 0 0.0133 1,100

Corn (ST) 2.6

Scout, irrigate, weed high

foliage 1,000 0

5.834

0.0333 450




Page 48 of 94


Exposure Duration

Application Rate



(cm2/hr) Day after

Treatment2 DFRt


(mg/kg/day)4 MOE5 Harvesting/ detassling 17,000 0 0.5667 26

Days till MOE > 100 13 Scout, weed low

foliage 100 0 0.0004 39,000



foliage 1,000 0 0.0038 3,900

Corn (IT) 0.3

Harvesting/ detassling 17,000 0

0.673

0.0654 230

Hedge, irrigate, weed, scout,

train, tie 500 0 0.0077 1,900

Scout, train, tie 1,000 0 0.0154 970 Harvest, pull, thin, prune,

train, tie 5,000 0 0.0769 200

Grapes (Table)

(ST) 1.2

Cane turning, girdle 10,000 0

2.693

0.1539 100


train, tie 500 0 0.0045 3,300

Scout, train, tie 1,000 0 0.0090 1,700 Harvest, pull, thin, prune,

train, tie 5,000 0 0.0449 330

Grapes (Table)

(IT) 0.7


1.571

0.0898 170

Mowing 500 0 0.004 3,800 Turf/ sod (ST) 2.6 Transplant,

weed, harvest 6,800 0 1.458

0.057 260

Mowing 500 0 0 31,000 Turf/ Sod (IT) 0.3 Transplant,

weed, harvest* 6,800 0 0.168

0.007 2,300

Insecticide Product Scenarios Scout, weed low

foliage 100 0 0.0013 12,000



foliage 1,000 0 0.0128 1,200

Corn (ST) 1.0


2.244

0.2180 69

Days till MOE > 100 4




Page 49 of 94


Exposure Duration

Application Rate



(cm2/hr) Day after

Treatment2 DFRt


(mg/kg/day)4 MOE5 Scout, weed low

foliage 100 0 0.0001 120,000



foliage 1,000 0 0.0013 12,000

Corn (IT) 0.1


0.224

0.0218 690


train, tie 500 0 0.0045 3,300


train, tie 5,000 0 0.0449 330

Grapes (Table)

(ST) 0.7


1.571

0.0898 170


train, tie 500 0 0.0019 7,800


train, tie 5,000 0 0.0192 780

Grapes (Table)

(IT) 0.3


0.673

0.0385 390

Mowing

500 0 0.002 10,000 Turf/ sod

(ST) 1.0 Transplant, weed, harvest 6,800 0

0.561 0.022 700

Mowing 500 0 0 94,000 Turf/ Sod

(IT) 0.1 Transplant, weed, harvest* 6,800 0

0.056 0.002 6,900

Fungicide Product Scenarios Scout, weed low

foliage 100 0 0.0006 24,000



foliage 1,000 0

0.0064 2,400 Corn (ST) 0.5


1.122

0.1090 140

Scout, weed low foliage 100 0 0.0001 120,000 Corn (IT) 0.1

Scout, weed high foliage 400 0

0.224

0.0005 29,000




Page 50 of 94


Exposure Duration

Application Rate



(cm2/hr) Day after

Treatment2 DFRt


(mg/kg/day)4 MOE5 Scout, irrigate,

weed high foliage

1,000 0 0.0013 12,000

Harvesting/ detassling 17,000 0 0.0218 690


train, tie 500 0 0.0032 4,700


train, tie 5,000 0 0.0321 470

Grapes (Table)

(ST) 0.5


1.122

0.0641 240


train, tie 500 0 0.0013 12,000


train, tie 5,000 0 0.0128 1,200

Grapes (Table)

(IT) 0.2


0.449

0.0256 580

Mowing

500 0 0.001 19,000 Turf/ sod

(ST) 0.5 Transplant, weed, harvest* 6,800 0

0.28 0.011 1,400

Mowing 500 0 0 94,000 Turf/ Sod

(IT) 0.1 Transplant, weed, harvest*

6,800 0 0.056 0.002 6,900

* The TC from this exposure scenario uses ARTF data - study ARF-035 (MRID 45432303). 9.0 Environmental Justice Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf). As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered



http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf�


Page 51 of 94

food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. 10.0 Human Studies This assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide. These studies, listed below, have received the appropriate ethical review for use in risk assessment.

The PHED Task Force, 1998. The Pesticide Handler Exposure Database (PHED), Version 1.1. Task Force members: Health Canada, U.S. Environmental Protection Agency, the California Department of Pesticide regulation, and the American Crop Protection Association; released August 1998.

ORETF Handler Studies (MRID 44972201): Outdoor Residential Exposure Task




Page 52 of 94

APPENDIX A A.1 Acute Toxicity Profile for Alkyl Amine Polyalkoxylates

Table A.1. Acute Toxicity Profile of Alkyl Amine Polyalkoxylates

Guideline No.

Study Type

MRIDs #

Results

Toxicity Category

81-1 Acute Oral – rat 46902001 MON 0818 (CAS 61791-26-2) Tallow, POE n=15

LD50 = ♂ 1436.7 mg/kg

LD50 = ♀ 1315.1 mg/kg

(reported as 1200 mg/kg)

III

81-1 Acute Oral – rat ICI CTL ATMER® 163 (CAS 70955-14-5) C13-C15, POE n=2

LD50 = 1500 mg/kg

III

81-1 Acute Oral – rat CIT Armoblen 557 (CAS 68213-26-3) Tallow, POE n=5/12

LD50 =1663 mg/kg

III

81-1 Acute Oral – rat CPT Ethomeen C/12 (CAS 61791-31-9)

Coco, POE 2 LD50 = 6600 mg/kg

IV

81-1 Acute Oral – rat Safepharm Ethomeen C/15 (CAS 61791-14-8) Coco, POE n=5 LD50 >200 mg/kg

II

81-1 Acute Oral – rat Safepharm Ethomeen T/12 (CAS 61791-44-4)

Tallow, POE 2 LD50 = >2000 mg/kg

III

81-1 Acute Oral – rat Safepharm Ethomeen S/12 (CAS 73246-96-5)

Soya, POE 2 LD50 = 1260 mg/kg

III

81-2 Acute Dermal -rabbit

46902001 MON 0818 (CAS 61791-26-2)

LD50 > 1260 mg/kg

II




Page 53 of 94


Guideline No.

Study Type

MRIDs #

Results

Toxicity Category

81-3 Acute Inhalation - rat

CIVO/TNO

Temple U

Temple U

Armoblen 557 (CAS 68213-26-3)

LC50 (4 hr) 0.66 mg/L (0.42-0.85)

Ethomeen C/12 (CAS 61791-31-9)

LC 50 (1 hr) 0.98 mg/L)

Ethomeen T/12 (CAS 61791-44-4)

LC50 (1 hr) 3.19 mg/L

III

III

IV

81-4 Primary Eye Irritation

Rabbit

46902001

CIVO/TNO

Leberco Lab

CPT

FDRL

PSL

CPT

MON 0818 (CAS 61791-26-2)

Corrosive

Armoblen 557 (CAS 68213-26-3)

Non-irritating/non-corrosive


Severely irritating (irreversible corneal opacity, iritis, redness, sewlling, discharge of conjunctiva (2 studies)


Corrosive


Persistent extreme corneal opacity, iritis, necrosis of conjunctiva tissue (3 studies)


Corrosive


Persistent extreme corneal opacity, iritis, necrosis; corrosive Ethomeen T/30 (CAS 61791-26-2)

Corrosive

I




Page 54 of 94


Guideline No.

Study Type

MRIDs #

Results

Toxicity Category

81-5 Primary Skin Irritation - rabbit

46902001

EB0467

CIT

Safepharm

Safepharm

IBR-US, Inc

Safepharm

MON 0818 (CAS 61791-26-2)

Severely irritating to skin

ATMER® 163 CAS 70955-14-5

Corrosive (undiluted)

Armoblen 557 (CAS 68213-26-3)

Non-irritant


Moderate to severe irritant (4 hr)


Moderate to severe irritant (4 hr)


Minimally irritating (4 hr)


Severely irritating but not corrosive (4 hr)

II

81-6 Dermal Sensitization

Guinea pig

46918001

Hill Top

MB Lab

MON 0818 (CAS 61791-26-2)

Dermal sensitizer


Not a sensitizer


May be a sensitizer to sensitive individuals (mice)




Page 55 of 94

A.2. Toxicity Profile for the Alkyl Amine Polyalkoxylates

Table A.2. Toxicology Profile of the Alkyl Amine Polyalkoxylates

Guideline No./ Study Type

MRID No. (year)/ Classification /Doses Results

870.3100 90-day/4-week oral toxicity SD rats

MON 0818

CAS 61791-26-2 (tallow, POE 15))

MRID 46918003C (90-day) 1990

MRID 46918002C (28-day) 1989

0, 500, 1500, 4500 ppm

0, 33/39.9, 99.3/123.1, 291.6/356.6 ♂/♀mg/kg/day

Acceptable/guideline

NOAEL = 500 ppm (33/39.9 mg/kg/day)

LOAEL = 1500 ppm (99.3/123.1 mg/kg/day, based on irritation in the intestines and colon (hypertrophy and vacoulation of histiocytes in lamina propria of jejunum and ileum and histiocytosis and accumulation of macrophage aggregates in mesenteric lymph nodes.

870.3100 4-week oral toxicity SD rats MON 0818 CAS 61791-26-2 (tallow, POE n=15)

MRID 46918002C/46918002/

47066302/47066302C (2006/2007)

0. 800, 2000, 5000 ppm (males 51.7, 122.8, 268.7 mg/kg/day; females 63.2, 159.9, 324.8 mg/kg/day)

Acceptable/nonguideline (RF)

NOAEL = males 51.7 mg/kg/day

LOAEL = males 122.8 mg/kg/day, based on reduced body weight gain and food consumption

NOAEL = females 159.9 mg/kg/day

LOAEL = females 324.8 mg/kg/day, based on reduced body weight, body-weight gain, food consumption, and irritation in the colon (soft stools).

870.3100 90-Day oral toxicity Sprague-Dawley (Crl:CD®BR) rats

AMTER® 163

CAS 70955-14-5 (C13-C15, POE n=2)

MRID 47041301 (1991)

0, 15, 30, or 150 mg/kg/day via gavage

Acceptable/guideline


LOAEL = 30 mg/kg/day, based on increased mortality, salivation, and posterior subcapsular cataracts in males as well as wheezing, and macro- and microscopic changes in the nonglandular stomach of both sexes.

2 death @30 mg/kg/day (days 36, 78); 5 deaths @150 mg/kg/day (males days 56, 59, 78 and 82; female day 79)

@150 mg/kg/day, males ↓BWG 30%/females 15%; wheezing & salivation from wk 2 on

870.3150

90-Day oral toxicity in nonrodents (beagles)

ATMER® 163

CAS 70955-14-5 (C13-C15, POE n=2)

MRID 47041302 (1991)

0, 15, 30, 100 mg/kg/day (capsules)

Acceptable/nonguideline

NOAEL = 30 mg/kg/day LOAEL = 100 mg/kg/day, based on clinical signs (increased incidence of salivation, emesis, and soft feces (with mucus alone or mucus and bile-like material)) in males and females, increased alanine aminotransferase (ALT/SGPT) levels in females, and an increased incidence of pigment accumulation in the Kupffer cells and bile canaliculi in the livers of females.




Page 56 of 94




870.3100

28-day oral toxicity

CD rats

Armoblen 557

CAS 68213-26-3 (Tallow, POE n=5/12)

MRID 47193901 (1994)

0, 15, 75, or 200 mg/kg/day (gavage)

Unacceptable (upgradeable)/guideline

(% a.i.)

NOAEL = 75 mg/kg/day (males)

LOAEL = 200 mg/kg/day, based on decreased body weight, body weight gain and food conversion efficiency in males;

NOAEL = 200 mg/kg/day (females) HDT

870.3700a Prenatal developmental (Charles River Crl:CDBr female rats ) MON 0818 CAS 61791-26-2 (tallow, POE n=15)

MRID 46902005 (1990) 0 (corn oil), 15, 100, 300 mg/kg/day GD 6-15 (gavage) 71.9% a.i. Acceptable/guideline

Maternal NOAEL = 100 mg/kg/day Maternal LOAEL = 300 mg/kg/day, based on mortality, clinical signs (rales, soft stools, mucoid feces, diarrhea; females rales, yellow anogenital staining), and decreased body weight, body-weight gain, food consumption. Developmental toxicity NOAEL = 300 mg/kg/day, HDT

870.3800 (screening) Reproduction and fertility effects Crl:CD(SD) IGS BR Sprague-Dawley rats (10 weeks old at start) Screening study (extended to two generations (↓ live litter size) assessed gonadal function, mating behavior, conception, parturition, lactation of F0 and F12 generations; developmental of F1 (PND 70) and F2 (PND 4) generations MON 0818 CAS 61791-26-2 (tallow, POE n=15)

MRID 47097401 (2007) 0, 100, 300, 1000 ppm (diet) males F0 (5.5, 16.6, 56.1)/ F1 (5.0, 14.9, 52.8) mg/kg/day females F0 (6.7, 19.5, 66.6)/ F1 (6.9, 18.9, 64.9) mg/kg/day 10 weeks prior to mating 69-73% a.i. Acceptable/nonguideline reproductive performance, fertility, mating performance, blood samples for testosterone &/or thyroid hormone conc. F1 (1/sex/litter @ necropsy); sperm evaluation (motility/morphology) F1 males; estrous cyclicity; litter size, viability, clinical signs, BW/BWG; developmental parameters (sexual & physical); macroscopic abnormalities @ necropsy (F1 & F2 pups)

Reproductive/offspring NOAEL = 300 ppm (F0/F1males 16.6/14.9; F0/F1 females 19.5/18.9 mg/kg/day Reproductive/offspring LOAEL =1000 ppm (F0/F1males 56.1/52.8; F0/F1 females 66.6/64.9 mg/kg/day, based on litter loss, increase mean number of unaccounted-for implantation sites and decreased mean number of pups born, live litter size and postnatal survival from birth to LD 4 (F1). At 1000 ppm, 3 F0 dams w/ small litters (2-4 pups/litter), and some of these pups died before PND 4; effect not repeated in F2 litters Systemic toxicity NOAEL = 1000 ppm (F0/F1males 56.1/52.8; P/F1 females 66.6/64.9 mg/kg/day, HDT




Page 57 of 94




OECD 422 Crl:CD(SD) IGS BR rats MON 0818 CAS 61791-26-2 (tallow, POE n=15) MON 8109 CAS 61791-31-9 (Coco, POE n=2)

MRID 47405101 (2008 ) MON 8109: 0, 30, 100, 300, 2000 ppm (diet; administered for 14 days prior to mating until study termination) males: 0, 2, 8, 23, 134 mg/kg/day females: 0, 3, 9, 26, 148 mg/kg/day MON 0818: 1000 ppm (diet; administered for 14 days prior to mating until study termination) males: 0, 76 mg/kg/day females: 0, 86 mg/kg/day

MON 0818: parental toxicity/reproductive/ developmental NOAEL = 1000 ppm males 76 mg/kg/day; females 86 mg/kg/day. MON 8109: reproductive NOAEL = 2000 ppm (males 134 mg/kg/day; females (148 mg/kg/day) reproductive LOAEL was not demonstrated. MON 8109 parental toxicity NOAEL = 300 ppm (males 23 mg/kg/day; females 26 mg/kg/day) LOAEL = 2000 ppm (males 134 mg/kg/day; females: 148 mg/kg/day), based on clinical signs, decreased body weight and food consumption (both sexes) MON 8109 developmental toxicity NOAEL = 300 ppm (males 23 mg/kg/day; females 26 mg/kg/day) Developmental toxicity LOAEL = 2000 ppm (males 134 mg/kg/day; females 148 mg/kg/day, based on decreased postnatal survival, reduced live litter size on postnatal day 0, reduced number of pups born, and reduced number of implantation sites.. FOB and locomotor activity (recorded for 6 males/group nearend of study; 6 females/group on LD 4) no treatment-related effects reported on FOB or motor activity

Bacterial reverse mutation test 870.5100 MON 59112 No CAS#

MRID 46914604 strains TA1535, TA1537, TA98 and TA100 of Salmonella typhimurium and strain WP2 uvrA of Eschericha coli 0, 1, 3.33, 10, 33.3, 100 or 333 μg/plate with and without S9 activation for the Salmonella strains and 0, 10, 33.3, 100, 333, 1000 or 3330 μg/plate +/-S9 for WP2 uvrA. Acceptable/guideline

No evidence of induced mutant colonies over background




Page 58 of 94




Bacterial reverse mutation test 870.5100

MON 0818

CAS 61791-26-2 (tallow)

MRID 46918004 strains TA1535, TA1537, TA98 and TA100 of Salmonella typhimurium (0.001, 0.003, 0.01, 0.03 or 0.1 mg/plate with S9 & 0.0003, 0.001, 0.003, 0.01 or 0.03 mg/plate without S9. repeat assay on TA1535 and TA1537 (± S9). cytotoxicity not observed; second cytotoxicity assay. Concentrations of MON 0818 ranging from 0.01 to 1.0 mg/plate +S9 and 0.003 to 0.3 mg/plate –S9 were tested in strain TA98; 0.001 to 0.10 mg/plate ±S9 in TA100; 0.001 to 0.1 mg/plate –S9 in TA1535; 0.003 to 0.3 mg/plate +S9 and 0.001 to 0.1 mg/plate –S9 in TA1537. Acceptable/guideline

MON 0818 was tested up to cytotoxic concentrations in all strains, but failed to induce a mutagenic response in this test system. The positive controls induced the expected mutagenic responses in the appropriate strain. There was no evidence of induced mutant colonies over background.

Mammalian erythrocyte micronucleus test 870. 5395 MON 0818 CAS 61791-26-2 (tallow)

MRID 46902007 (1998) 100 mg/kg Acceptable/guideline

No significant increase in frequency of micronecleated polychromatic erythrocytes in bone marrow after any harvest time up to maximum tolerated dose.

Mammalian erythrocyte micronucleus test 870. 5395

MON 59112

No CAS#

MRID 46930503 (2000) 0, 375, 750 or 1500 mg/kg male mice;0, 500, 1000 or 2000 mg/kg female mice Acceptable/guideline

No significant increase in the frequency of MPCEs in any treatment group at either harvest time

A.3. Toxicity Study Executive Summaries Subchronic repeat dose toxicity studies EXECUTIVE SUMMARY: In a 90-day oral toxicity study (MRID 46918003), MON 0818 (71.9% a.i., Lot No. PIT-8907-757-1) was administered in the diet ad libitum to three groups of 10 male and 10 female Sprague-Dawley rats for 90 days. Target test diet concentrations were 500, 1500, or 4500 ppm (equivalent to 33.0, 99.3, 291.6 mg/kg




Page 59 of 94

bw/day in males and 39.9, 123.1, and 356.6 mg/kg bw/day in females). A similar concurrent control group of rats received basal diet only. Doses were selected based on a previous 28-day range-finding study (MRID 46918002C). Exposure to MON 0818 in the diet at the mid- and high-dose levels of 1500 and 4500 ppm resulted in statistically- and toxicologically-significant effects. Toxicity observed at 4500 ppm consists of clinical signs (soft stools, 3 incidences in 2 males and 86 incidences in all females) observed from day 16 through day 92 of the study, decreased mean body weights throughout the study (ranging from 12-20% and 8-18% in males and females, respectively), and decreased mean total body weight gains in males (31%) and females (35%). Food consumption was also significantly reduced throughout most of the study (13 weeks for males and 10 weeks for females), particularly during the first week of the study (32% decrease in males and 27% decrease in females). Since a food efficiency assessment was not conducted, it is not possible to determine if the decreases in body weights, body weight gains, and food consumption were due, in part, to the unpalatability of the diet. Statistically-significant changes in hematological parameters observed in females may be a result of the inflammation observed in the intestines. Statistically-significant changes in clinical chemistry parameters and organ weights observed in high-dose males and females are likely a result of decreased food consumption/nutrient absorption and body weight. At both the 1500 and 4500 ppm dose levels, microscopic examination conducted at necropsy revealed lesions, including: (1) hypertrophy and/or vacuolation of histiocytes in the lamina propria of the ileum in all high-dose males and females, and 4 of 10 mid-dose males and 4 of 10 mid-dose females; (2) hypertrophy and/or vacuolation of histiocytes in the lamina propria of the jejunum in 4 of 10 high-dose males, 7 of 10 high-dose females, and 1 mid-dose female; and (3) sinus histiocytosis in 9 of 10 high-dose males, 6 of 10 high-dose females, and 2 of 10 mid-dose males and females; and (4) accumulation of macrophage aggregates in the cortex and medullary cords of the mesenteric lymph node in 8 of 10 high-dose males, 7 of 10 high-dose females, and 2 of 10 mid-dose females. These inflammatory changes are likely the cause of the soft stools observed during the study and are considered treatment-related. No statistically-significant treatment related effects on body weight, body weight gain, food consumption, hematological/clinical chemistry parameters, and organ weights were observed at the low-dose level of 500 ppm. In addition, no gross abnormalities or histopathological findings related to treatment were observed at this dose level. Based on review of the study, the no-observable-adverse-effect-level (NOAEL) for MON 0818 is 500 ppm (33.0 mg/kg bw/day in males and 39.9 mg/kg bw/day in females). The lowest-observable-adverse-effect-level (LOAEL) is 1500 ppm (99.3 mg/kg/day in males and 123.1 mg/kg bw/day in females), based on irritation in the intestines and colon (hypertrophy and vacuolation of histiocytes in the lamina propria of the jejunum and ileum, and histiocytosis and accumulation of macrophage aggregates in the mesenteric lymph nodes).




Page 60 of 94

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a 90-day oral toxicity study in rodents (OPPTS 870.3100). EXECUTIVE SUMMARY: In a 90-day oral gavage toxicity study (MRID 47041301), ATMER® 163 (100% a.i.; batch/lot # not reported) was administered to 20 Sprague-Dawley (Crl:CD®BR) rats/sex/dose at concentrations of 0, 15, 30 or 150 mg/kg bw/day. Deionized water was administered to controls. There were no toxicologically significant compound-related effects based on the assessment of clinical chemistry and the limited assessment of organ weights. Urinalysis was not done. Numerous clinical signs were observed in animals dosed at 150 mg/kg bw/day. The most notable signs were wheezing and salivation, which were seen from all animals and in some animals treated with 30 mg/kg bw/day. Other clinical signs observed in both sexes dosed at 150 mg/kg bw/day included blood crust and/or red discharge (nose), dyspnea, rhinorrhea, opaque eyes, redness, hunched posture, thin, urine stains, rough haircoat, desquamation and an increased incidence of alopecia. Two males treated with 30 mg/kg bw/day, as well as four males and one female treated with 150 mg/kg bw/day, died during the study. Statistically significant body weight and body weight gain deficits were observed in both sexes dosed at 150 mg/kg bw/day; overall body weight gains were 30.5% and 15.3% lower than control values in males and females, respectively. Statistically significant decreased food consumption was seen at 150 mg/kg bw/day in males only. The ophthalmoscopic assessment revealed posterior subcapsular cataracts in males at 30 and 150 mg/kg bw/day and in females at 150 mg/kg bw/day while complete cataracts were found only at 150 mg/kg bw/day in both sexes. Increased mean values for platelet count, white blood cell count, segmented neutrophil count and lymphocyte count were seen at the 150 mg/kg bw/day dose in both males and females; all of the increases were statistically significant except the increased lymphocyte count in males. These findings are often associated with tissue inflammation. Inflammation and other relevant findings were observed in the lungs and stomach of both sexes at this dosage. The only noteworthy compound-related gross pathology findings were in the nonglandular stomach and eyes. The findings in the nonglandular stomach, desquamation and alteration of mucosa, were found primarily in males and females dosed at 150 mg/kg bw/day, however, some alterations of mucosa were also seen in animals dosed at 30 mg/kg bw/day. Opaque eyes, which were seen in both sexes at 150 mg/kg bw/day were consistent with the ophthalmoscopic findings of complete cataracts. Compound-related histopathologic findings included inflammation in the lungs of males and females dosed at 150 mg/kg bw/day and the nonglandular stomach of males and females dosed at 30 and 150 mg/kg bw/day. The inflammation in lungs might have been associated with inadvertent aspiration since previous studies have established that ATMER® 163 is a primary irritant. Dose-related incidences of acanthosis in the nonglandular stomach were seen in males and females dosed at 30 and 150 mg/kg bw/day. The only noteworthy finding in the glandular stomach was suppurative inflammation at terminal sacrifice in two females dosed at 150 mg/kg bw/day. Additionally, the microscopic assessment




Page 61 of 94

showed cataracts in the eyes of both sexes dosed at 150 mg/kg bw/day; most were bilateral. The LOAEL for ATMER® 163 in Sprague Dawley rats in this study is 30 mg/kg bw/day based on increased mortality, salivation, and posterior subcapsular cataracts in males as well as wheezing, and macro- and microscopic changes in the nonglandular stomach of both sexes. The NOAEL is 15 mg/kg bw/day.

Although there were several deficiencies (See Study/Report Deficiencies), this 90-day oral toxicity study in rats is Acceptable/Guideline and satisfies the guideline requirement for a 90-day oral toxicity study (OPPTS 870.3100; OECD 408) in a rodent species. Although several guideline-recommended organs were not weighed, there were no compound-related gross or histopathologic changes observed in the omitted organs. EXECUTIVE SUMMARY: In a subchronic (90-day) oral toxicity study (MRID 47041302), ATMER® 163 (100% a.i.; batch/lot# not provided) was administered via capsule to three groups of 4 male and 4 female beagle dogs for 13 weeks at dose levels of 15, 30, or 100 mg/kg bw/day. A similar concurrent control group of dogs received empty capsules only. There were no unscheduled deaths during the study. All dogs survived until termination. Exposure to ATMER® 163 via capsules at the high-dose level of 100 mg/kg bw/day resulted in statistically- and toxicologically-significant effects. Toxicity observed at 100 mg/kg bw/day included the clinical signs of increased incidence of salivation, emesis, and soft feces (noted with mucus alone or mucus and bile-like material). Salivation was observed in all of the males and females beginning during week 3 of the study (6 of the 8 animals) and continuing over a period of 5 to 11 weeks. Emesis was also observed in all of the males and females and was first observed during the first two weeks of the study in 7 of the 8 animals and continued over a period of 1 to 11 weeks. Soft feces (mucoid) were observed in 3 of the 4 males and in all of the females over a period of 2-7 weeks; soft feces (mucoid/bilious) were observed in the high-dose animals (3 males and 2 females) over a period of 1-3 weeks. All of these clinical signs are considered treatment-related based on the high frequency of occurrence and clear dose-response relationship. In addition, mean alanine aminotransferase (ALT/SGPT) levels were significantly increased (154%), relative to controls, in females. Microscopic examination conducted at necropsy revealed an increased in pigment accumulation in the Kupffer cells and bile canaliculi in the livers of all females. The increased pigment accumulation was not observed in any of the treated males or in the low- and mid-dose females. Other microscopic findings were observed, but are not dose-related or are found in control animals as well as treated animals. The statistically-significant increase (22%) in mean red blood cell (RBC) counts, relative to controls, observed in high-dose females was within the historical control range. The significant increases (6%) in mean calcium levels observed in the mid- and high-dose females were small in magnitude, and the observed significant decrease (23%) in mean




Page 62 of 94

blood urea nitrogen (BUN) levels in the mid-dose males did not follow a dose response pattern. All of the changes are considered to be incidental to treatment. No statistically-significant effects on body weight, body weight gain, food consumption, or organ weights were observed at any dose level. In addition no gross abnormalities or ophthalmological changes related to treatment were observed. Based on review of the study, the no-observable-adverse-effect level (NOAEL) for ATMER® 163 is 30 mg/kg bw/day. The lowest-observable-adverse-effects-level (LOAEL) is 100 mg/kg bw/day, based on clinical signs (increased incidence of salivation, emesis, and soft feces (with mucus alone or mucus and bile-like material)) in males and females, increased alanine aminotransferase (ALT/SGPT) levels in females, and an increased incidence of pigment accumulation in the Kupffer cells and bile canaliculi in the livers of females. This study is classified as Acceptable/Nonguideline and does satisfy the guideline requirement for a 90-day oral toxicity study in nonrodents (OPPTS 870.3150). EXECUTIVE SUMMARY: In a four-week oral toxicity study (MRID 47193901), Armoblen 557 (a.i. not provided, Batch No. B.31401-1) was administered daily by gavage to groups of five male and five female CD rats at concentrations of 0, 15, 75, or 200 mg/kg bw/day. All rats survived until scheduled termination. Salivation in males and females at 75 and 200 mg/kg bw/day was probably due to the taste of the test material and was not considered toxicologically significant. Noisy respiration reported in 1-3 females receiving 200 mg/kg bw/day was not associated with postmortem effects and therefore, was not considered toxicologically significant. Brown staining around the muzzle observed occasionally in females at 75 mg/kg bw/day and males and females at 200 mg/kg bw/day was not considered toxicologically significant. Mean body weight was decreased in males (11-17% lower than controls) and females (4-7% lower than controls) at 200 mg/kg bw/day. The overall bodyweight gain was decreased in males receiving 75 mg/kg bw/day (13% lower than controls) and in males and females receiving 200 mg/kg bw/day (27% and 14% lower than controls, respectively). Overall food consumption for females receiving 200 mg/kg bw/day was decreased (10% lower than control). Food consumption was decreased in males at 200 mg/kg bw/day during Week 1 only. The overall food conversion efficiency was decreased in males at 75 and 200 mg/kg bw/day (13 and 23% lower than controls, respectively). Alterations in hematology and clinical chemistry parameters were either not treatment-related or not toxicologically significant. Increases in the absolute and relative adrenal weights in males and females at 200 mg/kg bw/day were not accompanied by microscopic findings and were not considered toxicologically significant.




Page 63 of 94

Based on decreased body weight, body weight gain and food conversion efficiency, a LOAEL of 200 mg/kg bw/day for Armoblen 557 in male CD rats was established; the NOAEL in male CD rats was 75 mg/kg bw/day. A LOAEL for Armoblen 557 in female CD rats was not established. The NOAEL in female CD rats was 200 mg/kg bw/day. This 28-day oral toxicity study in the rat is Unacceptable/Guideline/Upgradeable and does not satisfy the guideline requirement for a repeat dose 28-day oral toxicity study (OPPTS 870.3050; OECD 407) in rats. The study may be upgraded to acceptable with submission of the percent active ingredient used for the study. EXECUTIVE SUMMARY: In a 28-day oral toxicity study (MRID 46918002C), MON 0818 (70.6% a.i.; Lot XLI-320 [MRID 46918002]) was administered to groups of ten Sprague-Dawley rats/sex/dose in the diet at dose levels of 0, 800, 2000, and 5000 ppm (0, 51.7, 122.8, and 268.7 mg/kg bw/day for males, respectively, and 0, 63.2, 159.9, and 324.8 mg/kg bw/day for females, respectively). Males and females were sacrificed on Days 28 and 29, respectively, and subjected to gross necropsy. All rats survived until scheduled termination. No significant treatment-related effects were found at 800 ppm of MON 08189 in the diet. When fed a diet containing 2000 ppm of MON 0818, toxicity was evident in male rats over the first eight days of the study as a reduction in body weight gain (-62%), food consumption (-18% g/kg bw/day), and food efficiency (-80%). The male rats were not able to recover by the end of the study, with overall body weight gain reduced 34% relative to controls. No effects on body weight were observed in females fed 2000 ppm.

Dietary exposure to 5000 ppm resulted in toxicity as indicated by reduced body weight, body weight gain, food consumption, and food efficiency in males and females, and irritation of the colon, particularly in females. Mean average body weight in males and females was reduced by 15-19% and 10-13% of controls, respectively, with terminal body weight reduced by 23% and 15%, respectively. Body weight gain was most severely affected during the first week of dosing, with body weight gain in males and females reduced by 183% and 455% of controls, respectively; overall body weight gain (Days 1-28/29) was significantly reduced by 89% and 102%, respectively. Food consumption (g/day) was statistically reduced at all dosing intervals in males and females. When corrected for body weight, food consumption (g/kg bw/day) was reduced in males over days 1-8 and 8-16 by 51% and 11%, respectively, and in females on Days 1-8 by 48% and over the entire dosing period of Days 1-29 by 11%. Food efficiency was statistically decreased over Days 1-8 in high-dose males and females by 315% and 1091%, respectively, and increased in high-dose females on Days 16-22 by 131%. Irritation of the colon was evidenced as an increased incidence of soft stool in both sexes (3/10 males affected a total of 4 times; 8/10 females affected 24 times), and pathological findings of prominent/enlarged lymphoid aggregates in the colon of 5 of 10 treated females.




Page 64 of 94

Based on reduced body weight gain and food consumption in mid-dose male rats, a LOAEL of 2000 ppm for MON 0818 (122.8 mg/kg bw/day) was established. The NOAEL was 800 ppm (51.7 mg/kg bw/day) for males. A LOAEL of 5000 ppm for MON 0818 (324.8 mg/kg bw/day) was established for female Sprague Dawley rats based on reduced body weight, body weight gain, food consumption, and irritation in the colon. The corresponding NOAEL for female rats was 2000 ppm (159.9 mg/kg bw/day). This 28-day oral toxicity study in the rat is Acceptable/Non-guideline and does not satisfy the guideline requirement for a repeat dose 28-day oral toxicity study (OPPTS 870.3050; OECD 407). The study had a number of deficiencies, including lack of analyses of the concentration, stability, and homogeneity of the test material in the diet; no hematology or clinical chemistry analyses were performed; no rationale for dose selection was provided; and a full microscopic examination was not conducted on control and high-dose animals. These deficiencies did not compromise the integrity of the study, however, in that the study was designed to set dose levels for a subsequent 90-day oral rat study (MRID 46918003C). Developmental/Reproduction Toxicity Studies EXECUTIVE SUMMARY: In a developmental toxicity study (MRID 46902005), MON 0818 (71.9 % a.i., Lot No. PIT-8907-7571) was administered in Mazola® Corn Oil to 25 Charles River Crl:CDBr female rats/dose by gavage at dose levels of 0 (corn oil only), 15, 100 or 300 mg/kg bw/day from days 6 through 15 of gestation. On day 20 of gestation, all surviving females were sacrificed for a scheduled Cesarean section. Developmental parameters observed and noted included: number of viable fetuses, early and late resorptions, total implantations, total corpora lutea, sex and weight of fetuses and external, visceral and skeletal examinations of all fetuses. Six of the twenty-five high-dose females died during gestation days (GD) 8-13 (2 on GD 8; 1 on GD 10 and GD 11, and 2 on GD13). Clinical signs were also observed in the high-dose females and included: rales (12/25), labored respiration (3/25), yellow uro- (15/25) or anogenital (14/25) matting and mucoid feces (22/25) compared to none of the control animals. Few to no clinical signs were observed in the mid-dose and low-dose females. High-dose females weighed significantly (p<0.01) less than the controls from study day 9 until sacrifice at study day 20. High dose females also gained 59% less weight compared to controls during treatment (days 6-16). Body weight was similar to controls in the low- and mid-dose groups. Gravid uterine weight was not affected by treatment in any of the groups. High-dose females ate statistically (p < 0.01) less food compared to the control rats with the most significant decrease (55% less than controls) on days 6-9 before gradually improving to become comparable to controls by day 16. Overall for days 6-16, the high-dose group ate 29% less than the controls. Food consumption for the low-dose and mid-dose females was comparable to that of controls throughout the study, except for days 6-9 when the mid-dose group had a statistically




Page 65 of 94

significant (p<0.05) decrease. There were no treatment-related effects observed on liver weight or gross pathology at necropsy in any of the treated dams. The maternal lowest-observed-adverse-effect level (LOAEL) for MON 0818 in rats is 300 mg/kg bw/day, based on increased mortality, clinical signs, and decreased body weight, body weight gain, and food consumption. The maternal no-observed-adverse-effect level (NOAEL) for MON 0818 is 100 mg/kg bw/day. No treatment-related differences were observed in the mean number of corpora lutea, implantations, live fetuses or resorptions. Mean fetal weight was not affected by maternal treatment with the test article. The mean number of malformations on external examination of the fetuses from the high-dose dams appeared to be high but most were observed in a single one fetus and a dose response was not observed. On visceral examination, in the high-dose group, one fetus was missing a urinary bladder, one fetus had stenosis of the right carotid artery and two fetuses had situs inversus. One control fetus also had situs inversus. These were not considered treatment-related as there was not a dose response for the situs inversus and the others were within the historical control data range. Vertebral anomalies with or with/out rib anomalies were observed in one fetus in the high-dose group but this was within the range of historical control data. No malformations were observed in the low- or mid-dose groups. Several skeletal variations in the sternebrae and ribs were identified but they were observed in both the control and treated groups at similar incidences and are not considered treatment-related. The developmental lowest-observed-adverse-effect level (LOAEL) for MON 0818 in rats could not be determined as no effects were associated with treatment. The developmental no-observed-adverse-effect level (NOAEL) for MON 0818 is 300 mg/kg bw/day. The developmental toxicity study in the rat is classified acceptable/Guideline and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in the rat. EXECUTIVE SUMMARY: In a screening study (MRID 47097401), the potential reproductive toxicity and developmental (prenatal and postnatal) toxicity of the test article, MON 0818 (69-73% a.i.; Lot# GLP-0309-14324-I), was evaluated in CD (Sprague-Dawley) rats through two successive generations. The study was designed to evaluate the effects of MON 0818 on male and female reproduction within the scope of a screening study. The study was extended to a two-generation study when a decrease in live litter size was observed at the high-dose level. In the study, MON 0818 was administered orally via the diet to three groups of 20 male and 20 female CD rats. Target test diet concentrations were 100, 300 or 1000 ppm. A similar concurrent control group of rats received basal diet only. At approximately 10 weeks of age, the P animals were dosed via diet for at least 70 days prior to mating and continuing to sacrifice (males) or LD 21 (females). All P adults were sacrificed following selection of the F1 generation on PND 21.




Page 66 of 94

Selection of parents for the F1 generation was made from the weaned F1 litters. Between PND 21 or 22 and 70, the weanling F1 animals (3/sex/litter, if possible) were administered the test diet on a mg/kg basis (so not to overexpose the rapidly growing F1 animals) at target concentrations of 0, 6, 18, or 61 mg/kg/day for the F1 males and 0, 7, 22, or 74 mg/kg/day for the F1 females. Beginning on PND 70, the F1 animals selected for breeding from the control and high-dose groups only (2/sex/litter) were administered the test diet at a constant concentration (0 or 1000 ppm) for a minimum of 80 to 88 days prior to mating. The selected F1 males continued to receive the test diet throughout mating and continuing until sacrifice (after the F2 pups reached LD 4). The selected F1 females continued to receive the test diet throughout mating, gestation and lactation and until the day of sacrifice (after the F2 pups reached LD 4). Mortality and clinical signs, body weights, body weight gains, food consumption, reproductive function, fertility and mating performance, absolute and relative organ weights, macroscopic abnormalities at necropsy, and histopathological findings were recorded for all parental/adult animals. In addition, blood samples for testosterone and/or thyroid hormone concentration determinations were collected from one F1 male and one F1 female per litter at the scheduled necropsy. Sperm evaluation (motility and morphology) was also performed on all F1 male animals at termination. Litter size, viability, clinical signs, body weights, body weight gains, developmental (sexual and physical) parameters, and macroscopic abnormalities at necropsy were recorded for the F1 and F2 pups. Survival and clinical conditions, mean body weights and food consumption (pre-mating, gestation, and lactation), reproductive performance, mean organ weights, and macroscopic and microscopic morphology of the P and F1 parental generations were unaffected by administration of MON 0818 at all dose levels. Treatment-related effects were also not seen in estrous cyclicity, spermatogenic endpoints and testosterone and thyroid hormone levels of the F1 generation or in the clinical signs, mean body weights, and developmental landmarks of the F1 and F2 pups, as well as the litter viability and postnatal survival of the F2 litters. Potential treatment-related effects were observed in litter loss, increased mean number of unaccounted-for implantation sites, and decreased mean number of pups born, live litter size and postnatal survival from birth to LD 4 in the high-dose P females and F1 litters. These effects were limited to a small number of litters, not always statistically-significant, and were not reproduced in the F2 litters. However, the increased (statistically-significant) mean number of unaccounted-for implantation sites exceeded the maximum mean value in the laboratory historical control data. While not statistically-significant, the corresponding reduced number of pups born and live litter size, as well as the reduced postnatal survival, were at or below the limits observed in the laboratory historical control data. Therefore, the lowest-observed-adverse-effect level (LOAEL) for parental reproductive toxicity (P) and offspring developmental/neonatal toxicity (F1) is 1000




Page 67 of 94

ppm (56.1 and 52.8 mg product/kg/day (equivalent to 41 and 38.5 mg/kg/day) for the P and F1 males, respectively, and 66.6 and 64.9 mg product/kg/day (equivalent to 48.6 and 47 mg/kg/day) for P and F1 females, respectively), based on litter loss, increase mean number of unaccounted-for implantation sites and decreased mean number of pups born, live litter size and postnatal survival from birth to LD 4. The no-observed-adverse-effect level (NOAEL) is 300 ppm (16.6 and 14.9 mg product /kg/day (equivalent to 12 and 11 mg/kg/day) for the P and F1 males, respectively, and 19.5 and 18.9 mg product/kg/day (equivalent to 14 and 13.7 mg/kg/day) for the P and F1 females, respectively). The NOAEL for parental (P and F1) systemic toxicity is 1000 ppm. A LOAEL for parental systemic toxicity was not determined. This study is classified as Acceptable-Nonguideline. The study was conducted as an extended screening study. It does not fully satisfy the requirements for a two-generation reproductive study (OPPTS 870.3800) in rats because: (1) the test substance was not administered to the F1 offspring until the F2 generation was weaned; (2) only the F1 males and females from the control and high-dose group were selected for breeding; (3) the P generation did not contain a sufficient number of mating pairs to yield at least 20 pregnant females; and, (4) spermatogenic endpoints were only assessed for F1 males.

EXECUTIVE SUMMARY: In a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (MRID 47405101) MON 8109 (100% a.i., Lot # GLP-0611-17816-I ) or MON 0818 (100% a.i., Lot # GLP-0609-17646-I) was administered to 12 Crl:CD(SD) rats/sex/dose in the diet at dose levels of 0, 30, 100, 300, or 2000 ppm MON 8109 (males 0, 2, 8, 23, 134 mg/kg/day; females 0, 3, 9, 26, 148 mg/kg/day) or 1000 ppm MON 0818 (males 76 mg/kg/day; females 86 mg/kg/day) for 14 consecutive days prior to mating (both sexes) and throughout gestation and lactation day 4 (females). Males received the test or basal diets for a total of 71-72 days, and the females received the test or basal diets for a total of 69-72 days. Functional observational battery (FOB) and locomotor activity data were recorded for 6 males/group near the end of diet administration and for 6 females/group on lactation day 4. Parental animals were sacrificed approximately 2.5 weeks after lactation day 4, and offspring were sacrificed on lactation day 4. No mortality related to MON 8109 exposure occurred. Increased incidences of red material around the nose, reddened nose, and reddened mouth were test substance-related findings in males and females treated with 2000 ppm MON 8109. Mean body weight losses were noted at 2000 ppm MON 8109 in male and females during the first week of test diet administration. Lower mean body weight (8-12%) and/or body weight gain (males 37%; females 17%) with corresponding reduction in food consumption were observed in the animals from this group throughout the study. Male at the 2000 ppm MON 8109 dose level displayed decreased liver, kidney, thyroid, and heart weights, which can be attributed to the reduction in body weight. The females from this group had a lower number of implantation sites and lower live litter size. Offspring of these females had lower postnatal survival on PND0, PND0-1, PND1-4, and birth to PND4 compared to the control group. No effect of treatment was observed in male and female mating and fertility, male copulation and female conception indices, gestation length, functional




Page 68 of 94

observational battery, locomotor activity, hematology, or serum chemistry. No test substance-related findings were noted in the 30, 100, or 300 ppm MON 8109 group males, females, or offspring. No mortality related to MON 0818 exposure occurred. One female in the 1000 ppm MON 0818 group was found dead with dystocia on lactation day 1 and another was euthanized in extremis on gestation day 30 and found to have a ruptured uterus. No treatment-related effects were observed in male and female mating and fertility, male copulation and female conception indices, gestation length, functional observational battery, locomotor activity, hematology, or serum chemistry following exposure to 1000 ppm MON 0818. The parental systemic LOAEL is 2000 ppm MON 8109 (134 mg/kg bw/day in males, 148 mg/kg bw/day in females), based on clinical findings, decreased mean body weight and body weight gain, and food consumption. The parental systemic NOAEL is 300 ppm MON 8109 (23 mg/kg bw/day in males, 26 mg/kg bw/day in females). The developmental LOAEL is 2000 ppm MON 8109 (134 mg/kg bw/day in males, 148 mg/kg bw/day in females), based on decreased postnatal survival, decreased live litter size on postnatal day 0, reduced number of pups born, and reduced number of implantation sites. The developmental NOAEL is 300 ppm MON 8109 (23 mg/kg bw/day in males, 26 mg/kg bw/day in females). A reproductive LOAEL for MON 8109 was not demonstrated. The reproductive NOAEL is 2000 ppm MON 8109 (134 mg/kg bw/day in males, 148 mg/kg bw/day in females). A parental LOAEL for MON 0818 was not demonstrated. The parental NOAEL is 1000 ppm MON 0818 (76 mg/kg bw/day in males, and 86 mg/kg bw/day in females). The reproductive/developmental toxicity LOAEL for MON 0818 was not demonstrated in this study. The reproductive/developmental toxicity NOAEL is 1000 ppm MON 0818 (76 mg/kg bw/day in males, and 86 mg/kg bw/day in females). This study is acceptable (guideline) and satisfies the guideline requirement for a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (OECD 422) in the rat for MON 8109 and MON 0818 (limit test).

APPENDIX B

B.1. Structure-Activity Relationship (SAR) Discussion HED used DEREK for Windows (V. 11) to assess the potential toxicity of compounds in the inerts mixture. The products in this cluster are complex mixtures with compounds similar in structure, but of various carbon chain lengths. Therefore two compounds were




Page 69 of 94

subjected to the DEREK analysis: one compound that represented a larger molecule expected in the mixture, and a small molecule that represents a potential environmental degradate, based on the postulated environmental degradation pathway. These compounds were selected on the basis that potential toxicity of intermediate-sized chemicals will be represented by the large and small chemicals selected. The structures are shown in Figure 1 below. Figure 1. Structures of Compounds Subjected to Structure-Activity Analysis

N

O

O

O

O

O

O

O

O

O

O

NOO

Example large molecule Example Postulated Environmental Degradate Derek for Windows (LHASA Ltd.) is an expert system for the prediction of toxicity. It relies on a knowledge base of structural alerts and rules developed by scientists. When a test compound is inputted into the program, Derek for Windows scans the test compound for structural alerts contained within its database that are associated with specific toxicological endpoints and applies a series of reasoning rules to determine the likelihood of toxicity for the test compound. Information is provided on the rules used to make the prediction, along with descriptions of structural alerts identified, comments, available example compounds linked to the alerts and literature references. DEREK did not identify any structural alerts of concern for the larger molecule tested, and a single respiratory irritation alert was identified for the smaller molecule. The respiratory irritation alert is expected for small amine molecules, which are known to be irritating. DEREK has developed more alerts for genotoxicity and carcinogenicity than other endpoints in the system. Considering what is already known about these specific compounds and other long-chain fatty acid compounds, along with the lack of structural alerts for carcinogenicity, chronic toxicity, or genotoxicity, HED has no specific concerns regarding chronic exposures other than those identified in the subchronic toxicity studies for this cluster.




Page 70 of 94

APPENDIX C

C.1. Drinking Water Surrogate Analysis Summary of Drinking Water Estimates of Four Surrogate Inert Chemicals Notes: 1. Used a North Carolina cotton scenario with application date on July 1. This scenario

should be a good representative of the numbers that you can expect from EFED. Also tried manipulation of application dates and weather files to ensure that there are no aberrations; these values look good in that regard.

2. PCA factors were not applied, but the impact of applying such factors (i.e., 0.5 to 0.9)

would be insignificant in comparison to the vast uncertainties surrounding generation of concentrations from surrogate chemicals as well as uncertainties regarding the actual timing of applications.

3. All simulations were made at approximately 1 lb/A. Concentrations resulting from

other application rates will be directly proportional to the application rate. 4. Table 1 gives the normalized concentration estimates for the case where all mass is

applied on a single day. This should be the most conservative case. 5. Table 2 gives the normalized concentration estimates for the case where mass is

distributed evenly over a 100-day period (April to June). 6. A range of degradation rates were used because degradation information was not

available. 3 simulations were made 1) chemically stable in water and soil, 2) a 100 day half life in water and soil, and 3) a 10-day half life in water and soil. This should cover degradation.

7. Table 3 gives the chemical inputs used in the simulations.




Page 71 of 94

Table 1. DW concentration for application lumped on a single day. (This maximizes the acute concentrations.) All concentrations are normalized to a yearly application of 1 kg/hA (1.12 lb/acre).

Chemical 1

Chemical 2

Chemical 3

Chemical 4

Estimates based on Stable Assumption

Acute (ppb) 1.1 41 33 0.005 Chronic 0.69 15 19 0.003 Cancer 0.47 12 15 0.002 Estimates based on assumption of a 100-day half life in soil and water

Acute (ppb) 0.74 36 22 0.003 Chronic 0.33 8.8 7.7 0.002 Cancer 0.25 6.4 6.4 0.001 Estimates based on assumption of a 10-day half life in soil and water

Acute (ppb) 0.48 25 15 0.002 Chronic 0.04 1.1 0.96 0.0002 Cancer 0.03 0.65 0.60 0.0002 Table 2. DW concentration for applications spread out over a 100-day period. This simulates a more even distribution of pesticide over the growing season. All concentrations are normalized to a yearly application of 1 kg/hA (1.12 lb/acre).

Chemical 1

Chemical 2

Chemical 3

Chemical 4

Spread Out Values Estimates based on Stable Assumption Acute (ppb) 0.98 29 28 0.004 Chronic 0.70 13 18 0.003 Cancer 0.48 10 15 0.002 Estimates based on assumption of a 100-day half life in soil and water

0.57 21 17 0.003 0.36 6.9 7.2 0.002 0.27 5.3 6.4 0.001




Page 72 of 94

Chemical 1

Chemical 2

Chemical 3

Chemical 4

Estimates based on assumption of a 10-day half life in soil and water

0.16 7.8 4.3 0.001 0.04 0.79 0.77 0.0002 0.03 0.61 0.63 0.0002 Table 3 Chemical Inputs used in Simulations.

Chemical 1 Chemical 2 Chemical 3 Chemical 4 Chemical Inputs: MW 928 274 302 1185 Solubility (mg/L) 382 299 19.5 6.69e-8 V.P. (mmHg) 5.8e-27 1.76e-8 3.86e-8 3.77e-33 Koc (ml/g) 9.44e6 152 1345 2.57e9




Page 73 of 94

APPENDIX D

D.1. Listing of the Surrogate Active Ingredients Table D.1. Listing of the 57 “Significant” Surrogate Active Ingredients Insecticides (22) Herbicides (20) Fungicides (15) Acephate Acetochlor Azoxystrobin Aldicarb Alachlor Benomyl Azinphos-methyl Atrazine Captan Bifenthrin Bentazon Chlorothalonil Carbaryl Cyanazine (no food uses registered) Fenarimol Chlorpyrifos Dicamba Fosetyl-Al Cryolite Dimethenamid Iprodione Diazinon Diuron Mancozeb Dimethoate EPTC Maneb Endosulfan Ethafluralin Mefenoxam Ethion Fluometuron (registered on cotton only) Metiram Imidacloprid Glyphosate Tetraconazole Lambda-Cyhalothrin MCPA Thiram Methamid Metolachlor Thiophanate-methyl Methomyl Molinate (no food uses registered) Ziram Methyl Parathion Pendimethalin Oxydemeton-methyl Propanil Permethrin Simazine Phorate Trifluralin Phosmet 2,4-D Propargite Terbufos



Alkyl Amine Polyalkoxylates Human Health Risk Assessment

Page 74 of 94

5 gallons formulated pesticide solution*(9 lbs/gallon)*(1 part product concentrate/10 parts water) = 4.5 lbs product per day

APPENDIX E

E.1. Residential Exposure Assessment Introduction This document is a summary of the methods used to calculate residential exposures to the JITF inert cluster inert ingredients. These methods and a basic description of how they are used were taken from References A and B [available at the end of Appendix E]. These references also contain more detailed information on the rationale behind these methods. Only those methods pertinent to the JITF inert cluster inert ingredients exposures are discussed in this document. Tasks associated with residential pesticide handlers are categorized using one of the following terms:

• Mixers and/or Loaders: these individuals perform tasks in preparation for an application. For example, mixers/loaders would mix and prepare the product prior to application.

• Mixer/Loader/Applicators and or Loader/Applicators: these individuals are involved in the entire pesticide application process (they do all job functions related to a pesticide application event). These individuals would perform the mix/load function, transfer the product (containing the inert) into the application equipment, and then complete the product application.

A chemical can produce different effects based on how long a person is exposed, how frequently exposures occur, and the level of exposure. HED classifies exposures from 1 to 30 days as short-term and exposures 30 days to six months as intermediate-term. HED completes both short- and intermediate-term assessments for residential scenarios in all cases because these kinds of exposures are likely and acceptable use/usage data are not available to justify deleting intermediate-term scenarios. Based on use data, HED believes that residential exposures to the JITF inert cluster inert ingredients through applied pesticide formulations may occur over a single day or up to weeks at a time for many use-patterns and that intermittent exposure over several weeks may also occur. Long-term handler exposures are not generally expected to occur for long-term exposure scenarios, While occupational assessments are typically completed by HED using different levels of risk mitigation, residential handler scenarios are assessed assuming short-sleeve shirts and shorts for the handler. The exposure assessment team used a rate of 4.5 lbs product/A. This estimate is based on the following assumptions: Five (5) gallons of formulated pesticide solution are assumed to be used per day by a residential handler (Revised Residential SOPs Area Treated, February, 2001). Consistent with the residential SOPs, the density of the formulated pesticide solution is assumed to be 9 lbs/gallon. The product concentrate is assumed to be diluted at a 1 to 10 ratio with water.




Page 75 of 94

This application rate of product can be multiplied by the percentage of inert in each product type (herbicide, insecticide or fungicide) to be used as application rates in the risk assessment to account for inert in the product. E2. Residential Handler/Applicator Exposures

The Agency believes that there are distinct job functions or tasks related to applications and that exposures can vary depending on the specifics of each task. Job requirements (e.g., amount of chemical to be used in an application), the kinds of equipment used, the crop or target being treated, and the circumstances of the user (e.g., the level of protection used by an applicator) can cause exposure levels to differ in a manner specific to each application event.

Exposure Data Sources The Agency uses exposure scenarios to describe the various types of handler exposures that may occur for a specific active ingredient. The use of scenarios as a basis for exposure assessment is very common as described in the U.S. EPA Guidelines for Exposure Assessment (U.S. EPA; Federal Register Volume 57, Number 104; May 29, 1992). Information from the current labels, use and usage information, toxicology data, and exposure data were all key components in the development of the exposure scenarios. The Agency has developed a series of general descriptions for tasks that are associated with pesticide applications. A residential handler is a term used to describe those individuals who are involved in the pesticide application process. As residential products typically are already mixed, residential handler exposure scenarios are based on application exposure only.

A chemical can produce different effects based on how long a person is exposed, how frequently exposures occur, and the level of exposure. The Agency classifies exposures up to 30 days as short-term and exposures greater than 30 days up to several months as intermediate-term. Based on use data and label instructions, the Agency believes that residential exposures to the JITF inert cluster inert ingredients may occur over a single day or up to 30 days at a time for the use patterns. Long-term handler exposures are not expected to occur for chemicals in the JITF inert cluster inert ingredients cluster.

Other parameters are also defined from use and usage data such as application rates and application frequency. The Agency typically completes exposure assessments using maximum application rates for each scenario to ensure there are no concerns for each specific use. No chemical-specific handler exposure data were submitted in support of this action to inform daily dose calculations. It is the policy of HED to use data from PHED Version 1.1 as presented in the PHED Surrogate Exposure Guide (8/98) to assess handler exposures for regulatory actions when chemical-specific monitoring data are not available (HED Science Advisory Council for Exposure [ExpoSAC] Draft Policy # 7, dated 1/28/99). Additionally, typical HED standard values were used for the amount treated per day (ExpoSAC Policy # 9, dated 7/5/00).




Page 76 of 94

The residential handler/applicator exposures are calculated using unit exposure data from

the Pesticide Handlers Exposure Database (PHED). PHED was designed by a task force of representatives from the US EPA, Health Canada, the California Department of Pesticide Regulation, and member companies of the American Crop Protection Association. PHED is a software system consisting of two parts – a database of measured exposure values for workers involved in the handling of pesticides under actual field conditions and a set of computer algorithms used to subset and statistically summarize the selected data. Currently, the database contains values for over 1,700 monitored individuals (i.e., replicates). The distribution of exposure values for each body part (e.g., chest, upper arm) is categorized as normal, lognormal, or “other” (i.e., neither normal nor lognormal). A central tendency value is then selected from the distribution of the exposure values for each body part. These values are the arithmetic mean for normal distributions, the geometric mean for lognormal distributions, and the median for all “other” distributions. Once selected, the central tendency values for each body part are composited into a “best fit” exposure value representing the entire body. The unit exposure values calculated by PHED generally range from the geometric mean to the median of the selected data set. To add consistency and quality control to the values produced from this system, the PHED Task Force has evaluated all data within the system and has developed a set of grading criteria to characterize the quality of the original study data. The assessment of data quality is based upon the number of observations and the available quality control data. While data from PHED provide the best available information on handler exposures, it should be noted that some aspects of the included studies (e.g., duration, acres treated, pounds of active ingredient handled) may not accurately represent labeled uses in all cases. HED has developed a series of tables of standard unit exposures for many residential scenarios that can be used to ensure consistency in exposure assessments. Unit exposures are used which represent different levels of personal protection as described above. Protection factors were used to calculate unit exposures for varying levels of personal protection if data were not available.

ORETF Handler Studies (MRID 449722-01): A report was submitted by the ORETF (Outdoor Residential Exposure Task Force) that presented data in which the application of various products used on turf by homeowners and lawn care operators (LCOs) was monitored. All of the data submitted in this report were completed in a series of studies. These studies are summarized in the HED Memorandum “Summary of HED’s Reviews of ORETF Chemical Handler Exposure Studies: MRID 449722-01”, DP Barcode D261948 of April 30, 2001. The studies performed used dacthal as a surrogate compound with a target application rate of 2.0 lbs/ai. All studies were conducted in accordance with current Agency guidelines, have been reviewed by HED and Health Canada, and the data generated were of high quality. Assumptions for Handler Exposure Scenarios General assumptions regarding the residential handler scenarios assessed are as follows:




Page 77 of 94

• Residential handler exposure estimates were based on surrogate data from the Pesticide Handlers Exposure Database (PHED, V.1.1, 1998) and Outdoor Residential Exposure Task Force (ORETF) data. Appendix E contains additional information about the data sources used to assess residential exposure.

• HED has developed standard unit exposures for many scenarios to ensure consistency in exposure assessments. These standard values were used to calculate handler exposures for the associated scenarios.

• The adverse effects for the short- and intermediate-term dermal and inhalation endpoints are based on studies where the effects were not gender specific, therefore, the body weight of an average human (70 kg) was used to estimate exposure.

• The daily areas treated were defined for each handler scenario (in appropriate units) by determining the amount that can be reasonably treated by a residential handler in a single day. When possible, the assumptions for daily areas treated are taken from the Health Effects Division Science Advisory Committee on Exposure Policy 9: “Standard Values for Daily Acres Treated in Agriculture”.



Alk

yl A

min

e Po

lyal

koxy

late

s Hum

an H

ealth

Ris

k A

sses

smen

t

Page

78

of 9

4

Res

iden

tial H

andl

er E

xpos

ure

and

Ris

k C

alcu

latio

ns

R

esid

entia

l Han

dler

Exp

osur

e an

d R

isk

Cal

cula

tions

Po

tent

ial d

erm

al a

nd in

hala

tion

daily

exp

osur

es fo

r occ

upat

iona

l han

dler

s wer

e ca

lcul

ated

usi

ng th

e fo

llow

ing

form

ulas

:

Whe

re:

UE

= U

nit E

xpos

ure

(fro

m P

HED

) (µg

or m

g in

ert /

lb in

ert)

CF

= co

nver

sion

fact

or to

con

vert

µg to

mg

(1 m

g /1

000

µg)-

for i

nhal

atio

n ex

posu

re o

nly

AR

= a

pplic

atio

n ra

te (

lb in

ert/

A)

AT

= da

ily a

cres

trea

ted

(Acr

es/d

ay)

The

inha

latio

n an

d de

rmal

dai

ly d

oses

wer

e ca

lcul

ated

usi

ng th

e fo

llow

ing

form

ulas

:

Mar

gin

of E

xpos

ure:

Der

mal

and

inha

latio

n ris

ks fo

r eac

h ap

plic

atio

n ha

ndle

r sce

nario

are

cal

cula

ted

usin

g a

Mar

gin

of

Expo

sure

(MO

E), w

hich

is a

ratio

of t

he P

oD to

the

daily

dos

e of

con

cern

. A

ll M

OE

valu

es w

ere

calc

ulat

ed fo

r der

mal

and

in

hala

tion

expo

sure

leve

ls.

Dai

ly In

hala

tion

Expo

sure

(mg

iner

t /da

y) =

UE

(µg

iner

t/ lb

iner

t) *

CF

* A

R *

AT

Dai

ly D

erm

al E

xpos

ure

(mg

iner

t / d

ay) =

UE

(mg

iner

t / lb

iner

t) *

AR

* A

T

Dai

ly In

hala

tion

Dos

e (m

g /k

g/da

y) =

Dai

ly In

hala

tion

Expo

sure

(mg

/day

) * 1

/Bod

y W

eigh

t (kg

) * 1

(100

%

Inha

latio

n ab

sorp

tion)

Dai

ly D

erm

al D

ose

(mg

/kg/

day)

= D

aily

Der

mal

Exp

osur

e (m

g /d

ay) *

1/B

ody

Wei

ght (

kg) *

0.0

5 (5

% D

erm

al

abso

rptio

n)



Alk

yl A

min

e Po

lyal

koxy

late

s Hum

an H

ealth

Ris

k A

sses

smen

t

Page

79

of 9

4

Whe

re:

MO

E =

Mar

gin

of E

xpos

ure:

val

ue u

sed

by H

ED to

repr

esen

t ris

k or

risk

es

timat

es (u

nitle

ss)

PoD

= P

oint

of D

epar

ture

N

OA

EL =

No

Obs

erve

d A

dver

se E

ffec

t Lev

el: D

ose

leve

l in

a to

xici

ty st

udy

AD

D =

Ave

rage

Dai

ly D

ose:

the

abso

rbed

dos

e re

ceiv

ed fr

om e

xpos

ure

to a

pes

ticid

e in

a g

iven

scen

ario

R

isk

estim

ates

are

pre

sent

ed fo

r the

rout

e of

exp

osur

e in

eac

h sc

enar

io, b

ecau

se ri

sk m

itiga

tion

mea

sure

s are

spec

ific

to th

e ro

ute

of e

xpos

ure.

T

otal

Mar

gins

of E

xpos

ure:

Whe

re a

ppro

pria

te, t

he e

ndpo

int s

elec

ted

for b

oth

derm

al a

nd in

hala

tion

expo

sure

is c

ombi

ned

to

incl

ude

both

der

mal

and

inha

latio

n ro

utes

of e

xpos

ure

usin

g th

e fo

llow

ing

equa

tion.

Th

e le

vel o

f con

cern

for a

ll as

sess

men

ts is

est

ablis

hed

by th

e un

certa

inty

fact

or.

The

leve

l of c

once

rn is

an

MO

E of

100

for t

he

JITF

iner

t clu

ster

iner

t ing

redi

ents

der

mal

and

inha

latio

n re

side

ntia

l exp

osur

e sc

enar

ios (

shor

t- an

d in

term

edia

te-te

rm e

xpos

ure

dura

tion.

MO

E =

PoD

(m

g/kg

/day

) / A

DD

(mg/

kg/d

ay)

Tota

l MO

E =

1/ (1

/ Der

mal

MO

E +

1/ In

hala

tion

MO

E)



E3. Residential Postapplication Exposures No crop-specific dislodgeable foliar residue (DFR) or transferable turf residue (TTR) data is available for the JITF inert cluster inert ingredients. A default residential postapplication assessment was conducted, including a default 5% of the JITF inert cluster inert ingredients application rate as the initial concentration and a 10% daily dissipation rate. This is adapted from the ExpoSAC SOP No. 003 (May 7th, 1998 - Revised August 7th, 2000). Assumptions for Handler Exposure Scenarios General assumptions regarding the residential handler scenarios assessed are as follows:

• The average residential workday is assumed to be 8 hours. • The adverse effects for the short- and intermediate-term dermal PoDs are based

on studies where the effects were observed in both sexes, therefore, the body weight of an average human (70 kg) was used to estimate exposure.

• HED has developed standard transfer coefficient values for residential postapplication scenarios to ensure consistency in exposure assessments. These standard values were used to calculate postapplication exposures.

• No postapplication data were submitted for the inert cluster; a default 5% of the application rate is used in conjunction with 10% default daily dissipation rate.

Residential Postapplication Outdoor Exposure and Risk Calculations General assumptions regarding the occupational handler scenarios assessed are as follows:

• The adverse effects for the short- and intermediate-term dermal and inhalation endpoints are based on studies where the effects were observed in both sexes, therefore, the body weight of an average human (70 kg) was used to estimate exposure. The body weight of an average child is 15 kg.

• HED has developed standard transfer coefficient values for occupational postapplication scenarios to ensure consistency in exposure assessments.

Potential dermal postapplication exposure was calculated using the following formulas: Adult and Child Dermal Exposure to Treated Lawns:

Where: ADD= Average Daily Dose (mg/kg/day) TTR= Turf Transferable Residue (µg/cm2) TC = Transfer Coefficient (cm2/hr) (14,500 cm2/hr for adults, 5,200 cm2/hr for children for short-term exposure durations; and 7,300 cm2/hr for adults, 2,600 cm2/hr for children for intermediate-term exposure durations)

ADD = TTR * TC * ET * CF1 * DA BW




Page 81 of 94

ET = Exposure Time (2 hr) CF1 = Conversion Factor (1 mg / 1000 µg) DA = Dermal Absorption Factor (5%) BW = Body Weight (70 kg for adult, 15 kg for child)

Where: AR = Application Rate (lb inert/acre) F = fraction of inert retained on foliage or 5% (unitless) D = fraction of residue that dissipates daily or 10% (unitless) t = number of days after application day (Day 0; day of application) CF1 = 4.54 x 108 µg/lb CF2 = 24.7 x 10-9 acre/cm2

Hand to Mouth Exposure to Child on Treated Turf (from SOP 2.3.2): The following equation is used to calculate the nondietary ingestion exposures that are attributable to hand-to-mouth behavior on treated turf:

Where: ADD = Average daily dose (mg/kg/day) TTR= turf transferable residue (µg/cm2) SA= Surface area of child hand- 3 fingers (20 cm2/event) SE = Saliva Extraction Factor (0.5) Freq = Frequency of hand-to-mouth events (20 events/hr for short-term exposures, 9.5 events/hr for long-term exposures) CF1 = 1 mg/ 1000 µg ET = Exposure Time (2 hours) BW = Body weight (15 kg for child)

Where: AR = Application Rate (lb inert/acre) F = fraction of inert retained on foliage/surface or 5% (unitless) D = fraction of residue that dissipates daily or 10% (unitless) t = number of days after application day (0 days); day of application CF1 = 4.54 x 108 µg/lb CF2 = 24.7 x 10-9 acre/cm2

TTR = AR * (1-D)t * F * CF1 * CF2

TTR = AR * (1-D)t * F * CF1 * CF2

ADD = TTR * SA * SE * Freq * CF1 * ET BW




Page 82 of 94

Object to Mouth Exposure to Child: The following equation is used to calculate the nondietary ingestion exposures that are attributable to object-to-mouth behavior on treated turf:

Where: TTR = object transferable residue (µg/cm2) IgR = Ingestion Rate for mouthing per day (25 cm2/day) CF1 = 1 mg / 1000 µg BW = Body weight (15 kg for child)

Where: AR = Application Rate (lb inert/acre) F = fraction of inert retained on object or 20% (unitless) D = fraction of residue that dissipates daily or 10% (unitless) t = number of days after application day (0 days); day of application CF1 = 4.54 x 108 µg/lb CF2 = 24.7 x 10-9 acre/cm2 Soil Ingestion Exposure to Child: The following equation is used to calculate the nondietary ingestion exposures that are attributable to soil ingestion on treated turf:

Where: ADD = Average daily dose (mg/kg/day) SR = Soil Residue, 1 cm depth of surface soil, (µg/g) IgR = Ingestion Rate for daily soil ingestion (100 mg/day) CF1 = Conversion Factor (1 g / 1,000,000 µg) BW = Body weight (15 kg for child)

Soil Residue (SR) = AR * CF1 * CF2 * CF3 * F * (1-D)t

ADD = SR * IgR * CF1 BW

TTR = AR * (1-D)t * F * CF1 * CF2

ADD = TTR * IgR * CF1 BW




Page 83 of 94

Where: AR= application rate (lb inert/ A) CF1 = 4.54 x 108 µg/lb CF2 = 24.7 x 10-9 acre/cm2

CF3 = Conversion factor (0.67 cm3 / g soil) F = fraction of inert retained on soil or 100% (unitless) D = fraction of residue that dissipates daily (unitless) t = postapplication day on which exposure is being assessed (t = 0, day of application) The Aggregate Risk for inert cluster is calculated for residential postapplication by adding the daily doses for child dermal exposure to lawns and child hand-to-mouth exposure to treated lawns. This method is used because the PoD is the same for both of the above scenarios. Then, the risk estimate is calculated by dividing the PoD by the combined daily dose.

Assumptions for Dermal Dose from Pesticide Residues on Turf: • On the day of application, it may be assumed that 5% of the application rate are

available from the turfgrass as dislodgeable residue. • Postapplication is assessed on the same day the pesticide is applied because it is

assumed that the homeowner could be exposed to turfgrass immediately after application. Therefore, postapplication exposures are based on day 0 (i.e., the day of application).

• The upper percentile dermal transfer coefficient is assumed to be 14,500 cm2/hr for adults and 5,200 cm2/hr for children for short-term durations; and 7,300 cm2/hr for adults and 2,600 cm2/hr for children for intermediate-term durations. The transfer coefficient cm2/hr is a calculated mean, based on the Jazzercise method, which is believed to result in an upper percentile estimate of the transfer coefficient for this scenario.

• The duration of exposure for children and adults is assumed to be 2 hours per day. The 95th percentile value for playing on grass is 121 minutes per day for both age groups 1-4 years and 18-64 years (U.S. EPA 1996).

Assumptions for Potential Dose among children from Incidental Nondietary Ingestion of Pesticide Residues on Residential Lawns from Hand-to-Mouth Transfer: • On the day of application, it may be assumed that 5% of the application rate is

available on the turfgrass as dislodgeable residue. • Postapplication activities are assessed on the same day that the pesticide is applied

because it is assumed that children could play on the lawn immediately after application.

• The surface portion of three fingers of a toddler’s hand put in mouth is 20 cm2. • The Hand-to-Mouth (HTM) exposure frequency is 20 times per hour for short

term exposures. • The HTM exposure frequency is 9.5 times per hour for intermediate term

exposures.




Page 84 of 94

• The duration of exposure for toddlers is assumed to be 2 hours per day. The 95th percentile value for playing on grass is 121 minutes per day for both age groups 1-4 years and 18-64 years (U.S. EPA 1996).

• Toddlers (age 3 years), used to represent the 1 to 6 year old age group, are assumed to weigh 15 kg. (U.S. EPA 1996).

• The saliva extraction factor is 50%. Assumptions for Potential Dose among Toddlers from the Ingestion of Pesticide-Treated Turfgrass: • On the day of application, it may be assumed that 20% of the application rate is

available on the turfgrass as dislodgeable residue. • Postapplication activities are assessed on the same day that the pesticide is applied

because it is assumed that children could play on the lawn immediately after application.

• The assumed ingestion rate for grass for toddlers (age 3 years) is 25 cm2/day. This value is intended to represent the approximate area from which a child may grasp a handful of grass.

Assumptions for Potential Dose among Toddlers from Incidental Ingestion of Soil from Pesticide-Treated Residential Areas: • On the day of application, it is assumed 100% of the application rate is located

within the soil’s uppermost 1 cm. • Postapplication must be assessed on the same day the pesticide is applied because

it is assumed that toddlers could play on the lawn or other outdoor treated areas immediately after application.

• The assumed soil ingestion rate for children (age 1-6 years) is 100 mg/day (U.S. EPA 1996).

References (A) PHED Surrogate Exposure Guide, V1.1. Health Effects Division, Office of Pesticide

Program. August, 1998. (B) Series 875 - Occupational and Residential Exposure Test Guidelines, Group B - Post Application Exposure Monitoring Test Guidelines. U.S. EPA. February 10, 1998.




Page 85 of 94

APPENDIX F

F.1. Occupational Exposure Assessment Introduction This document is a summary of the methods used to calculate occupational exposures to the inert cluster inert ingredients. These methods and a basic description of how they are used were taken from References A and B. These references also contain more detailed information on the rationale behind these methods. Only those methods pertinent to the JITF inert cluster inert ingredients exposures are discussed in this document. Tasks associated with occupational pesticide handlers are categorized using one of the following terms:

• Mixers and/or Loaders: these individuals perform tasks in preparation for an application. For example, mixers/loaders would mix and prepare the product prior to application.

• Mixer/Loader/Applicators and or Loader/Applicators: these individuals are involved in the entire pesticide application process (they do all job functions related to a pesticide application event). These individuals would perform the mix/load function, transfer the product (containing the inert) into the application equipment, and then complete the product application.

A chemical can produce different effects based on how long a person is exposed, how frequently exposures occur, and the level of exposure. HED classifies exposures from 1 to 30 days as short-term and exposures 30 days to six months as intermediate-term. HED completes both short- and intermediate-term assessments for occupational scenarios in all cases because these kinds of exposures are likely and acceptable use/usage data are not available to justify deleting intermediate-term scenarios. Based on use data, HED believes that occupational exposures to the JITF inert cluster inert ingredients may occur over a single day or up to weeks at a time for many use-patterns and that intermittent exposure over several weeks may also occur. Some applicators may apply the products containing inerts over a period of weeks, because they are commercial applicators who are completing multiple applications for multiple clients. Long-term handler exposures can occur in ornamental treatment scenarios, where handlers can apply pesticides all year long in greenhouses and hothouses. Usually occupational handler exposure assessments are completed by HED using different levels of risk mitigation. Typically, HED uses a tiered approach. The lowest tier is designed as the baseline exposure scenario (i.e. long-sleeve shirt, long pants, shoes, socks, no respirator). If risks are of concern at the baseline exposure scenario, then increasing levels of PPE (i.e. gloves, respirators) are evaluated. If risk remains a concern with maximum PPE, then engineering controls (i.e. enclosed cabs or cockpits, water-soluble packaging, and closed mixing/loading systems) are evaluated. This approach is used to ensure that the lowest level of risk mitigation that provides adequate protection is selected, since the addition of PPE and engineering controls involves an additional expense to the user and (in the case of PPE) also involves an additional




Page 86 of 94

burden to the user due to decreased comfort and dexterity and increased heat stress and respiratory stress. F2. Occupational Handler/Applicator Exposures

The Agency believes that there are distinct job functions or tasks related to applications and that exposures can vary depending on the specifics of each task. Job requirements (e.g., amount of chemical to be used in an application), the kinds of equipment used, the crop or target being treated, and the circumstances of the user (e.g., the level of protection used by an applicator) can cause exposure levels to differ in a manner specific to each application event.

Exposure Data Sources

The Agency uses exposure scenarios to describe the various types of handler exposures that may occur for a specific active ingredient. The use of scenarios as a basis for exposure assessment is very common as described in the U.S. EPA Guidelines for Exposure Assessment (U.S. EPA; Federal Register Volume 57, Number 104; May 29, 1992). Information from the current labels, use and usage information, toxicology data, and exposure data were all key components in the development of the exposure scenarios. The Agency has developed a series of general descriptions for tasks that are associated with pesticide applications. Tasks associated with occupational pesticide handlers are categorized using one of the following terms:

• Mixers and/or Loaders: These individuals perform tasks in preparation for an application. For example, prior to application, mixer/loaders would mix the JITF inert cluster inert ingredients and load them into the holding tank of the groundboom.

• Applicators: These individuals operate application equipment during the release of a

pesticide product into the environment. These individuals can make applications using equipment such as groundboom.

• Mixer/Loader/Applicators and or Loader/Applicators: These individuals are involved in

the entire pesticide application process (i.e., they do all job functions related to a pesticide application event). These individuals would transfer the JITF inert cluster inert ingredients into the application equipment and then also apply it.

A chemical can produce different effects based on how long a person is exposed, how

frequently exposures occur, and the level of exposure. The Agency classifies exposures up to 30 days as short-term and exposures greater than 30 days up to several months as intermediate-term. Based on use data and label instructions, the Agency believes that occupational the JITF inert cluster inert ingredients exposures may occur over a single day or up to 30 days at a time for the use patterns. Long-term handler exposures are not expected to occur for the JITF inert cluster inert ingredients.




Page 87 of 94

Other parameters are also defined from use and usage data such as application rates and application frequency. The Agency typically completes exposure assessments using maximum application rates for each scenario to ensure there are no concerns for each specific use.

Occupational handler exposure assessments are completed by the Agency using different levels of risk mitigation. Typically, the Agency uses a tiered approach. The lowest tier is designated as the baseline exposure scenario (i.e., no respirator). If risks are of concern at baseline attire, then increasing levels of personal protective equipment or PPE (e.g., respirators) are evaluated. If risks remain of concern with maximum PPE, then engineering controls (e.g., enclosed cabs, water-soluble packaging, and closed mixing/loading systems) are evaluated. This approach is used to ensure that the lowest level of risk mitigation that provides adequate protection is selected, since the addition of PPE and engineering controls involves an additional expense to the user. PPE also involves an additional burden to the user due to decreased comfort and dexterity and increased heat stress and respiratory stress. No chemical-specific handler exposure data were submitted in support of this action to inform daily dose calculations. It is the policy of HED to use data from PHED Version 1.1 as presented in the PHED Surrogate Exposure Guide (8/98) to assess handler exposures for regulatory actions when chemical-specific monitoring data are not available (HED Science Advisory Council for Exposure [ExpoSAC] Draft Policy # 7, dated 1/28/99). Additionally, typical HED standard values were used for the amount treated per day (ExpoSAC Policy # 9, dated 7/5/00).

The occupational handler/applicator exposures are calculated using unit exposure data from the Pesticide Handlers Exposure Database (PHED). PHED was designed by a task force of representatives from the US EPA, Health Canada, the California Department of Pesticide Regulation, and member companies of the American Crop Protection Association. PHED is a software system consisting of two parts – a database of measured exposure values for workers involved in the handling of pesticides under actual field conditions and a set of computer algorithms used to subset and statistically summarize the selected data. Currently, the database contains values for over 1,700 monitored individuals (i.e., replicates). The distribution of exposure values for each body part (e.g., chest, upper arm) is categorized as normal, lognormal, or “other” (i.e., neither normal nor lognormal). A central tendency value is then selected from the distribution of the exposure values for each body part. These values are the arithmetic mean for normal distributions, the geometric mean for lognormal distributions, and the median for all “other” distributions. Once selected, the central tendency values for each body part are composited into a “best fit” exposure value representing the entire body. The unit exposure values calculated by PHED generally range from the geometric mean to the median of the selected data set. To add consistency and quality control to the values produced from this system, the PHED Task Force has evaluated all data within the system and has developed a set of grading criteria to characterize the quality of the original study data. The assessment of data quality is based upon the number of observations and the available quality control data. While data from PHED provide the best available information on handler




Page 88 of 94

exposures, it should be noted that some aspects of the included studies (e.g., duration, acres treated, pounds of active ingredient handled) may not accurately represent labeled uses in all cases. HED has developed a series of tables of standard unit exposures for many occupational scenarios that can be used to ensure consistency in exposure assessments. Unit exposures are used which represent different levels of personal protection as described above. Protection factors were used to calculate unit exposures for varying levels of personal protection if data were not available.

ORETF Handler Studies (MRID 449722-01): A report was submitted by the ORETF (Outdoor Residential Exposure Task Force) that presented data in which the application of various products used on turf by homeowners and lawn care operators (LCOs) was monitored. All of the data submitted in this report were completed in a series of studies. These studies are summarized in the HED Memorandum “Summary of HED’s Reviews of ORETF Chemical Handler Exposure Studies: MRID 449722-01”, DP Barcode D261948 of April 30, 2001. The studies performed used dacthal as a surrogate compound with a target application rate of 2.0 lbs/ai. All studies were conducted in accordance with current Agency guidelines, have been reviewed by HED and Health Canada, and the data generated were of high quality. Assumptions for Handler Exposure Scenarios General assumptions regarding the occupational handler scenarios assessed are as follows:

• Occupational handler exposure estimates were based on surrogate data from the Pesticide Handlers Exposure Database (PHED, V.1.1, 1998)

• HED has developed standard unit exposures for many occupational scenarios to ensure consistency in exposure assessments. These standard values were used to calculate handler exposures for the associated scenarios.

• The adverse effects for the short- and intermediate-term dermal and inhalation endpoints are based on studies where the effects were not gender specific, therefore, the average adult body weight representing the general U.S. population (70 kg) was used.

• The daily areas treated were defined for each handler scenario by determining the amount that can be reasonably treated in a single day. The assumptions for daily areas treated are taken from the Health Effects Division Science Advisory Committee on Exposure Policy 9: “Standard Values for Daily Acres Treated in Agriculture”.




Page 89 of 94

Table F2: Occupational Handler Dermal and Inhalation Unit Exposures used for Occupational Handler Assessments

Dermal Unit Exposure (mg/ lb ai) Inhalation Unit Exposure (µg/ lb ai)

Exposure Scenario*

Baseline Baseline + Gloves

Max PPE

Eng. Control Baseline

Baseline +

Gloves

Max PPE

Eng. Control

Mixer/Loader Scenarios Liquids/ Aerial Application/ High Acreage Crops Liquids/ Airblast/ Nut Tree Liquids/ Groundboom/ High Acreage Crops

Liquids/ Groundboom/ Turf

Liquids/ Low Pressure Handwand/ Turf

2.9 0.023 0.017 0.0086 1.2 0.24 0.12 0.083

Wettable Powder/ Airblast/ Nut Tree Wettable Powder/ Groundboom/ High Acreage Crops Wettable Powder/ Groundboom/ Turf Wettable powder/ Low Pressure Handwand/ Turf

3.7 0.17 0.13 0.0098 43 8.6 4.3 0.24

Applicator Scenarios Liquid/ Aerial Application/ High Acreage Crops NA NA NA 0.0055 NA NA NA 0.068

Airblast/ Nut Tree 0.36 0.24 0.13 0.019 4.5 0.9 0.45 0.09 Groundboom/ High Acreage Crops Groundboom/ Turf

0.014 0.014 0.011 0.0051 0.74 0.148 0.074 0.043

Mixer/Loader/Applicator Scenarios Low Pressure Handwand/ Turf (ORETF data) NA 0.65 0.36 NA 6.6 1.32 0.66 NA Wettable Powder/ Low Pressure Handwand/ Ornamentals

NA 8.6 6.2 NA 1100 220 110 NA

Liquid/ Low Pressure Handwand/ Ornamentals 100 0.43 0.37 NA 30 6 3 NA

Flagger Scenarios Liquid/ Flagger/ High Acreage Crops 0.011 0.012 0.011 0.0022 0.35 0.07 0.035 0.007

Values are reported in the PHED Surrogate Exposure Guide dated August 1998.

APPLICATION RATES USED FOR THE JITF INERT INGREDIENTS RISK ASSESSMENT




Page 90 of 94

Table F3: Application Rates* used for Occupational Handler Exposure Assessment

Exposure Scenario (Formulation/ Application/

Crop)

Product Type Short-Term (Maximum Rate)

Intermediate-term (Average Rate)

Mixer/Loader Scenarios Herbicide 10.4 2 Insecticide 2 0.7

Liquids/ Aerial Application/ High Acreage Crops Fungicide 5 0.7

Herbicide 7.2 3.2 Insecticide 9 2.5

Liquids/ Airblast/ Nut Tree

Fungicide 11 3 Herbicide 10.4 2 Insecticide 2 0.7

Liquids/ Groundboom/ High Acreage Crops

Fungicide 5 0.7 Herbicide 10.4 2 Insecticide 2 0.7

Liquids/ Groundboom/ Turf

Fungicide 5 0.7 Herbicide Insecticide

Liquids/ Low Pressure Handwand/ Turf

Fungicide

7.2 7.2

Herbicide 1.6 1.6 Insecticide 6 3

Wettable Powder/ Airblast/ Nut Tree

Fungicide 7 2 Herbicide 1.6 1 Insecticide 1.6 0.7

Wettable Powder/ Groundboom/ High Acreage Crops Fungicide 1 0.6

Herbicide 1.6 1 Insecticide 1.6 0.7

Wettable Powder/ Groundboom/ Turf

Fungicide 1 0.6 Herbicide Insecticide

Wettable powder/ Low Pressure Handwand/ Turf Fungicide

7.2 7.2

Applicator Scenarios Herbicide 10.4 2 Insecticide 2 0.7

Liquid/ Aerial Application/ High Acreage Crops Fungicide 5 0.7

Herbicide 1.6 1.6 Insecticide 9 2.5

Airblast/ Nut Tree

Fungicide 7 3 Herbicide 10.4 2 Insecticide 2 0.7

Groundboom/ High Acreage Crops

Fungicide 5 0.7




Page 91 of 94

Table F3: Application Rates* used for Occupational Handler Exposure Assessment Exposure Scenario

(Formulation/ Application/ Crop)

Product Type Short-Term (Maximum Rate)

Intermediate-term (Average Rate)

Herbicide 10.4 2 Insecticide 2 0.7

Groundboom/ Turf

Fungicide 5 0.7 Mixer/Loader/ Applicator Scenarios

Herbicide Insecticide

Low Pressure Handwand/ Turf (ORETF data) Fungicide


Wettable Powder/ Low Pressure Handwand/ Ornamentals Fungicide


Liquid/ Low Pressure Handwand/ Ornamentals

Fungicide

7.2 7.2

Flagger Scenarios Herbicide 10.4 2 Insecticide 2 0.7

Liquid/ Flagger/ High Acreage Crops

Fungicide 5 0.7 * Application rates are multiplied by the percentage of inert in each product type when used as application rates in the risk assessment. Occupational Handler Exposure and Risk Calculations

Daily Exposure: Daily inhalation handler exposure is estimated for each applicable handler task with the application rate, the amount handled in a day, and the applicable inhalation unit exposure using the following formula: Daily Exposure (mg ai/day) = Unit Exposure (mg ai/lb ai handled) * Application Rate (lbs ai/gal) * Daily Area Treated (gal/day) Where: Daily Exposure = Amount (mg or μg ai/day) inhaled that is available for inhalation absorption; Unit Exposure = Unit exposure value (mg or μg ai/day) derived from August 1998 PHED data; Application Rate = Normalized application rate based on a logical unit treatment, such as

gallons. Maximum values are generally used (lb ai/gal); and Daily Area Treated = Normalized application area based on a logical unit treatment such as

gallons per day (gal/day).




Page 92 of 94

Daily Dose: The daily inhalation dose is calculated by normalizing the daily exposure by body weight and adjusting, if necessary, with an appropriate inhalation absorption factor. For all inhalation exposure scenarios for the JITF inert cluster inert ingredients, an average adult body weight of 70 kilograms was used. For inhalation exposures, an absorption factor of 100% was assumed. Daily dose was calculated using the following formula: Average Daily Dose (mg/kg/day = (Daily Exposure (mg ai/day) * (Absorption Factor (100%) / Body Weight (kg) Where: Average Daily Dose = Absorbed dose received from exposure to a pesticide in a given scenario (mg pesticide active ingredient/kg body weight/day); Daily Exposure = Amount (mg ai/day) inhaled that is available for inhalation absorption; Absorption Factor = A measure of the amount of chemical that crosses a biological boundary such as the lungs (% of the total available absorbed); and Body Weight = Body weight determined to represent the population of interest in a risk

assessment (kg).

Margins of Exposure: Noncancer inhalation risks for each applicable handler scenario are calculated using a Margin of Exposure (MOE), which is a ratio of the daily dose to the toxicological endpoint of concern. All MOE values were calculated inhalation exposure levels using the formula below: MOE = (NOAEL (mg/kg/day) / Average Daily Dose (mg/kg/day) Where: MOE = Margin of Exposure, value used by HED to represent risk or how close a chemical exposure is to being a concern (unitless); ADD = Average Daily Dose or the absorbed dose received from exposure to a pesticide

in a given scenario (mg pesticide active ingredient/kg body weight/day); and NOAEL = Dose level in a toxicity study, where no observed adverse effects (NOAEL) occurred in the study The level of concern for all assessments is established by the uncertainty factor. The uncertainty factor is 100 for the JITF inert cluster inert ingredients inhalation occupational exposure scenarios for all exposure durations. Total Margins of Exposure: Where appropriate, the endpoint selected for both dermal and inhalation exposure is combined to include both dermal and inhalation routes of exposure using the following equation. Total MOE = 1/ (1/ Dermal MOE + 1/ Inhalation MOE)



F3. Occupational Postapplication Exposures No crop-specific dislodgeable foliar residue (DFR) or transferable turf residue (TTR) data is available for the JITF inert cluster inert ingredients. A default occupational postapplication assessment was conducted, including a default 20% of the JITF inert cluster inert ingredients application rate as the initial concentration and a 10% daily dissipation rate. This is adapted from the ExpoSAC SOP No. 003 (May 7th, 1998 - Revised August 7th, 2000). Assumptions for Handler Exposure Scenarios General assumptions regarding the occupational handler scenarios assessed are as follows:

• The average occupational workday is assumed to be 8 hours. • The adverse effects for the short- and intermediate-term dermal PoDs are based

on studies where the effects were observed in both sexes, therefore, the body weight of an average human (70 kg) was used to estimate exposure.

• HED has developed standard transfer coefficient values for occupational postapplication scenarios to ensure consistency in exposure assessments. These standard values were used to calculate postapplication exposures.

• No postapplication data were submitted for the JITF inert cluster inert ingredients; a default 20% of the application rate for foliar crop or 5% of the application rate for turf is used in conjunction with 10% default daily dissipation rate.

Because the postappplication assessment was conducted for a few specific crop groups with high exposure worker reentry activity patterns, HED customized the JITF inert cluster inert ingredient application rate for the three postapplication crop groupings (corn/grapes/turf & sod). See Table 3 below.

Table 3: Application Rates used for Occupational Postapplication Scenarios Crop Product Type Short-Term

(Maximum Rate) Intermediate-term

(Average Rate) Herbicide 10.4 1.2 Insecticide 10 1

Corn

Fungicide 5 1 Herbicide 4.8 2.28 Insecticide 7 3

Grapes

Fungicide 5 2 Herbicide 10.4 1.2 Insecticide 10 1

Turf/Sod

Fungicide 5 1 * Application rates are multiplied by the percentage of inert in each product type when used as application rates in the risk assessment to account for inert in the product.




Page 94 of 94

Occupational Postapplication Exposure and Risk Calculations Potential dermal postapplication exposure was calculated using the following formulas (Appropriate dermal absorption used): Where: AR = Application Rate (lb inert/acre) F = fraction of ai retained on foliage or 20% for foliar crop or 5% for turf (unitless) D = fraction of residue that dissipates daily or 10% (unitless) t = number of days after application day (days) CF1 = 4.54 x 108 µg/lb CF2 = 24.7 x 10-9 acre/cm2

Where: DFRt = dislodgable foliar residue on day “t” (µg/cm2) CF3 = 1 x 10-3 mg/µg Tc = transfer coefficient (cm2/hr) DA = dermal absorption factor (unitless) ET = exposure time (hr/day) BW = body weight (kg) Margin of Exposure: Dermal risks for the postapplication scenarios are calculated using a Margin of Exposure (MOE), which is a ratio of the toxicological point of departure to the daily dose of concern. Where: MOE = Margin of Exposure: value used by HED to represent risk or risk estimates (unitless) Po D = Point of Departure NOAEL = No Observed Adverse Effect Level: Dose level in a toxicity study ADD = Average Daily Dose: the absorbed dose received from exposure to a pesticide in a given scenario References (B) PHED Surrogate Exposure Guide, V1.1. Health Effects Division, Office of Pesticide

Program. August, 1998. (C) Series 875 - Occupational and Residential Exposure Test Guidelines, Group B - Post

Application Exposure Monitoring Test Guidelines. U.S. EPA. February 10, 1998.

Dislodgable Foliar Residue (µg/cm2) = AR * F * (1-D)t * CF1 * CF2

Daily Dermal Dose (mg/kg/day) = DFRt * CF3 * Tc * DA * ET BW (kg)

MOE = PoD (typically a NOAEL in mg/kg/day) / ADD (mg/kg/day)



ngth, four specific PEG cocamines were considered as theication. These were PEG‐2, PEG‐4, PEG‐10, and PEG‐15below are representative structures. CAS #s actually

Structure of InterestPEG‐10 Cocamine

Analogs

N

OO

O

O

OO

OH

OH

CAS# 26635‐92‐7PEG‐8 hydrogenatedtallow amine(Suitable)

CAS# 68213‐26‐3POE‐5/POP‐12 Tallowamine(Suitable with interpretation)*

CAS# 68308‐48‐5Tallow amine, phosphateester(Suitable with precondition)**

Physico‐chemical SimilarityKey Differences:• Average chain length distribu

molecular weight due to dipolyethoxylate chain length.

• Greater extent of ethoxylationimpact of increasing molecular w

• These differences may impactdifferences in the context of tox

Metabolism SimilarityPotential metabolic transformationpredictions and data for published d

*Designated suitable with interpretation due to presence of

N

O O

O

O

OO O

O

2

H

H

5

5

N

O O

O O

O O OH

O O OH

N

O OH

O O OP

O

OHOH



download pegs cocamine

Documents