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^to sr,,.UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

NATIONAL CENTER FOR ENVIRONMENTAL ASSESSMENTCINCINNATI, OH 45268

OFFICE OFRESEARCH AND DEVELOPMENT

MEMORANDUM

DATE:

SUBJECT:

FROM:

TO:

October 26, 1995

Oral and Inhalation Toxicity Information for 1,1-Dichloroethane (CASRN75-34-3)(Midco I Site/Gary, Indiana)

Harlal ChoudhuryAdministratorSuperiund Health Risk Technical Support Center

Sally JansenU.S. EPARegion 5

This memorandum responds to your request for oral and inhalation systemic andcarcinogenic information for 1,1-dichloroethane.

Carcinogenicity (Attachment 1)

An update literature search was conducted on 1,1-dichloroethane to determine whetherany new data are available that might affect the cancer weight-of-evidence classification for thischemical. No new data were located that would impact upon the verified weight-of-evidenceclassification available on IRIS We are providing a brief description of our findings.

Oral Reference Dose (Attachment 2)

The Risk Assessment Issue Paper for Derivation of a Provisional RfD for 1,1-Dichloroethane (94-012/03-25-94) was updated, including a literature search to determinewhether any new data are available that might affect the RfD for this chemical. No new data werelocated, and the RfD derivation was not changed. References were updated and minor revisionswere made

Printed with v&getabte Oil Based Inks cm 100% Recycled Paoen40% Postoonsumen

Inhalation Reference Concentration (Attachment 3)

The literature regarding 1,1-dichloroethane was examined to determine whether aprovisional RfC could be denved for this chemical. A provisional RfC was derived using currentmethodology in a manner consistent with the RfD derivation (based on route-to-routeextrapolation) and an RfC derivation previously submitted to the RfD/RfC Work Group (butnever verified). We are providing a new issue paper on the derivation of a provisional RfC for1,1 -dichloroethane This issue paper is very similar to the RfD issue paper which, being the basisfor a route-to-route extrapolation, included discussion of all the inhalation studies.

Please feel free to contact the Superfund Technical Support Center at (513) 569-7300 ifyou need additional assistance.

cc: D. Bennett (5203G)R. Boice (Region 5)

J

Attachment 1

Risk Assessment Issue Paper for:Update of Carcinogenicity Assessment

for 1,1-Dichloroethane (CASRN 75-34-3)

1,1-Dichloroethane has been assigned to cancer weight of evidence group C (possiblehuman carcinogen), based on no evidence of carcinogenicity in humans and limited evidence intwo animal species (rats and mice); this classification was verified by the CRAVE Work Groupon 12 " 89 and is available on IRIS (U.S. EPA. 19Q5a,b). The available data were considered bythe CRAVE Work Group to be inadequate to support quantitative assessment of carcinogenicrisk < U.S. EPA, 1989. 1995b).

Computer searches of TOXLINE (1989-1995), CANCERLINE (1989-1995). CCRIS andTSCATS were conducted in October, 1995. No new data were located regarding the potentialcarcinogenicity of 1.1-dichloroethane. Therefore, the verified carcinogenicity assessmentavailable on IRIS continues to reflect the best data available.

REFERENCES

U.S. EPA. 1989. CRAVE Verification Meeting Notes of 12/7,89. CRAVE Work Group.Available from: National Center for Environmental Assessment, Cincinnati. OH.

U.S. EPA. 1995a. Monthly status report of RfD/RfC and CRAVE Work Groups (As of0901 95). Office of Research and Development. National Center for EnvironmentalAssessment, Cincinnati, OH.

U.S. EPA. 1995b. Integrated Risk Information System (IRIS). Online. Office of Research andDevelopment. National Center for Environmental Assessment. Cincinnati. OH.

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Attachment 2

Risk Assessment Issue Paper for:Derivation of a Provisional RfD for1,1-Dichloroethane (CASRN 75-34-3)

INTRODUCTION

Computer searches of TOXLINE (1988-1992), HSDB, RTECS, TSCATS,CASONLINE (1984-1990) and TOXLINE (1984-1990) were conducted in August, 1992. Inaddition. literature searches of TOXLINE (1991-1994), RTECS and TSCATS were performedin March. 1994, and searches of TOXLINE (1994-1995), DART (1994-1995) and TSCATSwere performed in October, 1995. Documents listed on the CARA data bases (U.S. EPA,1991, 1994) that were consulted include a Health Effects Assessment for 1,1-Dichloroethane(U.S. EPA 1984) and a Health and Environmental Effects Profile on Dichloroethanes (U.S.EPA, 1985). Other sources of information that were consulted were IRIS (U.S. EPA. 1995a).the RfD/RfC and CRAVE Status Reports (U.S. EPA. 1995b>. the HEAST (U.S. EPA.1995c). the Drinking Water Regulations and Health Advisories list (U.S. EPA. 1995d),updated NTP Status Reports (NTP. 1995a,b), and a Toxicological Profile on 1.1-Dichloroethane<ATSDR, 1990).

Oral and inhalation toxicity values for 1,1-dichloroethane are under discussion by theRfD RfC Work Group (U.S. EPA. 1995b). U.S. EPA (1989ai proposed an RfD of IE-1mg kg-day for 1,1-dichloroethane based on a LOAEL of 109.8 mg/kg-day for renal tubulardegeneration in a subchronic inhalation study in cats exposed to the chemical at a TWAconcentration of 3038 mg/m3 6 hours/day, 5 days/week for 26 weeks (Hofmann et al., 1971);an inhalation absorption factor of 0.5 was applied and an uncertainty factor of 1000 was used.Using the same exposure dose, U.S. EPA (1990) proposed an RfC of 5E-2 mg/m j for 1,1-dichloroethane based on a LOAELHEC of 518 mg/m3 for elevated BUN and creatinine andkidney lesions in cats exposed to the chemical at a TWA concentration of 2902 mg/m3 6hours/day, 5 days/week for 23 weeks, the time at which renal toxicity became evident(Hofmann et al., 1971). An uncertainty factor of 10.000 was used.

The HEAST (U.S. EPA, 1995c) lists an RfD for 1,1-dichloroethane of IE-1 mg/kg-day. This RfD is derived from U.S. EPA (1983, 1984) and is based on an inhalation study inrats by Hofmann et al. (1971). The derivation concluded that the NOAEL was 500 ppm (2025mg/m3, 6 hours/day, 5 days/week) 1,1-dichloroethane; no LOAEL was identified. TheNOAEL was duration adjusted, multiplied by an absorption coefficient of 0.5 and by the ratioof the rat reference inhalation rate (0.22 nrVday) to a reference body weight (0.35 kg). Anuncertainty factor of 1000 was applied (for inter- and intraspecies variation and extrapolationfrom a subchronic study). The HEAST (U.S. EPA. 1995c) also lists an RfC for 1,1-


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dichloroethane of 5E-1 mg/m3. This RfC is derived from U.S. EPA (1984) and is based onthe inhalation study in cats by Hermann et al. (1971). The derivation concluded that theNOAEL was 500 ppm (2025 mg/m3) 1,1-dichloroethane and the LOAEL was 1000 ppm (4050mg/m3, 6 hours/day, 5 days/week) for kidney damage. The NOAEL was duration adjusted,multiplied by the ratio of the cat inhalation rate (1.26 mVday) to the cat body weight (3.3 kg)and multiplied by the ratio of the human reference body weight (70 kg) to the human referenceinhalation rate (20 nvVday). An uncertainty factor of 1000 was applied (for inter- andintraspecies variation and extrapolation from a subchronic study). This derivation is notconsistent with current methodology for the development of inhalation RfCs (U .S . EPA.1989b).

ACGIH (1991. 1995) has adopted a TLV-TWA of 100 ppm (405 mg/m3) with noSTEL to protect workers against liver injury' and anesthetic effects. The OSHA PEL andNIOSH REL are 100 ppm (OSHA, 1989, 1993; NIOSH, 1992).

1.1-Dichloroethane was used in the past as a general anesthetic at a pressure of 0.026atm, which is approximately equivalent to a concentration of 105.000 mg/m-1 (26.000 ppm)iMiller et al. . 1965). Its use was discontinued when it was discovered that it induced cardiacarrhythmias at anesthetic doses (Browning, 1965).

1.1-Dichloroethane has a verified carcinogenicity classification of Group C. based onno evidence of carcinogenicity in humans and limited evidence in 2 animal species: rats andmice (U.S. EPA. 1995b).

PHARMACOKCVETICS

Little is known regarding the pharmacokinetics of 1.1-dichloroethane. A breath-holding study in humans determined that approximately 88% of the inhaled 1,1-dichloroethanewas absorbed into the lung (Morgan et al., 1970). A subsequent study by the sameinvestigators estimated a 1-minute retention coefficient in humans of 68% (Morgan et al..1972). Quantitative inhalation data in animals were not available, but toxicity data indicatethat pulmonary absorption occurs (ATSDR, 1990; U.S. EPA. 1983. 1985, 1990). Limiteddata suggest that 1,1-dichloroethane is well absorbed from the gastrointestinal tract of rats andmice (Mitoma et al., 1985). Results based primarily on in vitro studies suggest thatbiotransformation of 1,1-dichloroethane is mediated by the hepatic microsomal cytochrome P-450 system. In rat liver microsomes, 1,1-dichloroethane was dechlorinated more rapidly than1,2-dichloroethane and the metabolites included acetic acid, chloroacetic acid. 2.2-dichloroethanol and trace amounts of dichloroacetic acid and chloroacetaldehyde iMcCall etal., 1983: Loew et al.. 1973; Salmon et al., 1981). By using a pharmacokinetics model. Satoand Nakajima (1987) calculated a respiratory- clearance rate of 72 L/hour (41%) and ametabolic clearance rate of 105 L/hour (59%) for 1,1-dichloroethane in humans. In rats, oral


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administration of a dose of 700 mg/kg 1,1-dichloroethane resulted in excretion of 5% of thedose as CO2 and 86% as unchanged compound in the expired air (Mitoma et al., 1985). Inmice, 70% of a dose of 1800 mg/kg was excreted unchanged in expired air, whereas 25% wasaccounted for as CO2 (Mitoma et al., 1985). Further information regarding pharmacokineticsof 1,1-dichloroethane was not located.

NONCARCEVOGENIC EFFECTS

Acute Data

Smyih (1956) observed no deaths in rats exposed to 4000 ppm (16,190 mg.nV) 1,1-dichloroethane for 8 hours, but exposure to a concentration of 16,000 ppm (64,759 mg m3) for8 hours was lethal. Browning (1965) reported that the lethal exposure level of 1,1-dichloroethane in mice was 17,500 ppm. Dow Chemical (1960) reported the results of singleexposure studies of rats to 1,1-dichloroethane vapors. Dose- and time-related lethality wasobserved in male rats exposed to concentrations of 8.000 to 64,000 ppm 1,1-dichloroethane(32.380-259,036 mg/m3 assuming 253C and 760 mm Hg) for 0.1-7 hours. Autopsy of theanimals that died revealed lung injury with slight liver and kidney pathology. Sax 11984)reported an oral LDSU of 725 mg/kg of 1.1-dichloroethane in rats. Dow Chemical < 1960)reported that single oral doses of 2 g/kg induced no adverse reactions in rats, but autopsyshowed some kidney injury.

Plaa and Larson (1965) measured impaired kidney function (increased levels of proteinand glucose in urine) in surviving mice given single intraperitoneal doses of 4 mLkg 1.1-dichloroethane that produced deaths in 6/10 of the mice. Single doses of 2 ml/kg producedincreased levels of urinary protein, but not glucose, in 4/10 mice. The kidneys of 5 micetreated with 2 mL/kg were examined histoiogically. No renal necrosis was found, but 3/5kidneys showed proximal convoluted tubules with more than 50% of their area swollen.Treatment with doses of 1 mL/kg did not increase urinary protein or glucose in 10 mice. Theauthors did not specify if kidneys from mice treated at the 1 or 4 mL/kg dose levels wereexamined histoiogically.

Subchronic and Chronic Data

Groups of 10 Sprague-Dawley rats, 10 Pirbright-White guinea pigs, 4 "colored" rabbitsand 4 cats were exposed to 0 or 500 ppm 1,1-dichloroethane (2024 mg/m3, assuming 25°C and760 mm Hg) for 6 hours/day, 5 days/week for 13 weeks followed by a 10- to 13-weekexposure period to 1000 ppm (4047 mg.'m3) (Hofmann et al., 1971). The TWA exposureconcentration was 717 ppm (2902 mg/m3) for cats and 750 ppm (3036 mg/m3) for guinea pigsand rabbits (because effects were noticeable in cats after a total of 23 weeks, 23 weeks wasused as the total duration in estimating the TWA for cats). Each group was composed of anequal number of males and females (2 each for cats and rabbits, 5 each for guinea pigs and


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rats). Behavior and body weight were monitored in all species. Hematologic and urinalysisvalues, SGPT, SGOT, serum urea and serum creatinine were monitored in rats, rabbits andcats. Sulfobromphthalein excretion was tested in rabbits and cats. It was not clearly specifiedwhat endpoints were tested in guinea pigs. After 13 weeks of treatment, none of the speciestested showed any clinical or biochemical changes attributable to treatment with 1,1-dichloroethane and were therefore, exposed to 1000 ppm for an additional 10-13 weeks. Uponstudy termination, all animals were necropsied; relative liver and kidney weights weredetermined and the liver, kidneys, and occasionally other selected organs (not specified) wereprocessed for histopathological examination. No effects were reported in treated rats, rabbitsor guinea pigs. Following the increase in concentration to 1000 ppm. cats had reduced bodyweight gain and elevated serum urea and serum creatinine levels relative to controls. One catwas removed from exposure due to poor general condition after 10 weeks at 1000 ppm; for theremaining animals exposure terminated at week 13. At the end of the experiment,histopathological examination of the kidneys revealed renal tubular dilation and degenerationin 3 of the 4 treated cats. No information was provided regarding effects at the portal of entry(i.e., pulmonary effects). 1,2-Dichloroethane, which was also tested in this study, appeared tobe considerably more toxic than 1.1-dichloroethane. Based on this study, a LOAEL of 2902mg/m- <TWA) for kidney effects in cats was derived- The TWA exposure of 3036 mg nV wasa NOAEL for rats, guinea pigs and rabbits.

Dow Chemical (1990) conducted a multispecies subchronic inhalation study, but theresults were reported only as an unpublished summary. Groups of 24 male and 36 femaleWistar-derived rats, 2 female dogs and 3 male and 3 female rabbits were exposed to 0, 500 or1000 ppm 1,1-dichIoroethane fO. 2024 or 4047 mg m3, assuming 25°C and 760 mm Hg) 7hours/day, 5 days/week for 6 months. Guinea pigs (7 males and 8 females) were exposed to2024 mg/m3 for 3 months. Hematologic parameters (PCV. hemoglobin, total and differentialleucocyte counts), determined at 4 months of treatment and prior to termination at 6 months.were not altered by exposure to 1,1-dichloroethane. Urinalyses performed at 5 months wereunremarkable. Clinical chemistry values (alkaline phosphatase, urea nitrogen. SGPT) werewithin normal ranges. At necropsy, gross and microscopic examination of all major organsand tissues revealed no treatment-related adverse effects. The NOAEL for rats, dogs, andrabbits is 4047 mg/m3; the guinea pig NOAEL is 2024 mg/m3

Union Carbide (1947) provided information on Sprague-Dawley rats (12/sex/group)and mongrel dogs (I/sex/group) exposed to 0 or 1000 ppm 1,1-dichloroethane 7 hours/day fora total of 75 exposures over a 6-month period. The results, however, are of questionablesignificance since high mortality occurred in rats due to endemic lung infection (50% incontrols, 51% in 1,1-dichloroethane groups). At the end of the 6-month period, the onlyeffects reported in the single dog exposed to 1,1-dichloroethane were significantly reducedbody weight gain throughout the study and marked lung congestion, but no other pathology.According to the investigators, the only effect in rats attributed to exposure to 1,1-dichloroethane was a significant decrease (p< 0.004) in body weight gain in female rats.


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NCI (1978) conducted a range-finding oral study in which groups of 5 Osborne-Mendelrats/sex and 5 B6C3F1 mice/sex were gavaged for 6 weeks with 1,1-dichloroethane in corn oilfollowed by a 2-week observation period. The test material was administered 5 days/week atdose levels of 0, 562. 1000, 1780, 3160 or 5620 mg/kg-day in rats and 0, 1000, 1780, 3160,5620 or 10,000 mg/kg-day in mice. In male rats, body weight decreased by 16% and 29% at562 and 1000 mg/kg-day, respectively. In female rats, body weight decreased by 20% at 1780and 3160 mg/kg-day and two animals died at the latter level. Body weight was not altered inmice, but two males and three females died at the 5620 mg/kg-day dose level. No otherendpoints were examined.

In a chronic oral study conducted by NCI (1978), Osborne-Mendel rats (50/sex/dosegroup) and B6C3F1 mice (50/sex/dose group) were administered 1,1-dichloroethane in cornoil 5 days/week for 78 weeks. An observation period of 33 weeks followed, after which allsurviving animals were sacrificed and examinations for gross and microscopic organ pathology iwere made. The time-weighted average dosages over the 78-week treatment period were: 382 ^*and 764 mg/kg-day for male rats, 475 and 950 mg.kg-day for female rats, 1442 and 2885mg/kg-day for male mice, and 1665 and 3331 mg/kg-day for female mice. Twenty animals ofeach sex and species served as vehicle and untreated controls. Treatment-related effects weredifficult to assess due to high mortality in rats due to pneumonia. Survival at the end of thestudy in the untreated control, vehicle control, low dose, and high dose groups was.respectively, 30, 5, 4. and &% in male rats; 40, 20. 16. 18^ in female rats; 35, 55, 62, and32*^ in male mice; and 80. 80. 80 and 5Q% in female mice. In male rats, but not female rats,survival in both treated groups during the study was significantly lower (p<0.006) than ineither the untreated control or vehicle treated group, although terminal survival rates betweenvehicle control and treated males were similar. In male mice, there was a significantassociation (significance not provided) between dosage and mortality and the trend for femalemice was highly significant (p<0.001); these findings were due mainly to mortality in thehigh-dose groups. The possible cause of death in mice was not discussed, but according to the iinvestigators (NCI 1978) it was not tumor-related. No treatment-related effects were observedin rats or mice regarding body weight, food consumption, appearance and behavior, orincidence of nonneoplastic lesions. Hematology and clinical chemistry parameters were notmonitored. No NOAELs or LOAELs can be defined in this study due to the high mortalityobserved at the lowest dose tested.

Limited information on the oral toxicity of 1,1-dichloroethane is available in a two-stage carcinogenesis study in mice (Klaunig et al.. 1986). Groups of 35 male B6C3F1 micewere administered 1.1-dichloroethane in the drinking water at 0, 835 or 2500 mg/L for up to52 weeks following treatment with either 10 mg/L diethylnitrosamine (DENA) in the drinkingwater or deionized water for 4 weeks. The investigators estimated that the weekly dose of1,1-dichloroethane \\as approximately 3.8 mg/g body weight (543 mg/kg-day) for the groupsgiven the chemical at 2500 mg/L, but provided no information regarding the low-dose level.At sacrifice at the end of 24 weeks (10 mice/group) or 52 weeks (25 mice/group) of


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promotion, all tissues were examined for gross pathological lesions, and sections of the liver,kidneys and lungs were processed for light microscopy. Body weights in all 1,1-dichloroethane-treated groups were slightly lower than untreated controls, but the differencewas not statistically significant. Treatment with 1,1-dichloroethane did not affect water intakeor survival. No nonneoplastic lesions were reported in 1,1-dichloroethane-treated groups. Inthis study, the dose of 543 mg/kg-day represents a NOAEL for mice.

Developmental and Reproductive Toxicirv

Groups of 46. 16 and 19 pregnant Sprague-Dawley rats were exposed to 0. 3800 or6000 ppm 1,1-dichloroethane 115.3SO or 24,284 mg/m-. assuming 253C and 760 mm Hg),respectively, for 7 hours/day on gestation days 6-15 {Schwetz et al . . 1974*. Foodconsumpcion was significantly decreased (p<0.05) during treatment at both concentrationlevels. Body weights were significantly reduced (p<0.05) in treated rats at both concentrationlevels on day 13 and in the 3800 ppm group on day 21 (other time points not examined).Treatment with 1.1-dichloroethane had no effect on maternal SGPT activity1 or grossappearance of the liver, but relative liver weight was significantly increased in nonpregnantrats f> days after the last exposure. Exposure to 1.1-dichloroethane did no: affect conceptionrate, number of implantations, litter size, incidence of fetal resorpnons. feral bodymeasurements or incidence of gross or soft tissue anomalies. Exposure to 6000 ppm 1,1-dichloroethane caused a significant increase <p<0.05) in the incidence of delayed ossificationof sternebrae; the incidence at the 3SOO ppm level was significantly lower than in controls. Inthis study, the exposure level of 15.380 mg/m3 represents a maternal LOAEL and adevelopmental NOAEL for 1.1-dichloroethane. The developmental LOAEL is 24.284 mg m1.

Studies of reproductive to.xicity were not located.

SCENARIO FOR THE DERIVATION OF AN ORAL RfD

Relevant information is available from five studies for derivation of a provisional RfDfor 1.1-dichloroethane. Three of these studies (Dow Chemical 1990; Hermann et al.. 1971;Schwetz et at . , 1974) used the inhalation route of exposure; in studies conducted by NCI(1978) and Klaunig et al. (1986), the chemical was administered by the oral route. In the 78-week chronic oral study in rats and mice (NCI 1978), high mortality occurred at the lowestdose level tested (382 mg/kg-day for rats), and therefore, neither NOAELs nor LOAELs couldbe defined. In the 52-week drinking water study conducted by Klaunig et al. (1986), noadverse effects were observed in mice at 543 mg/kg-day and this dose level represented aNOAEL for 1.1-dichloroethane. However, the scope of this study was rather limited sinceonly liver, kidney and lungs were examined histologically. and clinical chemistry andhematology values were not monitored. In the multispecies inhalation study conducted byDow Chemical (1990) (reported only as an unpublished summary), a NOAEL of 2024 mg m3

was identified for guinea pigs and a NOAEL of 4047 mg/m3 was defined for rats, dogs and

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rabbits; all species were exposed 7 hours/day, 5 days/week for 3 to 6 months; theseconcentration exposure levels were the highest tested. The results of Dow Chemical (1990)are supported by data reported by Hofmann et al. (1971), who found no adverse effects in ratsand rabbits exposed to TWA concentrations of 3036 mg/m3 1,1-dichloroethane (6 hours/day, 5days/week) for 26 weeks. Hofmann et al. (1971), however, reported kidney lesions andaltered serum urea and creatinine in cats exposed to TWA of 2902 mg/m3 1,1-dichloroethanefor 23 weeks. In the inhalation study conducted by Schwetz et al, (1974) in rats exposedduring pregnancy, a developmental NOAEL of 15,380 mg/m3 was identified for 1.1-dichloroethane: the LOAEL was 24.284 mg/m1 Thus, it appears that cats, which were nottested in the Dow Chemical (1990) study, are the most sensitive species.

Based on the information summarized above, a provisional RfD might be calculatedfrom ihe inhalation data in cats reported by Hermann et al. (1971). In that study, one out offour cats showed kidney lesions after a total of 23 weeks of exposure (earliest monitoring time)to 1,1-dichloroethane. Two additional cats showed kidney lesions after 26 weeks of exposure.Lesions consisted of crystal precipitation and obstruction of the tubules, consistent withhydronephrosis. and tubule degeneration.

It does not seem appropriate to base this provisional RfD on a NOAEL for the first 13weeks of exposure, a possibility raised by the RfD/RfC Work Group (U.S. EPA, 1990).because the kidneys were not examined during this first exposure period. Although serumcreatinine and urea were monitored throughout the study, and appearance of increased levelsappeared to coincide with raising the exposure concentration from 500 to 1000 ppm, it is notclear that these parameters are sufficiently sensitive to have revealed subtle renal damage thatmay have occurred during the 500 ppm exposure.

Supporting evidence that the kidney is a target for the toxicity of 1,1-dichloroethane isrestricted to observations of altered renal histology or impaired renal function after acuteintrapentoneal exposure to 2 or 4 mL/kg doses of 1.1-dichloroethane (Plaa and Larson. 1965)and kidney injury in rats following administration of single oral doses of 2 g/kg or singlelethal inhalation exposures (Dow Chemical, 1960).

The provisional RfD might be calculated as follows:

LOAEL^j = 2902 mg/m3 x 6/24 x 5/7 = 518 mg/m3

Inhaled Dose = 518 mg/m3 x 0.6739 m3/day / 3.5 kg = 99.8 mg/kg-day

where:

0.6739 = Inhalation rate for a 3.5 kg cat; determined from an allometricrelationship described in U.S. EPA (1987).


PaeeS

3.5 = Cat body weight throughout the study estimated from graphicdata in Hofmann et al. (1971).

The inhaled dose (LOAEL) of 99.8 mg/kg-day is lower than the lowest oral doseassociated with early mortality in rats (382 mg/kg-day) in the NCI (1978) study. A defaultratio of 1 was selected for oral:inhalation absorption factors, given the lack of data,

Thus.

RfD = Inhaled Dose / UF = 99.8 mg.kg-day / 10,000 = 0.01 mg.kg-day

where;

UF = Uncertainty factor (all five areas of uncertainty are involved, includinguse of a LOAEL, interspecies extrapolation, protection of sensitiveindividuals, use of a subchronic study, and for database limitations,including route-to-route extrapolation. Given that some areas ofuncertainty may overlap, a maximum UF of 10,000 is applied).

The provisional RfD of 0.01 mg/kg-day for 1.1-dichloroethane would be one order ofmagnitude lower than that derived from the same data and currently under review by theRfD RfC Work Group (U.S. EPA. 1989a). The difference is due to the following: U.S. EPA(1989a) considered a total exposure period of 26 weeks in estimating the TWA exposure; theinhalation rate for cats was estimated at 1.215 nvVday (Guyton, 1947); the cat body weightwas estimated as 3 kg; and, an absorption factor of 50% was used.

If such a scenario would be used to define the RfD, confidence in the key study wouldbe graded low because of the small number of animals used and because, other than for thekidneys, limited information was provided regarding organs and tissues examined. Confidencein the database is low because adequate chronic oral studies were not available and becausedevelopmental data in only one species were located. Confidence in the provisional RfDwould be low, reflecting low confidence in the database and key study.

Caution is advised in using the provisional RfD for 1,1-dichloroethane. Insufficientpharmacokinetic data are available for accurately determining the absorption ratio for a route-to-route extrapolation. Additionally, the Hofmann et al. (1971) cat study is, at best, marginalfor use in a risk assessment due to the small number of animals in the study and the lack ofcorroborative data from other repeated exposure studies. Therefore, if this provisional RfD ischosen, this office will not be able to attest to its scientific accuracy and use.

Deriving an RfD for 1,1-dichloroethane based on structural analogy to 1,2-dichloroethane is not recommended because of the evidence that this isomer has different


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pharmacokinetic and toxicologic properties from those of 1,1-dichloroethane. In vitrometabolism studies with rat liver microsomes showed that 1,1-dichloroethane is more rapidlydechlorinated than 1,2-dichloroethane (McCall et al., 1983; Loew et al., 1973; Salmon et al.,1981). Hofmann et al. (1971) reported that repeated inhalation exposure to 1,2-dichloroethaneat 500 ppm was lethal to rats, guinea pigs and rabbits, but not to cats, within a few weekscommencement of exposure. In contrast, exposure to 500 or 1000 ppm 1,1-dichloroethane bythe same protocol for up to 23 weeks produced no adverse effects in rats, guinea pigs orrabbits and only produced nonlethal renal effects in cats (Hofmann et al.. 1971).

REFERENCES

ACGIH (American Conference of Governmental Industrial Hygienists). 1991.Documentation of Threshold Limit Values and Biological Exposure Indices for ChemicalSubstances in the Workroom Air, 6th ed., Cincinnati, OH, pp. 425-428.

ACGIH (American Conference of Governmental Industrial Hygienists). 1995. 1995-1996Threshold Limit Values for Chemical Substances and Physical Agents and Biological ExposureIndices. ACGIH, Cincinnati, OH, p. 18.

ATSDR (Agency for Toxic Substances and Disease Registry). 1990. Toxicological Profilefor i,l-Dichloroethane. ATSDR, U.S. Public Health Service. Atlanta, GA. NTISPB\91\1S0539.

Browning. E. 1965. Dichloroethane. In: Toxicity and Metabolism of Industrial Solvents.Elsevier Publishing Co.. Amsterdam, pp. 247-252.

Dow Chemical Company. 1960. Results of range finding toxicological tests on 1.1-dichloroethane. TSCA submission OTS Fiche #OTS0515949.

Dow Chemical Company. 1990. Six month inhalation study with 1,1-dichloroeihane. Letterto Syracuse Research Corporation, February 14. 1990.

Guyton, A.C. 1947. Measurement of the respiratory volumes of laboratory animals. Am. J.Physiol. 150: 70-77.

Hofmann, H.T., H. Birnstiel and P. Jobst, 1971. On the inhalation toxicity of 1.1-dichloroethane. Arch. Toxicol. 27: 248-265. (English translation)

Klaunig, J.E., R.J, Ruch and M.A. Pereira. 1986. Carcinogenicity of chlorinated methaneand ethane compounds administered in drinking water to mice. Environ. Health Perspec. 69:29-93.


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Loew, G., J. Trudell and H. MotuLsky. 1973. Quantum chemical studies of the metabolismof a series of chlorinated ethane anesthetics. Mol. Pharmacol. 9:152-162.

McCall, S.N., P. Jurgens and K.M. Ivanetich. 1983. Hepatic microsomal metabolism ofdichloroethanes. Biochem. Pharmacol. 32: 207-213.

Miller, K.W., W.D.M. Paton and E.B. Smith. 1965. Site of action of general anesthetics.Nature 206. 574-577.

Mitoma. C.. T. Steeger. S.E. Jackson, K.P. Wheeler. J.H. Rogers and H.A. Milman. 1985.Metabolic disposition study of chlorinated hydrocarbons in rats and mice. Drug Chem.Toxicol. 8: 183-194.

Morgan, A., A. Black and D.R. Belcher. 1970. The excretion in breath of some aliphatichalogenated hydrocarbons following administration by inhalation. Ann. Occup. Hyg. 13:219-233.

Morgan. A.. A. Black and D.R. Belcher. 1972. Studies on the absorption of halogenatedhydrocarbons and their excretion in breath using *C\ tracer techniques. Ann. Occup. Hyg.15: 273-282.

NCI (National Cancer Institute). 1978. Bioassay of 1. l-dichloroethane for possiblecarcinogenicity. NCLNTP TR 066. DHEW Publ. No. (NIH) 78-1316.

NIOSH (National Institute for Occupational Safety and Health). 1992. Recommendations forOccupational Safety and Health. Compendium of Policy Documents and Statements. U.S.Department of Health and Human Services. DHHS (NIOSH) Publication No. 92-100. p. 71.

NTP (National Toxicology Program). 1995a. Management Status Report (7/7/95).

NTP (National Toxicology Program). 1995b. NTP Results Report (7/7/95).

OSHA (Occupational Safety and Health Administration). 1989. 29 CFR 1910. AirContaminants; Final Rule. Federal Register. 54(12): 2332-2983.

OSH A (Occupational Safety and Health Administration). 1993. 29 CFR 1910. AirContaminants; Rule. Federal Register. 58(124): 35338-35351.

Plaa, G.L. and R.E. Larson. 1965. Relative nephrotoxic properties of chlorinated methane,ethane and ethylene derivatives in mice. Toxicol. Appl. Pharmacol. 7: 37-44.


Page 11

Salmon, A.G., R.B. Jones and W.C, Mackrodt. 1981. Microsomal dechlorination ofchloroeihanes: Structure-reactivity relationships. Xenobiotica 11: 723-734.

Sato, A. and T. Nakajima. 1987. Pharmacokinetics of organic solvent vapors in relation totheir toxicity. Scand. J. Work Environ. Health 13: 81-93.

Sax, N.I. , Ed. 1984. Dangerous Properties of Industrial Materials, 6th ed. Van NostrandReinhoid Co., NY. pp. 1362-1363.

Schwetz. B.K., K.L. Leong and P.J. Gehring. 1974. Embryo- and fe:otoxic:ty of inhaledcarbon tetrachloride, 1,1-dichloroethane and methyl ethyl ketone in rats. Toxicol. Appl.Pharmacol. 28: 452-464.

Smyth, H.F. Jr. 1956. In: Handbook of Toxicology, Vol. 1, W.S. Spector. Ed. pp. 92-95. j

Union Carbide Corporation. 1947. Repeated exposure of rats and dogs to vapors of eightchlorinated hydrocarbons. TSCA Submission OTS,r0515559.

U.S. EPA. 1983. Drinking Water Criteria Document for 1.1-Dichleroeihane. Prepared bythe Office of Health and Environmental Assessment. Environmental Criteria and AssessmentOffice. Cincinnati, OH for the Office of Drinking Water, Washington. DC. ECAO-CIN-303.

U.S. EPA. 1984. Health Effects Assessment for l.l-Dichloroethane. Prepared by the Officeof Health and Environmental Assessment. Environmental Criteria and Assessment Office,Cincinnati, OH for the Office of Emergency and Remedial Response. Washington. DC.ECAO-CIN-H027.

U.S. EPA. 1985. Health and Environmental Effects Profile for Dichloroethanes. Prepared iby the Office of Health and Environmental Assessment. Environmental Criteria and >**^Assessment Office. Cincinnati. OH for the Office of Solid Waste and Emergency Response.Washington, DC. ECAO-CIN-P139.

U.S. EPA. 1987. Recommendation for and Documentation of Biological Values for Use inRisk Assessment. Prepared by Environmental Criteria and Assessment Office, Office ofHealth and Environmental Assessment. Cincinnati. OH for the Office of Solid Waste andEmergency Response. Washington DC. ECAO-CIN-554.

U.S. EPA. 1989a. Oral RfD Verification Meeting Notes of 9/21/89 i with attached summary-sheet). RfD and RfC Work Group. Available from: National Center for EnvironmentalAssessment, Cincinnati, OH.


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U.S. EPA. 1989b. Interim Methods for Development of Inhalation Reference Doses. Officeof Health and Environmental Assessment, Washington, DC. EPA 600/8-88/066F.

U.S. EPA. 1990. Inhalation RfC Verification Meeting Notes of 4/19/90 (with attachedsummary sheet). RfD and RfC Work Group. Available from: National Center forEnvironmental Assessment, Cincinnati, OH.

U.S. EPA. 1991. Office of Health and Environmental Assessment Chemical Assessments andRelated Activities. Office of Health and Environmental Assessment, Washington, DC. April.1991. OHEA-I-127.

U.S. EPA. 1994. Office of Health and Environmental Assessment Chemical Assessments andRelated Activities. Office of Health and Environmental Assessment, Washington, DC.December 1994. OHEA-I-127.

U.S. EPA. 1995a. Integrated Risk Information System (IR1SV Online. Office of Researchand Development. National Center for Environmental Assessment. Cincinnati, OH.

U.S. EPA. I995b. Monthly status report of RfD/RfC and CRAVE Work Groups (As of09/01/95). Office of Research and Development. National Center for EnvironmentalAssessment. Cincinnati. OH.

U.S. EPA. 1995c. Health Effects Assessment Summary Tables. FY-1995 Annual. Office ofResearch and Development. Office of Emergency and Remedial Response. Washington, DC.May. 1995. EPA/540/R-95/036. PB 95-921199.

U.S. EPA. 1995d. Drinking Water Regulations and Health Advisories. Office of Water.Washington, DC. May 1995.

Attachment 3

Risk Assessment Issue Paper for:Derivation of a Provisional RfC forU-Dichloroethane (CASRN 75-34-3)

INTRODUCTION

Computer searches of TOXLINE (1988-1992), HSDB. RTECS. TSCATS, CASONLINE(1984-1990) and TOXLINE (1984-1990) were conducted in August, 1992. In addition, literaturesearches of TOXLINE (1991-1994), RTECS and TSCATS were performed in March. 1994. andsearches of TOXLINE (1994-1995), DART (1994-1995) and TSCATS were performed in


Page 13

October, 1995. Documents listed on the CARA data bases (U.S. EPA, 1991, 1994) that wereconsulted include a Health Effects Assessment for 1,1-Dichloroethane (U.S. EPA 1984) and aHealth and Environmental Effects Profile on Dichloroethanes (U.S. EPA, 1985). Other sourcesof information that were consulted were IRIS (U.S. EPA, 1995a), the RfD/RfC and CRAVEStatus Reports (U.S. EPA, 1995b), the HEAST (U.S. EPA, 1995c), the Drinking WaterRegulations and Health Advisories list (U.S. EPA, 1995d), updated NTP Status Reports (NTP,1995a.b), and a Toxicological Profile on U-Dichloroethane (ATSDR, 1990).

Inhalation and oral toxicity values for 1,1-dichloroethane are under discussion by theRfD R:C Work Group (U.S. EPA, 1995b>. U.S. EPA (1990) proposed an RfC of 5E-2 mg/m3

tor 1.1 -Jichloroethane based on a LOAELHEC of 518 mg/m3 for elevated BUN and creatinine andkidney lesions in cats exposed to the chemical at a TWA concentration of 2902 mg/m3 6hours day, 5 days/week for 23 weeks, the time at which renal toxicity became evident (Hofmannet al.. 1971). An uncertainty factor of 10.000 was used. U.S. EPA (1989a) proposed an RfD ofIE-1 mg/kg-day for 1,1-dichloroethane based on a route-to-route extrapolation from the Hofmannet al. 11971) subchronic inhalation study in cats. In this derivation, the full experimental periodof 26 weeks 1.6 hours/day. 5 days/week) was used to calculate a TWA concentration of 3038mg m . which translated to a LOAEL of 109.8 mg/kg-day for renal tubular degeneration; antnhalur.on absorption factor of 0.5 was applied and an uncertainty factor of 1000 was used.

The HEAST (U.S. EPA, 1995c) lists an RfC for 1,1-dichloroethane of 5E-1 mg/m3. ThisRfC. presented in U.S. EPA (1984). is also based on the inhalation study in cats by Hofmann etal. (1971) . The derivation concluded that the NOAEL was 500 ppm (2025 mg/m3) 1,1-dichleroethane and the LOAEL was 1000 ppm (4050 mg/m3) for kidney damage. The NOAELwas duration adjusted (6 hours/day, 5 days week), multiplied by the ratio of the cat inhalation rate(1.26 nr'. day) to the cat body weight (3.3 kg) and multiplied by the ratio of the human referencebody weight (70 kg) to the human reference inhalation rate (20 mVday). An uncertainty factorof 1000 was applied (for inter- and intraspecies variation and extrapolation from a subchronicstudy i. This derivation is not consistent with current methodology for the development ofinhalation RfCs (U.S. EPA. 1989b). The HEAST (U.S. EPA, 1995c) also lists an RfD for 1,1-dichloroethane of IE-1 mg/kg-day. This RfD, presented in U.S. EPA (1983, 1984). is based onan inhalation study in rats by Hofmann et al. (1971). The derivation concluded that the NOAELwas 500 ppm (2025 mg/m3, 6 hours/day. 5 days/week) 1,1-dichloroethane; no LOAEL wasidentified. The NOAEL was duration adjusted, multiplied by an absorption coefficient of 0.5 andby the ratio of the rat reference inhalation rate (0.22 m3/day)


Page 14

to a reference body weight (0.35 kg). An uncertainty factor of 1000 was applied (for inter- andintraspecies variation and extrapolation from a subchronic study).

ACGffl {1991, 1995) has adopted a TLV-TWA of 100 ppm (405 mg/m3) with no STELto protect workers against liver injury and anesthetic effects. The OSHA PEL and NIOSH RELare 100 ppm (OSHA. 1989, 1993; NIOSH, 1992).

1.1-Dichloroethane was used in the past as a general anesthetic at a pressure of 0.026 arm,which is approximately equivalent to a concentration of 105.000 mg/m3 (26,000 ppm) (Miller eta l . . 1965>. Its use was discontinued when it was discovered that it induced cardiac arrhythmiasat anesthetic doses (Browning, 1965).

1,1-Dichloroethane has a verified carcinogenicity classification of Group C. based on noevidence of carcinogenicity in humans and limited evidence in 2 animal species: rats and mice(U.S. EPA, 1995b).~"

PHARMACOKINETICS

Little is known regarding the pharmacokinetics of 1,1-dichloroethane. A breath-holdingstudy in humans determined that approximately 88% of the inhaled 1,1-dichloroethane wasabsorbed into the lung (Morgan et al., 1970). A subsequent study by the same investigatorsestimated a 1-minute retention coefficient in humans of 68% (Morgan et al., 1972). Quantitativeinhalation data in animals were not available, but toxicity data indicate that pulmonary absorptionoccurs (ATSDR. 1990; U.S. EPA, 1983, 1985. 1990). Limited data suggest that 1,1-dichloroethane is well absorbed from the gastrointestinal tract of rats and mice (Mitoma et al..19851. Results based primarily on in vitro studies suggest that biotransformation of 1,1-dichloroethane is mediated by the hepatic microsomal cytochrome P-450 system. In rat livermicrosomes, 1.1-dichloroethane was dechlorinated more rapidly than 1,2-dichloroethane, and themetabolites included acetic acid, chloroacetic acid, 2,2-dichloroethanol and trace amounts ofdichloroacetic acid and chloroacetaldehyde (McCall et al., 1983; Loew et al., 1973; Salmon etal., 1981). By using a pharmacokinetics model, Sato and Nakajima (1987) calculated arespiratory clearance rate of 72 L/hour (41%) and a metabolic clearance rate of 105 L/hour (59%)for 1.1-dichloroethane in humans. In rats, oral administration of a dose of 700 mg/kg 1,1-dichloroethane resulted in excretion of 5% of the dose as CO2 and 86% as unchanged compoundin the expired air (Mitoma et al., 1985). In mice, 70% of a dose of 1800 mg/kg was excretedunchanged in expired air, whereas 25% was accounted for as CO2 (Mitoma et al., 1985), Furtherinformation regarding pharmacokinetics of 1,1-dichloroethane was not located.

NONCARCINOGENIC EFFECTS


Page 15

Acute Data

Smyth (1956) observed no deaths in rats exposed to 4000 ppm (16,190 mg/m3) 1,1-dichloroethane for 8 hours, but exposure to a concentration of 16,000 ppm (64,759 mg/m3) for8 hours was lethal. Browning (1965) reported that the lethal exposure level of 1,1-dichloroethanein mice was 17,500 ppm. Dow Chemical (1960) reported the results of single exposure studiesof rats to 1,1-dichloroethane vapors. Dose- and time-related lethality was observed in male ratsexposed to concentrations of 8,000 to 64.000 ppm 1,1-dichloroethane (32,380-259.036 mg/m3

assuming 25 °C and 760 mm Hg) for 0.1-7 hours. Autopsy of the animals that died revealed lunginjury with slight liver and kidney pathology. Sax < 1984) reported an oral LD50 of 725 mg kg ofl.l-dichloroethane in rats. Dow Chemical (I960) reported that single oral doses of 2 g kginduced no adverse reactions in rats, although autopsy showed seme kidney injury.

Plaa and Larson (1965) measured impaired kidney function (increased levels of protein andglucose in urine) in surviving mice given single intraperitoneal doses of 4 mL/kg 1,1-dichloroethane that produced deaths in 6/10 of the mice. Single doses of 2 mL/kg producedincreased levels of urinary protein, but not glucose, in 4/10 mice. The kidneys of 5 mice treatedw-i th 2 mL/kg were examined histologically. No renal necrosis was found, but 3/5 kidneysshowed proximal convoluted tubules with more than 50% of their area swollen. Treatment withdoses of I mL/kg did not increase urinary protein or glucose in 10 mice. The authors did notspecify if kidneys from mice treated at the 1 or 4 mL/kg dose levels were examined histologically.

Subchronic and Chronic Data

Groups of 10 Sprague-Dawley rats. 10 Pirbright-White guinea pigs, 4 "colored" rabbitsand 4 cats were exposed to 0 or 500 ppm 1.1-dichloroethane (2024 mg/m3, assuming 25 °C and760 mm Hg) for 6 hours/day, 5 days/week for 13 weeks followed by a 10- to 13-week exposureperiod to 1000 ppm (4047 mg/m3) (Hofrnann et al., 1971). The TWA exposure concentration was717 ppm (2902 mg/m3) for cats and 750 pprn (3036 mg/m3) for guinea pigs and rabbits (becauseeffects were noticeable in cats after a total of 23 weeks, 23 weeks was used as the total durationin estimating the TWA for cats). Each group was composed of an equal number of males andfemales (2 each for cats and rabbits, 5 each for guinea pigs and rats). Behavior and body weightwere monitored in all species. Hematologic and urinalysis values. SGPT. SGOT, serum urea andserum creatinine were monitored in rats, rabbits and cats. Sulfobromphthalein excretion wastested in rabbits and cats. It was not clearly specified what endpoims were tested in guinea pigs.After 13 weeks of treatment, none of the species tested showed any clinical or biochemicalchanges attributable to treatment with 1,1-dichloroethane and were therefore, exposed to 1000ppm for an additional 10-13 weeks. Upon study termination, all animals were necropsied; relativeliver and kidney weights were determined and the liver, kidneys, and occasionally other selectedorgans (not specified) were processed for histopathological examination. No effects were reportedin treated rats, rabbits or guinea pigs. Following the increase in concentration to 1000 ppm, catshad reduced body weight gain and elevated serum urea and serum creatinine levels relative to


Page 16

controls. One cat was removed from exposure due to poor general condition after 10 weeks at1000 ppm; for the remaining animals exposure terminated at week 13. At the end of theexperiment, histopathological examination of the kidneys revealed renal tubular dilation anddegeneration in 3 of the 4 treated cats. No information was provided regarding effects at theportal of entry (i.e., pulmonary effects). 1,2-Dichloroethane. which was also tested in this study,appeared to be considerably more toxic than 1,1-dichloroethane. Based on this study, a LOAELof 2902 mg/m3 (TWA) for kidney effects in cats was derived. The TWA exposure of 3036 mg/m3

was a NOAEL for rats, guinea pigs and rabbits.

Dow Chemical 11990) conducted a multispecies subchronic inhalation study, bu: :he resultswere reported only as an unpublished summary. Groups of 24 male and 36 female Wisar-derivedrats, 2 female dogs and 3 male and 3 female rabbits were exposed to 0, 500 or 1000 ppm 1,1-dichloroethane (0, 2024 or 4047 mg/m3, assuming 25°C and 760 mm Hg) 7 hours/day, 5days/week for 6 months. Guinea pigs (7 males and 8 females) were exposed to 2024 mg/m3 for3 months. Hematologic parameters (PCV, hemoglobin, total and differential leucocyte counts),determined at 4 months of treatment and prior to termination at 6 months, were net altered byexposure to 1,1-dichloroethane. Urinalyses performed at 5 months were unremarkable. Clinicalchemistry values (alkaline phosphatase. urea nitrogen, SGPT) were within normal ranges. Atnecropsy, gross and microscopic examination of all major organs and tissues :t\ealed notreatment-related adverse effects. The NOAEL for rats, dogs, and rabbits is 404" mg/m3 ; theguinea pig NOAEL is 2024 mg/m3

Union Carbide (1947) provided information on Sprague-Dawley rats (12. sex group) andmongrel dogs (I/sex/group) exposed to 0 or 1000 ppm 1.1-dichloroethane 7 hours/da;- for a totalof 75 exposures over a 6-month period. The results, however, are of questionable significancesince high mortality occurred in rats due to endemic lung infection (50% in controls. :\"c in 1.1-dichloroethane groups). At the end of the 6-month period, the only effects reported in the singledog exposed to 1.1-dichloroethane were significantly reduced body weight gain throughout thestudy and marked lung congestion, but no other pathology. According to the investigators, theonly effect in rats attributed to exposure to 1,1-dichloroethane was a significant decrease(p<0.004) in body weight gain in female rats.

Chronic oral cancer bioassays were conducted in rats and mice by NC1 (1978) and Klauniget al. (1986). In the NCI (1978) study, no treatment-related effects were observed in rats or miceregarding body weight, food consumption, appearance and behavior, or incidence of nonneoplasticlesions at doses up to 950 mg/kg-day in rats and 3331 mg/kg-day in mice (78-week gavageexposure). However, the study was compromised by high mortality in control and treatmentgroups, attributed in pan to pneumonia. Klaunig et al. (1986) found no effect on survival, bodyweight, water intake, or incidence of nonneoplastic lesions in the kidney, liver and King in malemice treated with up to 543 mg/kg-day in the drinking water for up to 52 weeks The RiskAssessment Issue Paper for Derivation of a Provisional RfD for 1,1-Dichloroethane contains moredetails regarding these studies.

DRAFT - Do not cite or quote. For internal use oni\.

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Developmental and Reproductive Toxicity

Groups of 46, 16 and 19 pregnant Sprague-Dawley rats were exposed to 0, 3800 or 6000ppm 1.1-dichloroethane (15,380 or 24,284 mg/m3, assuming 25°C and 760 mm Hg), respectively,for 7 hours/day on gestation days 6-15 (Schwetz et al., 1974). Food consumption wassignificantly decreased (p<0.05) during treatment at both concentration levels. Body weightswere significantly reduced (p<0.05) in treated rats at both concentration levels on day 13 and inthe 3800 ppm group on day 21 (other time points not examined). Treatment with 1.1-dichloroethane had no effect on maternal SGPT activity or gross appearance of the liver, butrelat ive liver weight was significantly increased in nonpregnant rats 6 days after the last exposure.Exposure to 1.1-dichloroethane did not affect conception rate, number of implantations, liner size,incidence of fetal resorptions, fetal body measurements or incidence of gross or soft tissueanomalies. Exposure to 6000 ppm 1,1-dichloroethane caused a significant increase (p <0.05> inthe incidence of delayed ossification of sternebrae; the incidence at the 3800 ppm level wassignificantly lower than in controls. In this study, the exposure level of 15,380 mg/m3 representsa maternal LOAEL and a developmental NOAEL for 1,1-dichloroethane. The developmentalLOAEL is 24.284 mg.m3.

Studies ot" reproductive toxicity were not located.

SCENARIO FOR THE DERIVATION OF AN INHALATION RfC

Relevant information is available from three studies for derivation of a provisional RfCfor 1.1-dichloroethane (Dow Chemical, 1990; Hofmann et al.. 1971; Schwetz et al.. 1974). Inthe multispecies inhalation study conducted by Dow Chemical (1990) (reported only as anunpublished summary), a NOAEL of 2024 mg/m3 was identified for guinea pigs and a NOAELof 4047 mg/m3 was defined for rats, dogs and rabbits; all species were exposed 7 hours/day. 5days/week for 3 to 6 months; these concentration exposure levels were the highest tested. The Iresults of Dow Chemical (1990) are supported by data reported by Hofmann et al. (1971). whofound no adverse effects in rats and rabbits exposed to TWA concentrations of 3036 mg'm3 1.1-dichloroethane (6 hours/day, 5 days/week) for 26 weeks. Hofmann et al. (1971), however,reported kidney lesions and altered serum urea and creatmine in cats exposed to TWA of 2902mg/m3 1,1-dichloroethane for 23 weeks. In the inhalation study conducted by Schwetz et al.(1974) in rats exposed during pregnancy, a developmental NOAEL of 15,380 mg/m3 wasidentified for 1,1-dichloroethane; the LOAEL was 24,284 mg/m3. Thus, it appears that cats.which were not tested in the Dow Chemical (1990) study, are the most sensitive species.

Based on the information summarized above, a provisional RfC might be calculated fromthe inhalation data in cats reported by Hofmann et al. (1971). In that study, one out of four catsshowed kidney lesions after a total of 23 weeks of exposure (earliest monitoring time) to 1.1-dichloroethane. Two additional cats showed kidney lesions after 26 weeks of exposure. Lesions


Page 18

consisted of crystal precipitation and obstruction of the tubules, consistent with hydronephrosis,and tubule degeneration.

It does not seem appropriate to base this provisional RfC on a NOAEL for the first 13weeks of exposure, a possibility raised by the RfD/RfC Work Group (U.S. EPA, 1990), becausethe kidneys were not examined during this first exposure period. Although serum creatinine andurea were monitored throughout the study, and appearance of increased levels appeared tocoincide with raising the exposure concentration from 500 to 1000 ppm. it is not clear that theseparameters are sufficiently sensitive to have revealed subtle renal damage that may have occurredduring the 500 ppm exposure.

Supporting evidence that the kidney is a target for the toxicity of 1,1-dichloroethane isrestricted to observations of altered renal histology or impaired renal function after acuteintraperitoneal exposure to 2 or 4 mL/kg doses of 1,1-dichloroethane (Plaa and Larson, 1965) andkidney injury in rats following administration of single oral doses of 2 g/kg or single lethalinhalation exposures (Dow Chemical. 1960).


Page 19

The case of renal effects produced by 1,1-dichloroethane in cats corresponds to anextrarespiratory effect produced by a gas/vapor. Therefore, the LOAELHEC would be calculatedas the product of the duration-adjusted exposure level and the blood:gas partition coefficient ratioin cats and humans (LA/LH). Because a value for LA is not available for 1,1-dichloroethane incats, the ratio is assumed to be 1 by default. The provisional RfC is calculated as the LOA£LHECdivided by an uncertainty factor of 10,000 (10 for use of a LOAEL, 10 for use of a subchronicstudy, 3 for extrapolation from cats to humans using the dostmetric adjustments, 3 for databaselimitations including lack of adequate study of respiratory and reproductive effects and study ofdevelopmental effects in only one species, and 10 for protection of sensitive individuals). Thederivation is shown below:

LOAELADJ = 2902 mg. m} \ 6 / 2 4 x 5 / 7 = 518mg/m3

LOAELHEC = 518 mg/m3 x LA/LH = 518 mg/m3 x 1 = 518 mg/m3

Provisional RfC - LOAELHEC^'F = 518 mg/m3 10.000 - 5E-2 mg/m3

The provisional RfC of 5E-2 mg m: for i.l-dichloroethane is the same as that currentlyunder review by the RfD/RfC Work Group (U.S. EPA. 1990). Although there is a difference incalculation of the uncertainw factor (factor of 3 instead of 10 for species-to-species extrapolationusing the dosimetric equations and factor of 3 added for database limitations), the total uncertaintyfactor remains unchanged.

For this provisional RfC. confidence in the key study is low because of the small numberof animals used, the inclusion of only one treatment group, the limited information providedregarding organs and tissues examined and the lack of data regarding potential effects on therespiratory tract. Confidence in the database is low because details regarding the supportingsubchronic study (Dow Chemical. 1990) are lacking and the study did not include cats (whichappear to be the most sensitive species), chronic inhalation studies were not available,reproductive effects were not studied and developmental data were located for only one species.Confidence in the provisional RfC is low. reflecting low confidence in the database and key study.

Caution is advised in using the provisional RfC for 1,1-dichloroethane. The Hermann etal. (1971) cat study is, at best, marginal for use in a risk assessment due to the small number ofanimals in the study, the limited nature of the histopathological examination (which did not includethe respiratory tract) and the lack of corroborative data from other repeated exposure studies.Therefore, if this provisional RfC is chosen, this office will not be able to attest to its scientificaccuracy and use.

Deriving an RfC for 1,1-dichioroethane based on structural analogy to 1,2-dichloroethaneis not recommended because of the evidence that this isomer has different pharmacokinetic and

DRAFT - Do not cue or quote. For internal use only.

Page 20

toxicologic properties from those of 1,1-dichloroethane. In vitro metabolism studies with rat livermicrosomes showed that 1,1-dichloroethane is more rapidly dechlorinated than 1,2-dichloroethane(McCall et al., 1983; Loew et al., 1973; Salmon et al., 1981). Hermann et al. (1971) reportedthat repeated inhalation exposure to 1,2-dichloroethane at 500 ppm was lethal to rats, guinea pigsand rabbits, but not to cats, within a few weeks commencement of exposure. In contrast,exposure to 500 or 1000 ppm 1,1-dichloroethane by the same protocol for up to 23 weeksproduced no adverse effects in rats, guinea pigs or rabbits and only produced nonlethal renaleffects in cats (Hofmann et al., 1971).

REFERENCES

ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Documentationof Threshold Limit Values and Biological Exposure Indices for Chemical Substances in theWorkroom Air, 6th ed., Cincinnati, OH, pp. 425-428.

ACGIH .(American Conference of Governmental Industrial Hygienists). 1995. 1995-1996Threshold Limit Values for Chemical Substances and Physical Agents and Biological ExposureIndices. ACGIH, Cincinnati, OH. p. 18.

ATSDR (Agency for Toxic Substances and Disease Registry). 1990. Toxicological Profile for1.1-Dichloroethane. ATSDR. U.S. Public Health Service, Atlanta, GA. NTIS PB\9l\180539.

Browning. E. 1965. Dichloroethane. In: Toxicity and Metabolism of Industrial Solvents.Elsevier Publishing Co., Amsterdam, pp. 247-252.

Dow Chemical Company. 1960. Results of range finding toxicological tests on 1,1-dichloroethane. TSCA submission OTS Fiche #OTS0515949.

Dow Chemical Company. 1990. Six month inhalation study with 1,1-dichloroethane. Letter toSyracuse Research Corporation, February 14, 1990.

Hofmann, H.T., H. Birnstiel and P. Jobst. 1971. On the inhalation toxicity of 1,1-dichloroethane. Arch. Toxicol. 27: 248-265. (English translation)

Klaunie, J.E., R.J. Ruch and M.A. Pereira. 1986. Carcinogenicity of chlorinated methane andethane compounds administered in drinking water to mice. Environ. Health Perspec. 69: 29-93.

Loew. G . J. Trudell and H. Motulsky. 1973. Quantum chemical studies of the metabolism ofa series of chlorinated ethane anesthetics. Mol. Pharmacol. 9:152-162.


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McCall, S.N., P. Jurgens and K.M. Ivanetich. 1983. Hepatic microsomal metabolism ofdichloroethanes. Biochem. Pharmacol. 32: 207-213.

Miller, K.W., W.D.M. Paton and E.B. Smith. 1965. Site of action of general anesthetics.Nature 206: 574-577.

Mitoma, C., T. Steeger, S.E. Jackson. K.P. Wheeler, J.H. Rogers and H.A. Milman. 1985.Metabolic disposition study of chlorinated hydrocarbons in rats and mice. Drug Chem. Toxicol.8: 183-194.

Morgan. A., A. Black and D.R. Belcher. 1970. The excretion in breath of some aliphatichalogenated hydrocarbons following administration by inhalation. Ann. Occup. Hyg. 13: 219-233.

Morgan, A., A. Black and D.R. Belcher. 1972. Studies on the absorption of halogenatedhydrocarbons and their excretion in breath using 38C1 tracer techniques. Ann. Occup. Hyg. 15:273-282.

NCI (National Cancer Institute). 1978. Bioassay of 1,1-dichloroethane for possiblecarcinogenicity. NCI/NTP TR 066. DHEW Publ. No. (NIH) 78-1316.

NIOSH (National Institute for Occupational Safety and Health). 1992. Recommendations forOccupational Safety and Health. Compendium of Policy Documents and Statements. U.S.Department of Health and Human Services. DHHS (NIOSH) Publication No. 92-100. p. 71.

NTP (National Toxicology Program). 1995a. Management Status Report (7/7/95).

NTP (National Toxicology Program). I995b. NTP Results Report (7/7/95).

OSHA (Occupational Safety and Health Administration). 1989. 29 CFR 1910. AirContaminants; Final Rule. Federal Register. 54(12): 2332-2983.

OSHA (Occupational Safety and Health Administration). 1993. 29 CFR 1910. AirContaminants; Rule. Federal Register. 58(124): 35338-35351.

Plaa, G.L. and R.E. Larson. 1965. Relative nephrotoxic properties of chlorinated methane,ethane and ethylene derivatives in mice. Toxicol. Appl. Pharmacol. 7: 37-44.

Salmon. A.G., R.B. Jones and W.C. Mackrodt. 1981. Microsomal dechlorination ofchloroethanes: Structure-reactivity relationships. Xenobiotica 11: 723-734.


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Sato, A. and T. Nakajima. 1987. Pharmacokinetics of organic solvent vapors in relation to theirtoxicity. Scand. J. Work Environ. Health 13:81-93.

Sax, N.I., Ed. 1984. Dangerous Properties of Industrial Materials, 6th ed. Van NostrandReinhold Co., NY. pp. 1362-1363.

Schwetz, B.K., K.L. Leong and P.J. Gehring. 1974. Embryo- and fetotoxicity of inhaled carbontetrachloride, 1,1-dichloroethane and methyl ethyl ketone in rats. Toxicol. Appl. Pharmacol. 28:452-464.

Smyth, H.F. Jr. 1956. In: Handbook of Toxicology, Vol. 1, W.S. Spector, Ed. pp. 92-95.

Union Carbide Corporation. 1947. Repeated exposure of rats and dogs to vapors of eightchlorinated hydrocarbons. TSCA Submission OTS#0515559.


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U.S. EPA. 1983. Drinking Water Criteria Document for 1,1-Dichloroethane. Prepared by theOffice of Health and Environmental Assessment, Environmental Criteria and Assessment Office,Cincinnati, OH for the Office of Drinking Water, Washington, DC. ECAO-CIN-303.

U.S. EPA. 1984. Health Effects Assessment for 1,1-Dichloroeihane. Prepared by the Officeof Health and Environmental Assessment, Environmental Criteria and Assessment Office,Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. ECAO-CIN-HO27.

U.S. EPA. 1985. Health and Environmental Effects Profile for Dichloroethanes. Prepared bythe Office of Health and Environmental Assessment, Environmental Criteria and AssessmentOffice, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC.ECAO-CIN-P139.

U.S. EPA. 1989a. Oral RfD Verification Meeting Notes of 9/21/89 (with attached summarysheet). RfD and RfC Work Group. Available from: National Center for EnvironmentalAssessment, Cincinnati, OH.

U.S. EPA. 1989b. Interim Methods for Development of Inhalation Reference Doses. Office ofHealth and Environmental Assessment, Washington, DC. EPA 600/8-88/066F.

U.S. EPA. 1990. Inhalation RfC Verification Meeting Notes of 4/19/90 (with attached summarysheet). RfD and RfC Work Group. Available from: National Center for EnvironmentalAssessment, Cincinnati, OH.

U.S. EPA. 1991. Office of Health and Environmental Assessment Chemical Assessments andRelated Activities. Office of Health and Environmental Assessment, Washington, DC. April,1991. OHEA-M27.

U.S. EPA. 1994. Office of Health and Environmental Assessment Chemical Assessments andRelated Activities. Office of Health and Environmental Assessment, Washington, DC. December1994. OHEA-I-127.

U.S. EPA. 1995a. Integrated Risk Information System (IRIS). Online. Office of Research andDevelopment. National Center for Environmental Assessment, Cincinnati, OH.

U.S. EPA. 1995b. Monthly status report of RfD/RfC and CRAVE Work Groups (As of09/01/95). Office of Research and Development. National Center for EnvironmentalAssessment. Cincinnati, OH.


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U.S. EPA. 1995c. Health Effects Assessment Summary Tables. FY-1995 Annual. Office ofResearch and Development, Office of Emergency and Remedial Response, Washington, DC.May. 1995. EPA/540/R-95/036. PB 95-921199.

U.S. EPA. 1995d. Drinking Water Regulations and Health Advisories, Office of Water,Washington, DC. May 1995.


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