health risk assessment – systemic effects (1) reminder of inhaled dose pg intake of 3.2 mg/day or...
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Health risk assessment –systemic effects (1)
REMINDER OF INHALED DOSE
PG intake of 3.2 mg/day or 0.053 mg/kg bw/day for a 60-kg bw consumer
Systemic absorption likely to be extensive. Ready metabolism to simple natural compounds
Genotoxicity, carcinogenicity, reproductive/developmental toxicity, sensitisation data are reassuring
Repeated dose toxicity is low – JECFA set an ADI of 25 mg/kg bw
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A key study is the subchronic rat inhalation study by Suber et al.
Ideally would assess study quality in terms of group sizes, extent of examination etc though such data not present in citing abstract
Despite lack of detailed description, this study is deemed critical for the current assessment since it is subchronic in duration and involves the inhalation route of exposure
Health risk assessment –systemic effects (2)
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Systemic NOAEC = 160 mg/m3, 6 hr/day, 5 days/wk for 90 daysFirst, convert to a 13-wk NOAELUse REACH default - a rat inhales 0.29 m3/kg bw over 6 hr
Health risk assessment –systemic effects (2)
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So in 6 hr, a rat inhales 46 mg/kg bw (160 x 0.29) = study NOAEL
Next, a factor to account for the 5 days/wk exposure schedule
NOAEL = 46 mg/kg bw/day x 5 days/7 days = 33 mg/kg bw/day
Health risk assessment –systemic effects (2)
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Health risk assessment –systemic effects (3)
Next, convert to chronic value using REACH AF of 2
Lifetime NOAEL = 16.5 mg/kg bw/day
Next convert to a human HCV by using traditional factors of 10 for interspecies and 10 for intraindividual differences
Human HCV = 0.17 mg/kg bw/day
The inhaled dose is 3.2 times lower than the derived HCV
Conclusion: Based on this subchronic inhalation study, the exposure is tolerable6
Health risk assessment –systemic effects (4)
Useful also to consider
Additional sources of exposure e.g. PG intake of 14.01 mg/kg bw/day as a food additive
Humans are highly efficient at metabolising PG to innocuous products
AFs of 10 may not be necessary for inter- and intra-individual differences7
Health risk assessment –systemic effects (5)
Use oral data for additional risk insights
Absorption likely to be similar and extensive from both routes
JECFA ADI of 25 mg/kg bw is almost 500 times higher than the exposure being assessed here (0.053 mg/kg bw/day)
Typical dose from diet = 840 mg/day (for a 60‑kg adult)
263 times more than e-liquid dose (3.2 mg/day) 8
Health risk assessment –systemic effects (6)
Oral HCVs can be derived from the (sub)chronic rat feeding studies
Oral TDI from 2-yr study. NOAEL = 1300 mg/kg bw/day
AFs of 10 for interspecies and 10 for intraspecies variations
Lifetime study so no duration AF needed
Apply total AF = 100, yields an Oral TDI = 13 mg/kg bw/day
This is 240-fold higher than the (inhaled) dose (0.053 mg/kg bw/day)9
Health risk assessment –systemic effects (7)
A long-term inhalation DNEL could also be derived from this study
For absorption differences between routes, the default is to assume 100% inhalation and 50% oral, introducing an AF of 2 when deriving an inhalation DNEL from an oral study10
Health risk assessment –systemic effects (7)
This is considered unnecessary for PG – absorption likely to be 100% from both routes
Health-precautionary to add an AF for first pass metabolism – perhaps 2 or 3 is adequate
Leads to an inhalation DNEL of about 6.5 mg/kg bw/day (about 120-fold higher than the estimated dose)
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Health risk assessment –systemic effects (8)
Oral TDI from 140-day study. NOAEL = 7700 mg/kg bw/day
AFs of 10 for interspecies and 10 for intraspecies variations and 2 for the use of a subchronic study
Apply total AF = 200, yields an Oral TDI = 38.5 mg/kg bw/day
This is 720-fold higher than the (inhaled) dose (0.053 mg/kg bw/day) 12
Health risk assessment –systemic effects (9)
A long-term inhalation DNEL could also be derived from this study
The default AF of 2 when deriving an inhalation DNEL from an oral study is considered unnecessary as absorption is likely to be 100% from both routes
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Health risk assessment –systemic effects (9)
Health-precautionary to add an AF for first pass metabolism – perhaps 2 or 3 is adequate
Leads to an inhalation DNEL of about 19 mg/kg bw/day (about 360-fold higher than the estimated dose)14
Use of OELs insetting systemic HCVs
OELs range from 10-474 mg/m3
Assume 10 m3 air/work shift
Inhaled doses of 100-4740 mg/day are acceptable
Apply a factor of 5/7 to account for days/wk of exposure
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Use of OELs insetting systemic HCVs
Normal to apply a factor of 2 to account for higher susceptibility in general population[Possibly unnecessary for PG]Tolerable doses for consumers = 36-1690 mg/day
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Systemic health risk overview table
Summary table showing Margins of Exposure
Conclusion: Highly unlikely to pose any systemic toxicity risks
Benchmark Relevant route
Benchmark(mg/kg bw/day)
Exposure(mg/kg bw/day)
MoE
Diet Oral 14.01 0.053 263REACH DNEL
from unknown inhalation study
Inhalation 25 0.053 469
Bibra DNEL from 13-wk inhalation
study
Inhalation 0.17 0.053 3.2
JECFA ADI Oral 25 0.053 470Bibra DNEL from 2-yr oral study
Oral 13 0.053 243
Bibra DNEL from 2-yr oral study
Inhalation 6.5 0.053 122
Bibra DNEL from 140-day oral
study
Oral 38.5 0.053 722
Bibra DNEL from 140-day oral
study
Inhalation 19 0.053 361
OELs 10-474 mg/m3
36-1690 mg/day(10-474 mg/m3)
3.2(mg/day)
11-52817
Health risk assessment –respiratory tract irritation (1)
REMINDER OF INHALED CONCENTRATION
PG intake of 3.2 mg/day
600 puffs/day
Puff volume 55 mL
Total puff volume = 0.033 m3
Assumed even distribution in puffs
Puff PG concentration = 97 mg/m3
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Health risk assessment –respiratory tract irritation (2)
Key study 1 – Human data (Wieslander et al.)
Volunteers exposed at mean conc of 309 mg/m3 for 1 min - reduced tear film stability and sensations of eye irritation
Likely to be whole-body exposure
More detailed concentration data would be preferable
Best estimate of LOAEC for acute exposure = 309 mg/m3
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Health risk assessment –respiratory tract irritation (2)
No interspecies AF required as human data
Factor of 3 for use of an LOAEC, not an NOAEC
Debatable whether an intraspecies factor of 10 is required for a local effect, bibra prefers 3.2 (arguing that toxicokinetics are irrelevant)
Generates a tolerable 1-min concentration of about 32 mg/m3
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Health risk assessment –respiratory tract irritation (3)
For interest: Key study 2 – Rat data (Werley et al.)
Rats exposed (nose-only) at 44.9 g/m3 for 4 hr - mild respiratory tract irritation (localised bleeding around eyes/nose) seen on day 7
In the absence of further conc data in the Profile, LOAEC for acute exposure = 44.9 g/m3
Further investigation reveals two lower concs (14.4 and 30.5 g/m3) were tested and showed the same irritant effects
More appropriate to use 14.4 g/m3 as the LOAEC
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Health risk assessment –respiratory tract irritation (3)
Factor of 2.5 for interspecies toxicodynamics (toxicokinetic AF not required for local effects)
Factor of 3 for use of an LOAEC, not an NOAEC
More debatable whether an intraspecies factor of 10 is required for a local effect, bibra prefers 3.2 (arguing that toxicokinetics are again irrelevant)
Generates a tolerable concentration of about 600 mg/m3 (for human 4-hr exposure)
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Health risk assessment –respiratory tract irritation (4)
Consumer use - peak PG exposure at 97 mg/m3
Such exposure will last for a few seconds, for 2/12 breaths during each minute
Lasting maybe 10-40 minutes, repeated several times each day
Such a concentration is roughly 3 times higher than the human derived NOAEC (32 mg/m3) from human data but 6-fold lower than the human derived NOAEC (600 mg/m3) from rat data
The peak puff concentration is higher than the derived human “tolerable figure” (97 mg/m3 cf 32 mg/m3)
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However, the e-cigarette exposure would be briefly (a 5-second puff) with rapid dilution from subsequent normal breaths
The difference (12x) in the exposure duration for the human experiment (60 seconds) and the e-cigarette exposure (5 seconds) is greater than the exposure margin (3). Implies tolerability
The rat LC50 study was not designed to assess irritation so a lower LOAEC may exist. However, not considered to be influential as human data exist
Health risk assessment –respiratory tract irritation (5)
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Health risk assessment –respiratory tract irritation (6)
Consider the human exposure time in more detail
Compare human exposure time (60 seconds) with the cumulative consumer exposure time during a similar 1-min period (5 sec/puff x 2 puffs/min = 10 secs)
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Health risk assessment –respiratory tract irritation (6)
Tolerable human exposure of 32 mg/m3 based on volunteers exposed for a total of 60 seconds; consumers exposed at 97 mg/m3 for 10 seconds
Consumer exposure would be about 3 times higher but 6 times shorter duration
Provides some evidence that respiratory tract irritation would not occur
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Health risk assessment –respiratory tract irritation (7)
Also useful to consider ratio of exposure to non-exposure parameters
Take a single “intense” 40‑minute session
Ratio of e-cigarette exposure to non-exposure time is 1/5 (400 seconds/2000 seconds; assuming a 5-second puff exposure)
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Health risk assessment –respiratory tract irritation (7)
Ratio of exposure puffs to non‑exposure breaths is 1/5 (80/400)
Ratio of exposure puff volume to non-exposure breath volume is 1/150 (0.0044 m3/0.6623 m3) [worst-case]
The 0.6623 m3 figure is calculated by subtracting the total exposure puff volume in the 40‑minute intense period from the total inhaled volume in 40 minutes (assuming a 1 m3 per hour inhalation rate during the 16-hr day)28
Health risk assessment –respiratory tract irritation (8)
Take the full 16-hr daily use period
Ratio of e-cigarette exposure to non-exposure time is 1/18 (3000 seconds/55,200 seconds)
Ratio of exposure puffs to non‑exposure breaths is 1/18 (600/11,040)
Ratio of exposure puff volume to non-exposure breath volume is 1/480 (0.033 m3/15.97 m3)
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Health risk assessment –respiratory tract irritation (9)
Seems unlikely that exposure would be irritant
80/480 breaths (in a 40-min session) or 600/11,520 breaths (over a 16-hr use period)
Exposure is limited to about 17% of the inhaled breaths in an intense session, so recovery time may be sufficient
Critical studies involved whole-body exposure of humans and nose-only exposure of rats
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Health risk assessment –respiratory tract irritation (9)
e-Cigarette exposure is mouth-only
Rodents are obligate nose-breathers and the nasal epithelium is a dry tissue compared with the mouth, where the production of about 1 L/day of saliva in humans keeps tissues moist
In the human study the whole body exposure only induced irritant effects on the eyes (i.e. not as relevant here)31
Health risk assessment –respiratory tract irritation (10)
PG expected to dissolve in saliva; local tissues might experience an average concentration of around 0.0015% each minute
Neat PG only mildly irritant to human eye and non-irritant to rabbit eye (presumably neat)
Oral cavity tissues are probably less susceptible than nasal tissues
E-cigarette exposure is mouth only; the effects in rats occurred in the (drier) nasal tissue
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Health risk assessment –respiratory tract irritation (10)
Conclusion: the intermittent nature of the brief exposures and the moist conditions in the mouth (compared to the rat nose) mean that respiratory tract irritation is unlikely
[In 1 minute, 0.0107 mg of PG would be inhaled (3.2 mg/day x 2 puffs/min / 600 puffs/day) while 1 L/day of saliva is equivalent to 0.69 mL/min (1 x 1000 mL/1440 min). Therefore, if all the inhaled PG were to dissolve in the saliva, a concentration of about 0.0015% PG would result (0.0107 mg/0.69 mL = 0.015 mg/mL, equivalent to 0.0015 g in 100 mL i.e. 0.0015%)]
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