health risk assessment – systemic effects (1) reminder of inhaled dose pg intake of 3.2 mg/day or...

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


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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


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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


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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


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


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


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


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


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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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


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-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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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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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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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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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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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


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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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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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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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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


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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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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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


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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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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health risk assessment – systemic effects (1) reminder of inhaled dose pg intake of 3.2 mg/day or...

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