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Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

151.3 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

6

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

42.9 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

24

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

85.8 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 929 µg/cm²

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

3

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3 858 µg/cm²

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Dose descriptor starting point:

other: NOAEL

Additional information - workers

The calculation of the DNELs is performed in accordance with the principles given in ECHA (2008) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.”

Since RAV 7NG contains as main ingredient 'diallyl 2,2'oxydiethyl dicarbonate' and experimental data are lacking for RAV 7NG, the experimental data from 'diallyl 2,2'oxydiethyl dicarbonate' were used in a read-across approach.

Justification for read-across from supporting substance RAV 7AT (diallyl 2,2'-oxydiethyl dicarbonate; CAS 142-22-3; EC 205-528-7): about 70 % of RAV 7NG (EC 700-483-4) consists of components that can be found in the commercial ADC grades known as RAV 7AT, Nouryset 200 and CR39. Merely from comparing the similar production processes of these two substances it is apparent that RAV 7AT and RAV 7NG are closely related to each other.  Finally, the physical-chemical, toxicological and ecotoxicological properties of RAV 7NG and RAV 7AT are almost equal and as a result, read across is justified.

Available dose descriptors:

From all available data for the different human health endpoints it is clear that diallyl diglycol carbonate exerts its effect by a threshold mode of action. Thus, DNELs can be calculated for the different threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived from the available toxicity data of diallyl diglycol carbonate, reflecting the routes, duration and frequency of exposure. DNELs are derived for workers and the general population. The general population includes consumers and humans exposed via the environment.There are following annotations for each endpoint:

o  DNELs for acute/short-term systemic effects (dermal) are established because diallyl diglycol carbonate considered to be of low acute toxicity and classified as acute oral toxic Cat. 4 (Xn, R22 Harmful if swallowed).

o  A qualitative approach should be considered in case of acute/short term systemic effects (inhalation) since no dose descriptor available on this endpoint. Moreover, a long-term inhalation DNEL (calculated by extrapolation) is too uncertain to cover short-term peak exposures.

o  DNELs for local effects dermal (short-term and long-term) are established because diallyl diglycol carbonate is classified as skin and eye irritant Cat.2 (Xi, R36/38 Irritant, Irritating to eyes and skin) and dermal exposure is the relevant route of exposure.

o  No DNELs can be derived for local effects inhalation (short-term and long-term) since inhalation is not relevant route of exposure for this substance and therefore there is no information available on irritating effects to respiratory tract.

o  A qualitative approach for the risk assessment of eye and respiratory tract irritation/corrosion and skin sensitization is used since no dose descriptors are available on these endpoints.

o  DNELs for long-term systemic effects are derived using data from the Combined Repeat Dose Dermal Toxicity Study with a reproduction/Developmental Toxicity Screening Test (OECD 422).

o  For the non-threshold endpoints (mutagenicity and carcinogenicity) no DNELs can be derived because a No-Effect Level could not be established from the relevant studies. Hence, the hazard characterization is based on a qualitative approach.

o  No DNELs are derived for reproductive toxicity because diallyl diglycol carbonate is not toxic to reproduction. Long-term systemic DNELs are sufficient to ensure that reprotoxic effects by humans will not occur.

In order to address the differences between toxicological effect data obtained in animal studies and the real human situation, assessment factors are applied. The function of assessment factors (AFs) is to correct uncertainties and variability within and between species in the effect data. First of all, available dose descriptors were converted into a correct starting point to take into account differences in routes of exposure between experimental animals and humans, differences in human and animal exposure conditions and possible differences in absorption between routes and between experimental animals and humans. Consecutively, the assessment factors have been applied to the correct starting point to obtain the endpoint specific DNELs.

The assessment factors are applied in accordance with ECETOC Technical Report No 86, referenced in Table R.8-19 of ECHA (2008) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health”.

Modification of the relevant dose descriptors to the correct starting point:

Bioavailability (absorption)

o Bioavailability for experimental animals and humans for all exposure routes was assumed to be same because of the absence of information.

o  100% dermal absorption is assumed, based on the criteria set out in Annex IV-B of the EU Technical Guidance Document on Risk Assessment (TGD; 2003, Part I).

Route-to-route extrapolation:

o  A default factor of 2 (50% for dermal absorption and 100% for inhalation) is applied when dermal-to-inhalation extrapolation is performed.

Exposure conditions:

o  Exposure time differed in the repeated dose dermal study (OECD 422) and the exposure time by workers. The dose descriptor was corrected as described in the Appendix R.8-2 (Example A.1 in case of dermal exposure in experimental animals and humans and Example B.3 in case of dermal exposure in animals and inhalation in humans).

Respiratory volumes:

o  Differences in the respiratory volumes between experimental animals and humans were used as well as differences in the respiratory volumes by light activity in workers.

Applying of assessment factors:

 Interspecies differences:

o  The species-specific default assessment factor for allometric scaling from Table R.8-3 is applied in case of dermal exposure in animals and humans.

o  No species-specific default assessment factor for allometric scaling is applied in case of dermal-to-inhalation extrapolation. No additional assessment factors are applied for inhalation route to obtain a corrected starting point (Example B.3).

o  In deriving of dermal irritation DNELs no allometric scaling is applied because of local effects (Section R.8.4.3.1., p.31-32 and Appendix R.8-9, p.119).

o  No additional assessment factors are applied for remaining interspecies differences (according to ECETOC)

 Intraspecies differences: 

o  Assessment factors of 3 and 5 are applied for workers and general population, respectively, for all endpoints and all exposure routes.

Extrapolation of duration:The relevant default assessment factors from Table R.8-5 are applied.

Issues related to dose response: factor of 1.

Quality of data base: factor of 1.

Additional assessment factors:

Acute toxicity:

o  An uncertainty factor of 100 was applied to cover all possible effects based on the criteria given in Appendix R.8-8 of ECHA REACH Guidance R.8. However, the values calculated in such a way are high uncertain (they appear to be lower as those calculated for long-term exposures). Therefore, long-term DNELs are taken to obtain short-term DNELs by multiplying with a factor of 2 (default conservative factor).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

44.8 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

10

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

25.8 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

40

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

51.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 157 µg/cm²

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

5

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2 315 µg/cm²

Most sensitive endpoint:

repeated dose toxicity

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

25.8 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

40

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.2 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

DNEL related information

Overall assessment factor (AF):

2 000

Additional information - General Population

The principles of the DNEL calculation for the general population are the same as already described for workers. However, there are some deviations:

o  A higher assessment factor of 5 (in place of 3 for workers) for intraspecies variation/differences of human population was taken (refer to Table R.8-19, ECETOC values).

o  No differences in the respiratory volumes under normal conditions and by light activity in human were taken into account.

o  No default factor (i.e. factor 1) is applied when dermal-to-oral extrapolation is performed in accordance with Section R.8.4.2 (p.25).

The dose descriptor was corrected to the correct starting point as described in the Appendix R.8-2 (Example A.1 in case of dermal exposure in experimental animals and humans and Example B6. in case of oral exposure in humans and dermal NOAEL in animals).

o  The conversion of the repeated dermal NOAEL into inhalation NOAEC was performed as follows:

Corrected inhalation NOAEC = rat dermal NOAEL x (1/1.15 m³/kg bw/day) x (ABS dermal-rat/ABS inh-human), where 1.15 is standard respiratory volume of rats during 24 h exposure, ABS is absorption (in worst case considered to be of 50% by dermal exposure in animals and 100% for inhalation in humans).