Reaction mass of 3,7-dimethyl-1-octyl acetate and citronellyl acetate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

14.7 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

6

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

88 mg/m³

Explanation for the modification of the dose descriptor starting point:

The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 2 in case of oral to inhalation extrapolation. The respiratory volume of rats (0.38 m³/kg bw) is multiplied by the respiratory volume of human (6.7 m³/person) and corrected for the respiratory volume for light activity to address the workers (10 m³/person). Therefore, the modified dose descriptor is calculated as follows: 100/ 2 / 0.38 x (6.7/10) = 88 mg/m³.

AF for dose response relationship:

1

Justification:

No additional assessment factor for dose response is needed because the dosing was well spaced in the OECD TG 414 study (ECHA’s guidance, R.8.4.3.1, November, 2012).

AF for differences in duration of exposure:

2

Justification:

There are two pieces of repeated dose toxicity information that need to be considered for the AF for duration of exposure. One is from a sub-chronic study and one from a developmental toxicity study. The effects seen in dams in the developmental toxicity are similar to what is seen in the repeated dose sub-chronic exposure, which is body weight decrease. The NOAEL for repeated dose toxicity has been derived from the pregnant dams in the developmental toxicity study and as such this NOAEL covers the body weight effects seen in this sensitive period. During other than pregnant periods the NOAEL is 2000 mg/kg bw. Using the lowest repeated dose NOAEL for pregnant dams this covers the body weight effects during sub-chronic exposure . This means that for duration of exposure the sub-chronic duration can be used because the body weight effects are already accounted for in the NOAEL of 100 mg/kg bw. Therefore an AF of 2 can be used.

AF for interspecies differences (allometric scaling):

1

Justification:

An assessment factor of 1 has been used because the difference in metabolic rate between rat and humans has been accounted for in the conversion of NOAEL in mg/kg bw to the NOAEC in mg/m3, as presented in ECHA’s guidance R.8, figure R. 8-2 (November, 2012).

AF for other interspecies differences:

1

Justification:

Additional assessment factors for interspecies differences are not needed as has been presented in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).

AF for intraspecies differences:

3

Justification:

An assessment factor of 3 has been used to account for the intraspecies differences. This factor has been retrieved by ECETOC (TR110, 2010). The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients; this represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species, and includes intraspecies differences.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database, the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.2 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

24

Dose descriptor starting point:

NOAEL

Value:

100 mg/m³

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The substance fulfils the REACH Annex VII to Annex XI information requirements in accordance with R 7.5-7.7 (2016) for assessing long-term systemic toxicity. The substances is not classified and labelled for this endpoint but adverse effects were seen in the developmental toxicity study (from read-across substance). The NOAEL from the oral developmental toxicity study is used for derivation of the DNEL long-term for the dermal route. No repeated dose dermal toxicity data are available. Route-to route extrapolation can be done because there is adequate oral toxicity data; the critical effect is systemic rather than at the site of contact. Also there is no evidence that the compound is subject to ‘first-pass’ metabolism which would lead to higher dermal toxicity compared to oral toxicity. To account for any uncertainties considering the toxicity potential via the oral and the dermal route, the absorption via the dermal route is the same as for the oral route (IGHRC, 2006 as mentioned in the ECHA guidance, R.8.4.2, November, 2012). In absence of dermal absorption information a factor of 1 for oral versus dermal absorption is applicable as proposed in ECHA guidance, Chapter R.8.4.2 (November, 2012).

AF for dose response relationship:

1

Justification:

No additional assessment factor for dose response is needed because the dosing was well spaced in the OECD TG 414 study (ECHA’s guidance, R.8.4.3.1, November, 2012).

AF for differences in duration of exposure:

2

Justification:

There are two pieces of repeated dose toxicity information that need to be considered for the AF for duration of exposure. One is from a sub-chronic study and one from a developmental toxicity study. The effects seen in dams in the developmental toxicity are similar to what is seen in the repeated dose sub-chronic exposure, which is body weight decrease. The NOAEL for repeated dose toxicity has been derived from the pregnant dams in the developmental toxicity study and as such this NOAEL covers the body weight effects seen in this sensitive period. During other than pregnant periods the NOAEL is 2000 mg/kg bw. Using the lowest repeated dose NOAEL for pregnant dams this covers the body weight effects during sub-chronic exposure . This means that for duration of exposure the sub-chronic duration can be used because the body weight effects are already accounted for in the NOAEL of 100 mg/kg bw. Therefore an AF of 2 can be used.

AF for interspecies differences (allometric scaling):

4

Justification:

For allometric scaling a factor of 4 is applicable to convert rat to human data in accordance with ECHA guidance.

AF for other interspecies differences:

1

Justification:

Additional assessment factors for interspecies differences are not needed as has been presented in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).

AF for intraspecies differences:

3

Justification:

An assessment factor of 3 has been used to account for the intraspecies differences. This factor has been retrieved by ECETOC (TR110, 2010). The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients; this represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species, and includes intraspecies differences.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database, the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

382 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

9

Dose descriptor:

LOAEC

Value:

3 435 µg/m³

AF for dose response relationship:

3

Justification:

Because the value is a LOAEC in ug/cm2, this AF needs to be applied. The conversion from percentate to ug/cm2 is: LOAEC[%]*250 [ug/cm2/%] = 13.74*250 = 3435 ug/cm2 (based on 25 µL of test substance applied onto 1 cm2 area of a mouse ear, and a density of 1).

AF for differences in duration of exposure:

1

Justification:

The exposure duration is sufficiently covered in the LLNA test and therefore no assessment factor as duration not relevant for skin sensitisation.

AF for interspecies differences (allometric scaling):

1

Justification:

No difference in metabolic rate has to be included for sensitisers as it is the parent substance which causes the sensitisation.

AF for other interspecies differences:

1

Justification:

The assessment factor for remaining uncertainties can be 1. For vehicle effects: an assessment factor of 1 is applied as the matrices of the products compiled from the substance are not intended to enhance penetration. For type of skin (skin thickness and skin integrity) it can be seen that the human skin (exposed hands) to be similarly or less sensitive compared to the skin of the mouse ear. The LLNA is selected as a model because the mouse ear is considered very thin with high blood flow and as such reflect a similar thickness and integrity compared to human skin in general

AF for intraspecies differences:

3

Justification:

AF for intraspecies differences: 3 (ECETOC TR No. 110 (2010) The intraspecies variation in humans is greater than that in the more homogenous experimental animal population. Based on an evaluation of the scientific literature by ECETOC, an AF of 3 for workers is advised after a detailed review of the literature. The ECETOC review is based on systemic effect. Sensitisation results from systemic exposure and therefore these ECETOC AFs can be applied here.)

AF for the quality of the whole database:

1

Justification:

An assessment factor of 1 is applicable because the information fulfils the REACH requirements: Read across is applie from a close analogue and information which informatio was derived from an LLNA study according to OECD TG 429

AF for remaining uncertainties:

1

Justification:

An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

The DNELs for long term exposure (systemic effects) were derived in accordance with the Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health with the exception of two assessment factors:

1.       Interspecies differences, remaining differences. For remaining differences it is considered that those already have been taken into account when applying an assessment factor for allometric scaling. The argumentation for this can be found in the ECETOC Guidance on Assessment Factors to Derive a DNEL (Technical Report No. 110, 2010). It is concluded that the concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans. As the human population under investigation comprised cancer patients, this represents a very sensitive subpopulation. Thus, this additional’ variability represented by the GSD of 2.5-2.6 is probably due to not only potential differences in biological sensitivity between species, but also intraspecies differences. The intraspecies variability in humans is taken into account by the specific Assessment Factors for workers (3) and the general population (5). The introduction of the ‘remaining’ AF of 2.5 for interspecies variability would therefore mean an unjustified compilation of AF. Therefore, although ‘residual’ interspecies variability may remain following allometric scaling, this is largely accounted for in the default AF proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies AF.

2.       Intraspecies differences. The current proposed AF for intraspecies extrapolation of systemic effects for workers and the general population in the ECHA guidance differ from those proposed in the ECETOC guidance (2010). After studying both guidances it is concluded that the AF proposed by ECETOC are based on an evaluation of the scientific literature while the REACH TGD refers to standard default procedures. Therefore, the ECETOC guideline will be followed until the scientific basis for using an alternative approach has been established. This means that for workers instead of an AF of 5 as proposed in the ECHA guidance an AF of 3 will be used and for the general population instead of an AF of 10 and AF of 5.

ECETOC, 2010, http://www.ecetoc.org/wp-content/uploads/2014/08/ECETOC-TR-110-Guidance-on-assessment-factors-to-derive-a-DNEL.pdf

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.7 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

43.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

The substance fulfils the REACH Annex VII to Annex XI information requirements in accordance with ECHA guidance R7.5-7.7 (2016) for assessing long-term systemic toxicity. Adverse effects were seen in the develpmental toxicity study (from read across substance). In absence of inhalation toxicity data, the NOAEL from the oral developmental toxicity study is used for derivation of the DNEL-long-term for the inhalation route. Route-to route extrapolation can be done because there is adequate oral toxicity data; the critical effect is systemic rather than the site of contact. Also there is no evidence that the compound is subject to ‘first pass’ metabolism which would lead to higher inhalation toxicity compared to oral toxicity. Route-to-route extrapolation was applied in accordance with ECHA’s Guidance R.8. In the route to route extrapolation for the inhalation route a correction for respiratory volume is applied.  In the route to route extrapolation via the inhalation route a correction for respiratory volume is applied by using 1.15 m3/kg bw (ECHA’s guidance R.8, November, 2012).

Therefore, the modified dose descriptor is calculated as follows: 100/ 2 / 1.15 = 43.5 mg/m³.

AF for dose response relationship:

1

Justification:

No additional assessment factor for dose response is needed because the dosing was well spaced in the OECD TG 414 study and in the 13 wk study (ECHA’s guidance, R.8.4.3.1, November, 2012).

AF for differences in duration of exposure:

2

Justification:

There are two pieces of repeated dose toxicity information that need to be considered for the AF for duration of exposure. One is from a 13 wk sub-chronic study and one from a developmental toxicity study. The effects seen in dams in the developmental toxicity are similar to what is seen in the repeated dose sub-chronic exposure, which is body weight decrease. The NOAEL for repeated dose toxicity has been derived from the pregnant dams in the developmental toxicity study and as such this NOAEL covers the body weight effects seen in this sensitive period. During other than pregnant periods the NOAEL is 2000 mg/kg bw. Using the lowest repeated dose NOAEL for pregnant dams this covers the body weight effects during sub-chronic exposure . This means that for duration of exposure the sub-chronic duration can be used because the body weight effects are already accounted for in the NOAEL of 100 mg/kg bw. Therefore an AF of 2 can be used.

AF for interspecies differences (allometric scaling):

1

Justification:

An assessment factor of 1 has been used because the difference in metabolic rate between rat and humans has been accounted for in the conversion of NOAEL in mg/kg bw to the NOAEC in mg/m3, as presented in ECHA’s guidance R.8, figure R. 8-2 (November, 2012).

AF for other interspecies differences:

1

Justification:

Additional assessment factors for interspecies differences are not needed as has been presented in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).

AF for intraspecies differences:

5

Justification:

Retrieved by ECETOC (TR 110, 2010) based on scientific literature. The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients, which represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species, but includes intraspecies differences.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database, the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

40

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The substance fulfils the REACH Annex VII to Annex XI information requirements in accordance with R 7.5-7.7 (2016) for assessing long-term systemic toxicity. The substances is not classified and labelled for this endpoint but adverse effects were seen in the developmental toxicity study (from read-across substance). The NOAEL from the oral developmental toxicity study is used for derivation of the DNEL long-term for the dermal route. No repeated dose dermal toxicity data are available. Route-to route extrapolation can be done because there is adequate oral toxicity data; the critical effect is systemic rather than at the site of contact. Also there is no evidence that the compound is subject to ‘first-pass’ metabolism which would lead to higher dermal toxicity compared to oral toxicity. To account for any uncertainties considering the toxicity potential via the oral and the dermal route, the absorption via the dermal route is the same as for the oral route (IGHRC, 2006 as mentioned in the ECHA guidance, R.8.4.2, November, 2012). In absence of dermal absorption information, a factor of 1 for oral versus dermal absorption is applicable as proposed in ECHA guidance, Chapter R.8.4.2 (November, 2012).

AF for dose response relationship:

1

Justification:

No additional assessment factor for dose response is needed because the dosing was well spaced in the OECD TG 414 and in the OECD TG 408 studies used for repeated dose toxicity (ECHA’s guidance, R.8.4.3.1, November, 2012)

AF for differences in duration of exposure:

2

Justification:

There are two pieces of repeated dose toxicity information that need to be considered for the AF for duration of exposure. One is from a sub-chronic study and one from a developmental toxicity study. The effects seen in dams in the developmental toxicity are similar to what is seen in the repeated dose sub-chronic exposure, which is body weight decrease. The NOAEL for repeated dose toxicity has been derived from the pregnant dams in the developmental toxicity study and as such this NOAEL covers the body weight effects seen in this sensitive period. During other than pregnant periods the NOAEL is 2000 mg/kg bw. Using the lowest repeated dose NOAEL for pregnant dams this covers the body weight effects during sub-chronic exposure . This means that for duration of exposure the sub-chronic duration can be used because the body weight effects are already accounted for in the NOAEL of 100 mg/kg bw. Therefore an AF of 2 can be used.

AF for interspecies differences (allometric scaling):

4

Justification:

For allometric scaling a factor of 4 is applicable to convert rat to human data in accordance with ECHA guidance.

AF for other interspecies differences:

1

Justification:

Additional assessment factors for interspecies differences are not needed as has been presented in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).

AF for intraspecies differences:

5

Justification:

This factor has been retrieved by ECETOC (TR 110, 2010) based on scientific literature. The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients, which represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species but includes intraspecies differences.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database, the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

229 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

15

Dose descriptor:

NOAEC

Value:

3 435 µg/m³

AF for dose response relationship:

3

Justification:

Because the value is a LOAEC in ug/cm2, this AF needs to be applied. The conversion from percentate to ug/cm2 is: LOAEC[%]*250 [ug/cm2/%] = 13.74*250 = 3435 ug/cm2 (based on 25 µL of test substance applied onto 1 cm2 area of a mouse ear, and a density of 1).

AF for differences in duration of exposure:

1

Justification:

The LLNA represents a sufficient long exposure time to induce skin sensitisation and therefore no assessment factor for duration is needed.

AF for interspecies differences (allometric scaling):

1

Justification:

An assessment factor for allometric scaling is not needed since local effects are independent of the basal metabolic rate, allometric scaling should not be applied (allometric scaling factor of 1) ECHA, 2012, Chapter R8

AF for other interspecies differences:

1

Justification:

For vehicle effects an assessment factor of 1 is applied as the matrices of the products compiled from the substance are not intended to enhance penetration. For type of skin (skin thickness and skin integrity) it can be seen that the human skin (exposed hands) to be similarly or less sensitive compared to the skin of the mouse ear. The LLNA is selected as a model because the mouse ear is considered very thin with high blood flow and as such reflect a similar thickness and integrity compared to human skin in general.)

AF for intraspecies differences:

5

Justification:

The intraspecies variation in humans is greater than that in the more homogenous experimental animal population. Based on an evaluation of the scientific literature by ECETOC (ECETOC TR No. 110 (2010) , an AF of 5 for general population is advised after a detailed review of the literature. The ECETOC review is based on systemic effect. Sensitisation results from systemic exposure and therefore these ECETOC AFs can be applied here.

AF for the quality of the whole database:

1

Justification:

An assessment factor of 1 is applicable because the information fulfils the REACH requirements reliable information from a close analogue is used, which was tested in an LLNA study according to OECD 429.

AF for remaining uncertainties:

1

Justification:

An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

40

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The substance fulfils the REACH Annex VII to Annex XI information requirements in accordance with R.7.5-7.7 for assessing long-term systemic toxicity. Adverse effects were seen in the developmental toxicity study (from read across substance). A DNEL derivation for the oral route is considered necessary, because oral exposure is likely via the environment.

AF for dose response relationship:

1

Justification:

No additional assessment factor for dose response is needed because the dosing was well spaced in the OECD TG 414 and in the OECD TG 408 studies used for repeated dose toxicity (ECHA’s guidance, R.8.4.3.1, November, 2012).

AF for differences in duration of exposure:

2

Justification:

There are two pieces of repeated dose toxicity information that need to be considered for the AF for duration of exposure. One is from a sub-chronic study and one from a developmental toxicity study. The effects seen in dams in the developmental toxicity are similar to what is seen in the repeated dose sub-chronic exposure, which is body weight decrease. The NOAEL for repeated dose toxicity has been derived from the pregnant dams in the developmental toxicity study and as such this NOAEL covers the body weight effects seen in this sensitive period. During other than pregnant periods the NOAEL is 2000 mg/kg bw. Using the lowest repeated dose NOAEL for pregnant dams this covers the body weight effects during sub-chronic exposure . This means that for duration of exposure the sub-chronic duration can be used because the body weight effects are already accounted for in the NOAEL of 100 mg/kg bw. Therefore an AF of 2 can be used.

AF for interspecies differences (allometric scaling):

4

Justification:

For allometric scaling a factor of 4 is applicable to convert rat to human data in accordance with ECHA guidance.

AF for other interspecies differences:

1

Justification:

Additional assessment factors for interspecies differences are not needed as has been presented in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).

AF for intraspecies differences:

5

Justification:

An assessment factor of 5 has been used to account for the intraspecies differences. This factor has been retrieved by ECETOC (TR 110, 2010) based on scientific literature. The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients, which represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species, but includes intraspecies differences.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database, the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

The DNELs for long term exposure (systemic effects) were derived in accordance with the Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health with the exception of two assessment factors:

1.       Interspecies differences, remaining differences. For remaining differences it is considered that those already have been taken into account when applying an assessment factor for allometric scaling. The argumentation for this can be found in the ECETOC Guidance on Assessment Factors to Derive a DNEL (Technical Report No. 110, 2010). It is concluded that the concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans. As the human population under investigation comprised cancer patients, this represents a very sensitive subpopulation. Thus, this additional’ variability represented by the GSD of 2.5-2.6 is probably due to not only potential differences in biological sensitivity between species, but also intraspecies differences. The intraspecies variability in humans is taken into account by the specific Assessment Factors for workers (3) and the general population (5). The introduction of the ‘remaining’ AF of 2.5 for interspecies variability would therefore mean an unjustified compilation of AF. Therefore, although ‘residual’ interspecies variability may remain following allometric scaling, this is largely accounted for in the default AF proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies AF.

2.       Intraspecies differences. The current proposed AF for intraspecies extrapolation of systemic effects for workers and the general population in the ECHA guidance differ from those proposed in the ECETOC guidance (2010). After studying both guidances it is concluded that the AF proposed by ECETOC are based on an evaluation of the scientific literature while the REACH TGD refers to standard default procedures. Therefore, the ECETOC guideline will be followed until the scientific basis for using an alternative approach has been established. This means that for workers instead of an AF of 5 as proposed in the ECHA guidance an AF of 3 will be used and for the general population instead of an AF of 10 and AF of 5.

ECETOC, 2010, http://www.ecetoc.org/wp-content/uploads/2014/08/ECETOC-TR-110-Guidance-on-assessment-factors-to-derive-a-DNEL.pdf