5H-Cyclopenta[h]quinazoline, 6,7,8,9-tetrahydro-7,7,8,9,9-pentamethyl-

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.45 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):

18

Dose descriptor starting point:

NOAEL

Value:

9.1 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

8 mg/m³

Explanation for the modification of the dose descriptor starting point:

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. The oral rat study NOAEL is modified into a NOAEC for human inhalation using ECHA guidance: 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). In addition, the inhalation absorption is expected to by 100 % and the oral absorption is 50 % (see Toxicokinetic Statement). Therefore, the modified dose descriptor is calculated as follows: 9.1 mg/kg bw NOAEL * (50%/100%) / 0.38 x (6.7/10) = 8.0 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 study and a NOAEL was derived in an OECD TG 421 study of 28 days (ECHA’s guidance, R.8.4.3.1, November, 2012).

AF for differences in duration of exposure:

6

Justification:

An assessment factor of 6 has been applied to extrapolate the NOAEL from a subacute to a chronic study as presented in R.8.4.3.1 and table R.8-5 (ECHA’s guidance, November, 2012).

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 mg/m3, as presented in ECHA’s guidance R.8, figure R. 8-2 (November, 2012).

Justification:

Additional assessment factors for interspecies differences are not needed as has been derived 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:

0.63 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):

72

Dose descriptor starting point:

NOAEL

Value:

9.1 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

45.5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Route-to-route extrapolation was applied in accordance with ECHA’s Guidance R.8.The value of 10 % for dermal absorption and an oral absorption value of 50 % (see Toxicokinetic Statement) were applied in the route-to-route extrapolation. In the route to route extrapolation for the dermal route the value of 10 % as applied for dermal absorption (based on toxicokinetics). Therefore, the modified dose descriptor is calculated as follows: 9.1 mg/kg bw NOAEL * (50%/10%) = 45.5 mg/kg bw.

AF for dose response relationship:

1

Justification:

No additional assessment factor for dose response is needed because the dosing was well spaced in the study and a NOAEL was derived in an OECD TG 421 study (ECHA’s guidance, R.8.4.3.1, November, 2012).

AF for differences in duration of exposure:

6

Justification:

An assessment factor of 6 has been applied to extrapolate the NOAEL from a sub-acute to a chronic study as presented in R.8.4.3.1 and table R.8-5 (ECHA’s guidance, November, 2012).

AF for interspecies differences (allometric scaling):

4

Justification:

For allometric scaling a factor of 4 is applicable to convers rat to human data, as determined by ECHA (Table R.8-3, 2012).

AF for other interspecies differences:

1

Justification:

Additional assessment factors for interspecies differences are not needed as has been derived 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:

9 422 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

Dose descriptor:

other: NOEL

AF for dose response relationship:

1

Justification:

For the HRIPT study an assessment factor of 1 is applicable, because 1) the NOEL is used as a starting point; 2) the doses were well separated (10, 15 and 20 %)

AF for differences in duration of exposure:

1

Justification:

An assessment factor of 1 is applicable, because the HRIPT is considered to be sufficiently sensitive for assessing skin sensitisation.

AF for interspecies differences (allometric scaling):

1

Justification:

An assessment factor for allometric scaling is not needed because the DNEL is derived from human data.

AF for other interspecies differences:

1

Justification:

An assessment factor for allometric scaling is not needed because the DNEL is derived from human data.

AF for intraspecies differences:

1

Justification:

An AF for intraspecies is not needed. The possible influence of intraspecies variation is already sufficiently accounted for in the HRIPT study since the worker population is considered to be similar to the healthy volunteers in the HRIPT study. Therefore, an AF for intraspecies is not needed according to Table 10 of ECETOC TR110 (Oct 2010).

AF for the quality of the whole database:

1

Justification:

An assessment factor for the quality of the database is not needed because a well-conducted HRIPT guideline study is available.

AF for remaining uncertainties:

1

Justification:

Assessment factor for remaining uncertainties is not needed. 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) the assessment factor is 1 as human skin was tested. Therefore, an AF is not needed.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

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 guidance’s, 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:

0.13 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):

30

Dose descriptor starting point:

NOAEL

Value:

9.1 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

3.96 mg/m³

Explanation for the modification of the dose descriptor starting point:

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. The oral rat study NOAEL is modified into a NOAEC for human inhalation for the General population using ECHA guidance: Starting point is the NOAEL of 9.1 mg/kg bw. In addition, the inhalation absorption is expected to by 100 % and the oral absorption is 50 % (see Toxicokinetic Statement). Therefore, the modified dose descriptor is calculated as follows: 9.1 mg/kg bw NOAEL * (50%/100%) / 1.15 = 3.96 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 study and a NOAEL was derived in an OECD TG 421 study of 28 days (ECHA’s guidance, R.8.4.3.1, November, 2012).

AF for differences in duration of exposure:

6

Justification:

Since the dose descriptor is derived from an OECD TG 421 study, an additional assessment factor of 6 to take account of extrapolation of sub-acute data to chronic exposure (ECHA 2012, Chapter R8, p 29).

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:

An assessment factor of 1 has been applied because besides allometric differences no other interspecies differences need to be accounted for which has been shown by ECETOC TR 110 (2010) after a review of the scientific literature. ECETOC concludes that adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. The application the ‘remaining’ AF of 2.5 for interspecies variability would mean an unjustified compilation of AF. The ‘residual’ interspecies variability may remain following allometric scaling, but this is largely accounted for in the default AF proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies AF.

AF for intraspecies differences:

5

Justification:

An assessment factor of 5 has been used to account for the intraspecies differences as has been derived by ECETOC (TR110, 2010) based on a review of the 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, 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 but includes intraspecies differences.

AF for the quality of the whole database:

1

Justification:

An assessment factor of 1 is applicable because the information fulfils the REACH requirements: an OECD TG 421 (2017 under GLP) is available (ECHA’s Guidance, R.8.4.3.1, November 2012).

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties were identified.

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:

0.38 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):

120

Dose descriptor starting point:

NOAEL

Value:

9.1 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

45.5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Route-to-route extrapolation was applied in accordance with ECHA’s Guidance R.8. The value of 10 % for dermal absorption and an oral absorption value of 50 % (see Toxicokinetic Statement) were applied in the route-to-route extrapolation.In the route to route extrapolation for the dermal route the value of 10 % as applied for dermal absorption (based on toxicokinetics. Therefore, the modified dose descriptor is calculated as follows: 9.1 mg/kg bw NOAEL * (50%/10%) = 45.5 mg/kg bw.

AF for dose response relationship:

1

Justification:

No additional assessment factor for dose response is needed because the dosing was well spaced in the study and a NOAEL was derived in an OECD TG 421 study (ECHA’s guidance, R.8.4.3.1, November, 2012).

AF for differences in duration of exposure:

6

Justification:

An assessment factor of 6 has been applied to extrapolate the NOAEL from an OECD TG 421 (28 days) to a chronic study as presented in R.8.4.3.1 and table R.8-5 (ECHA’s guidance, November, 2012).

AF for interspecies differences (allometric scaling):

4

Justification:

For allometric scaling a factor of 4 is applicable to convers rat to human data, as determined by ECHA (Table R.8-3, 2012).

AF for other interspecies differences:

1

Justification:

Additional assessment factors for interspecies differences are not needed as has been derived 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

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4 711 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

2

Dose descriptor:

other: NOEL

AF for dose response relationship:

1

Justification:

For the HRIPT study an assessment factor of 1 is applicable, because 1) the NOEL is used as a starting point; 2) the doses were well separated (10, 15 and 20 %)

AF for differences in duration of exposure:

1

Justification:

An assessment factor of 1 is applicable, because the HRIPT is considered to be sufficiently sensitive for assessing skin sensitisation.

AF for interspecies differences (allometric scaling):

1

Justification:

An assessment factor for allometric scaling is not needed because the DNEL is derived from human data.

AF for other interspecies differences:

1

Justification:

An assessment factor for allometric scaling is not needed because the DNEL is derived from human data.

AF for intraspecies differences:

2

Justification:

An AF for intraspecies is required, since the possible influence of intraspecies variation is not sufficiently accounted for in the HRIPT study, since this study only includes healthy volunteers. Therefore, an AF of 2 for intraspecies is applied, based on Table 10 of ECETOC TR110 (Oct 2010).

AF for the quality of the whole database:

1

Justification:

An assessment factor for the quality of the database is not needed because a well-conducted HRIPT guideline study is available.

AF for remaining uncertainties:

1

Justification:

Assessment factor for remaining uncertainties is not needed. 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) the assessment factor is 1 as human skin was tested. Therefore, an AF is not needed.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.076 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):

120

Dose descriptor starting point:

NOAEL

Value:

9.1 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

9.1 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The selected conservative NOAEL has been derived from an oral OECD TG 421 study dose toxicity test has been performed via the oral route and therefore route to route extrapolation is not needed, because there are no indications that rat has a different oral absorption compared to humans.

AF for dose response relationship:

1

Justification:

No additional assessment factor for dose response is needed because the dosing was well spaced in the study and a NOAEL an OECD TG 421 study of 28 days was derived (ECHA’s guidance, R.8.4.3.1, November, 2012).

AF for differences in duration of exposure:

6

Justification:

Since the dose descriptor is derived from an OECD TG 421 study, an additional assessment factor of 6 to take account of extrapolation of sub-acute data to chronic exposure (ECHA 2012, Chapter R8, p 29).

AF for interspecies differences (allometric scaling):

4

Justification:

For allometric scaling a factor of 4 is applicable to convers rat to human data, as determined by ECHA (Table R.8-3, 2012).

AF for other interspecies differences:

1

Justification:

Additional assessment factors for interspecies differences are not needed as has been derived 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:

An assessment factor of 1 is applicable because the information fulfils the REACH requirements: an OECD TG 421 (2017 under GLP) is available (ECHA’s Guidance, R.8.4.3.1, November 2012).

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties were identified.

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 guidance’s, 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