5H-Cyclopenta[h]quinazoline, 6,6a,7,8,9,9a-hexahydro-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:

6.94 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:

22.1 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

124.9 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 3.2 times lower than oral absorption.

Therefore, the modified dose descriptor is calculated as follows: oral NOAEL * 1/sRVrat * ABSoral-rat /ABSinhal-human * sRVhuman/wRV

= 22.1 * 1/0.38 m³/kg/8h * 100 /31.2 * 6.7 m3 (8h)/10 m³(8h)

= 22.1 * 1/0.38 m³/kg/8h * 3.2 * 6.7 m3 (8h)/10 m³(8h)

= 22.1 /0.38 * 3.2* (6.7/10) = 124.9 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 in the reproductive/developmental screening study was derived (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 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):

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).

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:

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:

2.05 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:

22.1 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

147.3 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. In the route to route extrapolation for the dermal route no correction is applied and absorption of 100% is used for oral and 15% for dermal absorption. Therefore, the modified dose descriptor is calculated as follows: Starting point is theoral rat study NOAEL of 22.1 mg/kg bw/day. A factor of 6.67 is applied for route-to-route extrapolation: oral (100%) to dermal (15%). 22.1 * (100/15) = 147.3 mg/kg bw/day

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 the study similar to OECD 407 (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 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:

2 650 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

Dose descriptor:

NOAEC

Value:

2 650 µg/m³

AF for dose response relationship:

1

Justification:

As the NOAEC was taken as the dose descriptor starting point no (additional) assessment factor is needed (ECHA’s guidance, R.8.4.3.1, November, 2012).)

AF for differences in duration of exposure:

1

Justification:

Repeated exposure is taken into account in the exposure assessment by using events/day.)

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:

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:

1

Justification:

Two HRIPT tests in healthy volunteers are available with 5% and 10% test solutions. The study with 10% solution presents a NOEC of 5840 µg/cm2 ((the applied dose (0.2 mL) * 0.1) / 3.63 (3.63 cm2 is the applied area)) * 1.06 (correction for density) * 1000000 (g to µg), which is ca twice the NOAEC found in the LLNA (2650 µg/cm2). By using the lower NOAEC from the LLNA as the basis for the DNEL, combined with the existing intraspecies variation in the human population tested in the HRIPT study, the possible influence of intraspecies variation is already sufficiently accounted for and an AF for intraspecies is not needed.

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 LLNA study according to OECD guideline was used.

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

In deriving the DNELs for hazard identification for inhalation and the dermal route of exposure mostly ECHA’s guidance is used, which is generally conservative by using default values in absence of data outside the requirements of REACH regulation Annex VII to Annex XI. In addition, the used assessment factors used have been adequately documented. For inter and intraspecies assessment factors have been used which were conducted to be scientifically sound by ECETOC (TR 110, 2010) and which are based on a thorough review of the scientific literature. Therefore, the DNELs for all human health endpoints relevant for workers are considered sufficiently conservative to be used in risk characterization.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.05 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:

22.1 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

61.6 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 22.1 mg/kg bw/day. A factor of 3.2 is applied for route-to-route extrapolation: oral (100%) to inhalation (31.2%). In addition, for rat to human extrapolation the following formula is used: (22.1 mg/kg bw NOAEL * 3.2 (oral versus inhalation)) / 1.15 = 61.6 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 in the OECD TG 407 study 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 407 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 407 (2015 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:

1.23 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:

22.1 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

147.3 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Route-to route extrapolation can be done because there is adequate oral toxicity data; the NOAEL for effects at the site of contact is not lower than the NOAEL for systemic effects. There here is no evidence that the compound is subject to ‘first-pass’ metabolism which would lead to higher dermal 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 dermal route no correction is applied and absorption of 100% is used for oral and 15% for dermal absorption. Therefore, the modified dose descriptor is calculated as follows: Starting point is theoral rat study NOAEL of 22.1 mg/kg bw/day. A factor of 6.67 is applied for route-to-route extrapolation: 22.1 * (100/15) = 147.3 mg/kg bw/day

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 in the OECD TG 407 study 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 a OECD TG 407 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 407 (2015 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:

DNEL (Derived No Effect Level)

Value:

2 650 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

Dose descriptor:

NOAEC

Value:

2 650 µg/m³

AF for dose response relationship:

1

Justification:

As the NOAEC was taken as the dose descriptor starting point no (additional) assessment factor is needed (ECHA’s guidance, R.8.4.3.1, November, 2012).

AF for differences in duration of exposure:

1

Justification:

Repeated exposure is taken into account in the exposure assessment by using events/day.

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:

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:

1

Justification:

Two HRIPT tests in healthy volunteers are available with 5% and 10% test solutions. The study with 10% solution presents a NOEC of 5840 µg/cm2 ((the applied dose (0.2 mL) * 0.1) / 3.63 (3.63 cm2 is the applied area)) * 1.06 (correction for density) * 1000000 (g to µg), which is ca twice the NOAEC found in the LLNA (2650 µg/cm2). By using the lower NOAEC from the LLNA as the basis for the DNEL, combined with the existing intraspecies variation in the human population tested in the HRIPT study, the possible influence of intraspecies variation is already sufficiently accounted for and an AF for intraspecies is not needed.

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 LLNA study according to OECD guideline was used.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties were identified.

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:

0.184 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:

22.1 mg/kg bw/day

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 in the OECD TG 407 study 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 a OECD TG 407 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 407 (2015 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:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

In deriving the DNELs for hazard identification for inhalation and the dermal route of exposure mostly ECHA’s guidance is used, which is generally conservative by using default values in absence of data outside the requirements of REACH regulation Annex VII to Annex XI. In addition, the used assessment factors used have been adequately documented. For inter and intraspecies assessment factors have been used which were conducted to be scientifically sound by ECETOC (TR 110, 2010) and which are based on a thorough review of the scientific literature. Therefore, the DNELs for all human health endpoints relevant for the general population are considered sufficiently conservative to be used in risk characterization.