Reaction mass of 1-(3,3-dimethylcyclohex-1-en-1-yl)pent-4-en-1-one and 1-(5,5-dimethylcyclohex-1-en-1-yl)pent-4-en-1-one

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.2 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:

42 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

37 mg/m³

Explanation for the modification of the dose descriptor starting point:

No inhalation toxicity data are available. The NOAEL from the 90-day repeated-dose oral toxicity study with reproduction/developmental toxicity screening 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 ‘firstpass’ metabolism which would lead to higher inhalation toxicity compared to oral toxicity. To account for any uncertainties considering the toxicity potential via the oral and the inhalation route, the absorption via the inhalation route is chosen twice as high as the oral route (IGHRC, 2006 as mentioned in the ECHA guidance, R.8.4.2, November, 2012). 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 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).

AF for dose response relationship:

1

Justification:

Starting point is NOAEL

AF for differences in duration of exposure:

2

Justification:

An assessment factor of 2 has been applied to extrapolate the NOAEL from sub chronic 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:

No correction for caloric demand for inhalation; is included in dose descriptor starting point.

AF for other interspecies differences:

1

Justification:

No remaining 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:

Reliable studies used.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

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:

1.75 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):

24

Dose descriptor starting point:

NOAEL

Value:

42 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

42 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOAEL from the 90-day repeated-dose oral toxicity study with reproduction/developmental toxicity screening is used for derivation of the DNEL long-term for the dermal route. No repeated dose dermal toxicity data are available. The NOAEL from the 90-day repeated-dose oral toxicity study was used for derivation of the DNEL-long-term for the dermal route. 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 and 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, though some higher absorption is expected 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:

Starting point is NOAEL

AF for differences in duration of exposure:

2

Justification:

An assessment factor of 2 has been applied to extrapolate the NOAEL from sub chronic to a chronic study as presented in ECHA’s guidance R.8.4.3.1 and table R.8-5 (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. ECETOC (TR110, 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.

AF for other interspecies differences:

1

Justification:

No remaining 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 (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, and includes intraspecies differences.

AF for the quality of the whole database:

1

Justification:

Reliable studies used.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

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:

232 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:

232

AF for dose response relationship:

1

Justification:

Starting point is NOAEC

AF for differences in duration of exposure:

1

Justification:

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:

In view of mice being 10 times more sensitive compared to humand no assessment factor for interspecies differences is needed.

AF for intraspecies differences:

1

Justification:

The HRIPT test shows that healthy volunteers are 10 times less susceptible to sensitisation compared to the mice used in the test NOAEC is. Healthy volunteers are considered as sensitive as workers and therefore no assessment factor is needed.

AF for the quality of the whole database:

1

Justification:

Adequate and reliable information is available.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

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

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 concluded 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 points 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:

1.83 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:

42 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

18.3 mg/m³

Explanation for the modification of the dose descriptor starting point:

No inhalation toxicity data are available. The NOAEL from the 90-day repeated-dose oral toxicity study with reproduction/developmental toxicity screening 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 at the site of contact and there is no evidence that the compound is subject to ‘firstpass’ metabolism which would lead to higher inhalation toxicity compared to oral toxicity. To account for any uncertainties considering the toxicity potential via the oral and the inhalation route, the absorption via the inhalation route is chosen twice as high as the oral route (IGHRC, 2006 as mentioned in the ECHA guidance, R.8.4.2, November, 2012) Route-to-route extrapolation was applied in accordance with ECHA’s Guidance R.8 (November, 2012). 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).

AF for dose response relationship:

1

Justification:

Starting point is NOAEL

AF for differences in duration of exposure:

2

Justification:

An assessment factor of 2 has been applied to extrapolate the NOAEL from sub chronic 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:

No correction for caloric demand for inhalation; is included in dose descriptor starting point.

AF for other interspecies differences:

1

Justification:

No remaining differences

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:

Reliable studies used

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

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:

1.05 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):

40

Dose descriptor starting point:

NOAEL

Value:

42 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

42 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOAEL from the 90-day repeated-dose oral toxicity study with reproduction/developmental toxicity screening is used for derivation of the DNEL long-term for the dermal route. No repeated dose dermal toxicity data are available. The NOAEL from the 90-day repeated-dose oral toxicity study was used for derivation of the DNEL-long-term for the dermal route. 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 and 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, though some higher absorption is expected 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:

Starting point is NOAEL

AF for differences in duration of exposure:

2

Justification:

An assessment factor of 2 has been applied to extrapolate the NOAEL from sub chronic to a chronic study as presented in ECHA’s guidance R.8.4.3.1 and table R.8-5, (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. ECETOC (TR110, 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 interand intraspecies AF.

AF for other interspecies differences:

1

Justification:

No remaining 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, and includes intraspecies differences.

AF for the quality of the whole database:

1

Justification:

Reliable studies used.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

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:

116 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

2

Dose descriptor:

other: Corrected NOAEC value from the LLNA study, resulting in 116 ug/cm2

AF for dose response relationship:

1

Justification:

Starting point is NOAEC

AF for differences in duration of exposure:

1

Justification:

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:

No assessment factor is needed for interspecies because it has been shown that the mice are >10 times more sensitive compared to humans (LLNA versus HRIPT)

AF for intraspecies differences:

2

Justification:

The general population is circa 2 times more vulneralble compared to healthy volunteers and therefore an assessment factor 2 is applied, which is in accordance with the ECHA guidance.

AF for the quality of the whole database:

1

Justification:

Reliable studies used.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

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:

1.05 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):

40

Dose descriptor starting point:

NOAEL

Value:

42 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The repeated 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:

Starting point is NOAEL

AF for differences in duration of exposure:

2

Justification:

An assessment factor of 2 has been applied to extrapolate the NOAEL from sub chronic to a chronic study as presented in ECHA’s guidance R.8.4.3.1 and table R.8-5, (November, 2012)

AF for interspecies differences (allometric scaling):

4

Justification:

For allometric scaling a factor of 4 is applicable to convert rat to human data. ECETOC (TR110, 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.

AF for other interspecies differences:

1

Justification:

No remaining 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:

Reliable studies used.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

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

In deriving the DNELs for hazard identification for inhalation, dermal route and oral 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 have been adequately documented. For inter and intraspecies assessment factors have been used which were concluded 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 points relevant for the general population are considered sufficiently conservative to be used in risk characterization.