reaction mass of 3-methyl-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-3-en-2-one and 1-(2,6,6-trimethylcyclohex-2-en-1-yl)pent-1-en-3-one

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.5 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:

40 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

35.3 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no adequate experimental data on the inhalation route available. Therefore, the worker-DNEL long-term for inhalation route - systemic is derived from the oral NOAEL of 40 mg/kg bw/day, obtained in the key "Extended One-generation reproduction toxicity study, rats, oral administration (gavage)" (OECD TG 443). The NOAECcorr. is calculated as follows:

- standard respiratory volume rat = 0.38 m³/kg/8h

- standard respiratory volume human = 6.7 m³/8h

- worker respiratory volume = 10 m³/8h

- absorption (oral, rat) = 50 % (default)

- absorption (inhalative, human) = 100 % (default). As worst case, inhalative absorption is assumed to be two times more than oral absorption which allows for a modification of the starting point by factor 2.

--> modified dose descriptor (corrected inhalatory NOAEC) = 40 mg/kg bw/day * (1/0.38 m³/kg/d) * (6.7 m³ (8h)/10 m³ (8h)) * (50%/100%) = 35.3 mg/m³

 

 

Route to route extrapolation:

On the basis of the low vapor pressure (0.0022 hPa at 20°C), the exposure with methyl ionone via inhalation as a vapor is low. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information to include a default factor in the case of inhalation-to-oral extrapolation, assuming 50% oral and 100% inhalation absorption.

AF for dose response relationship:

1

Justification:

ECHA REACH Guidance: starting point for the DNEL calculation is a NOAEL, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

ECHA REACH Guidance: The recommended AF for the extrapolation from sub-chronic to chronic exposure is applied.

AF for interspecies differences (allometric scaling):

1

Justification:

ECHA REACH Guidance: no additional factor needed for extrapolation from oral to inhalation route

AF for other interspecies differences:

1

Justification:

At the lowest effect level of 40 mg/kg bw/d, a microsomal liver enzyme induction (clinical chemistry parameters, increased liver weights, hepatocellular hypertrophy) was observed in both sexes as the main systemic toxic effect. Altered thyroid hormone levels, increased thyroid weights in combination with histopathologic findings in the thyroid are indicative for a secondary hypothyroidism by
increased clearance of T4 levels via the liver and a compensatory increase of the TSH levels. In F1 animals these effects were observed at the high dose (600 mg/kg bw/d) only. Hepatic enzyme induction is generally an adaptive response not showing cell death or severe organ toxicity. Therefore, a factor of 2.5 for ‘remaining‘ interspecies differences does not need to be applied.

In general, although ‘residual’ interspecies variability may remain following allometric scaling, this is largely accounted for in the assessment factors proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies assessment factors (see also Calabrese et al., 1993, Regul. Toxicol. Pharmacol. 17: 44-51). Furthermore, within the ERASM project, it was found, that species are on average equally sensitive to equipotent doses, if doses are related to energy turnover. An animal to human interspecies extrapolation distribution with a geometric mean identical to the allometric scaling factor (e.g. 4 rat/human, 7 mouse/human) was identified, without an additional factor of 2.5 for putative toxicodynamic differences. Therefore, a factor of 2.5 for ‘remaining‘ interspecies differences may be questionable as a standard procedure (see also Escher et al., 2013, Toxicology Letters 218; 159-165). 

AF for intraspecies differences:

5

Justification:

ECHA REACH Guidance: The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

ECHA REACH Guidance: The quality of the whole data base is considered to be sufficient.

AF for remaining uncertainties:

1

Justification:

ECHA REACH Guidance: default factor. The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2 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:

40 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

80 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no adequate experimental data on the dermal route available. Therefore, the worker-DNEL long-term for dermal route - systemic is derived from the oral NOAEL of 40 mg/kg bw/day, obtained in the key "Extended One-generation reproduction toxicity study, rats, oral administration (gavage)" (OECD TG 443). The NOAELcorr. is calculated as follows:

- absorption oral animal = 100%

- absorption dermal human = 50%

--> modified dose descriptor (corrected dermal NOAEL) = 40 mg/kg bw/day * (100% rat oral / 50% human dermal) = 80 mg/kg bw/day.

 

 

Route to route extrapolation:

In an in vitro dermal penetration/permeability study, only 0.7% or undetectable amounts of methyl ionone (mixture of isomers) were recovered in the fluid beneath the skin preparations of rats and pigs, respectively, 6 h after application of a 3000 µg dose (600 µg/cm² over 5 cm² of skin) (RIFM, 1984a). In this study, approximately 50% (rat) and 10% (pig) of methyl ionone-¹⁴C penetrated into, but not through the epidermis and dermis, while another 30% was lost to evaporation (Belsito, 2007).

Skin penetration potential through human skin is generally much closer to that of porcine skin than to that of rat skin. The morphology of porcine skin corresponds much better to that of human skin than that of fur bearing animals, which presents numerous hair follicles. Hair follicles act as shunt ways of resorption and hence, chemical substances penetrate into or through fur bearing skin much easier. Van Ravenzwaay and Leibold (2004) have compared the differences in absorption for a large number of chemicals and found the dermal absorption through rat skin is generally at least 2.3 times greater than through human skin. Taking this information together with the values of the in vitro study (50% penetration into rat skin and 10% penetration into porcine skin, but no penetration through either kind of skin), a maximal penetration of ca. 20% into but not through human skin might be assumed. A worst case of 50% penetration through human skin is assumed, although realistic values may be considerably lower. Hence, an assessment factor of 0.5 was chosen.

AF for dose response relationship:

1

Justification:

ECHA REACH Guidance: starting point for the DNEL calculation is a NOAEL, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

ECHA REACH Guidance: The recommended AF for the extrapolation from sub-chronic to chronic exposure is applied.

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA REACH Guidance: The default allometric scaling factor for the differences between rats and humans is applied.

AF for other interspecies differences:

1

Justification:

At the lowest effect level of 40 mg/kg bw/d, a microsomal liver enzyme induction (clinical chemistry parameters, increased liver weights, hepatocellular hypertrophy) was observed in both sexes as the main systemic toxic effect. Altered thyroid hormone levels, increased thyroid weights in combination with histopathologic findings in the thyroid are indicative for a secondary hypothyroidism by
increased clearance of T4 levels via the liver and a compensatory increase of the TSH levels. In F1 animals these effects were observed at the high dose (600 mg/kg bw/d) only. Hepatic enzyme induction is generally an adaptive response not showing cell death or severe organ toxicity. Therefore, a factor of 2.5 for ‘remaining‘ interspecies differences does not need to be applied.

In general, although ‘residual’ interspecies variability may remain following allometric scaling, this is largely accounted for in the assessment factors proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies assessment factors (see also Calabrese et al., 1993, Regul. Toxicol. Pharmacol. 17: 44-51). Furthermore, within the ERASM project, it was found, that species are on average equally sensitive to equipotent doses, if doses are related to energy turnover. An animal to human interspecies extrapolation distribution with a geometric mean identical to the allometric scaling factor (e.g. 4 rat/human, 7 mouse/human) was identified, without an additional factor of 2.5 for putative toxicodynamic differences. Therefore, a factor of 2.5 for ‘remaining‘ interspecies differences may be questionable as a standard procedure (see also Escher et al., 2013, Toxicology Letters 218; 159-165). 

AF for intraspecies differences:

5

Justification:

ECHA REACH Guidance: The recommended default AF for other interspecies differences is applied.

AF for the quality of the whole database:

1

Justification:

ECHA REACH Guidance: The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

ECHA REACH Guidance: default factor. The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.87 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):

20

Dose descriptor starting point:

NOAEL

Value:

40 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

17.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no adequate experimental data on the inhalation route available.Therefore, general population DNEL long-term for inhalation route - systemic is derived from the oral NOAEL of 40 mg/kg bw/day, obtained in the key "Extended One-generation reproduction toxicity study, rats, oral administration (gavage)" (OECD TG 443). The NOAECcorr. is calculated as follows:

- standard respiratory volume rat = 1.15 m³/kg/24h

- absorption (oral, rat) = 50 % (default)

- absorption (inhalative, human) = 100 % (default).As worst case, inhalative absorption is assumed to be two times more than oral absorption which allows for a modification of the starting point by factor 2.

--> modified dose descriptor (corrected inhalatory NOAEC) = 40 mg/kg bw/day * (1/1.15 m³/kg/d) * (50%/100%) = 17.4 mg/m³

 

Route to route extrapolation:

On the basis of the low vapor pressure (0.0022 hPa at 20°C), the exposure with methyl ionone via inhalation as a vapor is low. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information to include a default factor in the case of inhalation-to-oral extrapolation, assuming 50% oral and 100% inhalation absorption.

AF for dose response relationship:

1

Justification:

ECHA REACH Guidance: starting point for the DNEL calculation is a NOAEL, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

ECHA REACH Guidance: The recommended AF for the extrapolation from sub-chronic to chronic exposure is applied.

AF for interspecies differences (allometric scaling):

1

Justification:

ECHA REACH Guidance: no additional factor needed for extrapolation from oral to inhalation route.

AF for other interspecies differences:

1

Justification:

At the lowest effect level of 40 mg/kg bw/d, a microsomal liver enzyme induction (clinical chemistry parameters, increased liver weights, hepatocellular hypertrophy) was observed in both sexes as the main systemic toxic effect. Altered thyroid hormone levels, increased thyroid weights in combination with histopathologic findings in the thyroid are indicative for a secondary hypothyroidism by
increased clearance of T4 levels via the liver and a compensatory increase of the TSH levels. In F1 animals these effects were observed at the high dose (600 mg/kg bw/d) only. Hepatic enzyme induction is generally an adaptive response not showing cell death or severe organ toxicity. Therefore, a factor of 2.5 for ‘remaining‘ interspecies differences does not need to be applied.

In general, although ‘residual’ interspecies variability may remain following allometric scaling, this is largely accounted for in the assessment factors proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies assessment factors (see also Calabrese et al., 1993, Regul. Toxicol. Pharmacol. 17: 44-51). Furthermore, within the ERASM project, it was found, that species are on average equally sensitive to equipotent doses, if doses are related to energy turnover. An animal to human interspecies extrapolation distribution with a geometric mean identical to the allometric scaling factor (e.g. 4 rat/human, 7 mouse/human) was identified, without an additional factor of 2.5 for putative toxicodynamic differences. Therefore, a factor of 2.5 for ‘remaining‘ interspecies differences may be questionable as a standard procedure (see also Escher et al., 2013, Toxicology Letters 218; 159-165). 

AF for intraspecies differences:

10

Justification:

ECHA REACH Guidance: The default value for the relatively heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

ECHA REACH Guidance: The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

ECHA REACH Guidance: default factor. The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 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):

80

Dose descriptor starting point:

NOAEL

Value:

40 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

80 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no adequate experimental data on the dermal route available. Therefore, the general population-DNEL long-term for dermal route - systemic is derived from the oral NOAEL of 40 mg/kg bw/day, obtained in the key "Extended One-generation reproduction toxicity study, rats, oral administration (gavage)" (OECD TG 443). The NOAELcorr. is calculated as follows:

- absorption oral animal = 100%

- absorption dermal human = 50%

--> modified dose descriptor (corrected dermal NOAEL) = 40 mg/kg bw/day * (100% absorption oral animal / 50% absorption dermal human) = 80 mg/kg bw/day

 

Route to route extrapolation:

In an in vitro dermal penetration/permeability study, only 0.7% or undetectable amounts of methyl ionone (mixture of isomers) were recovered in the fluid beneath the skin preparations of rats and pigs, respectively, 6 h after application of a 3000 µg dose (600 µg/cm² over 5 cm² of skin) (RIFM, 1984a). In this study, approximately 50% (rat) and 10% (pig) of methyl ionone-¹⁴C penetrated into, but not through the epidermis and dermis, while another 30% was lost to evaporation (Belsito, 2007).

Skin penetration potential through human skin is generally much closer to that of porcine skin than to that of rat skin. The morphology of porcine skin corresponds much better to that of human skin than that of fur bearing animals, which presents numerous hair follicles. Hair follicles act as shunt ways of resorption and hence, chemical substances penetrate into or through fur bearing skin much easier. Van Ravenzwaay and Leibold (2004) have compared the differences in absorption for a large number of chemicals and found the dermal absorption through rat skin is generally at least 2.3 times greater than through human skin. Taking this information together with the values of thein vitrostudy (50% penetration into rat skin and 10% penetration into porcine skin, but no penetration through either kind of skin), a maximal penetration of ca. 20% into but not through human skin might be assumed. A worst case of 50% penetration through human skin is assumed, although realistic values may be considerably lower. Hence, an assessment factor of 0.5 was chosen.

AF for dose response relationship:

1

Justification:

ECHA REACH Guidance: starting point for the DNEL calculation is a NOAEL, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

ECHA REACH Guidance: The recommended AF for the extrapolation from sub-chronic to chronic exposure is applied.

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA REACH Guidance: The default allometric scaling factor for the differences between rats and humans is applied.

AF for other interspecies differences:

1

Justification:

At the lowest effect level of 40 mg/kg bw/d, a microsomal liver enzyme induction (clinical chemistry parameters, increased liver weights, hepatocellular hypertrophy) was observed in both sexes as the main systemic toxic effect. Altered thyroid hormone levels, increased thyroid weights in combination with histopathologic findings in the thyroid are indicative for a secondary hypothyroidism by
increased clearance of T4 levels via the liver and a compensatory increase of the TSH levels. In F1 animals these effects were observed at the high dose (600 mg/kg bw/d) only. Hepatic enzyme induction is generally an adaptive response not showing cell death or severe organ toxicity. Therefore, a factor of 2.5 for ‘remaining‘ interspecies differences does not need to be applied.

In general, although ‘residual’ interspecies variability may remain following allometric scaling, this is largely accounted for in the assessment factors proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies assessment factors (see also Calabrese et al., 1993, Regul. Toxicol. Pharmacol. 17: 44-51). Furthermore, within the ERASM project, it was found, that species are on average equally sensitive to equipotent doses, if doses are related to energy turnover. An animal to human interspecies extrapolation distribution with a geometric mean identical to the allometric scaling factor (e.g. 4 rat/human, 7 mouse/human) was identified, without an additional factor of 2.5 for putative toxicodynamic differences. Therefore, a factor of 2.5 for ‘remaining‘ interspecies differences may be questionable as a standard procedure (see also Escher et al., 2013, Toxicology Letters 218; 159-165). 

AF for intraspecies differences:

10

Justification:

ECHA REACH Guidance: The default value for the relatively heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

ECHA REACH Guidance: The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

ECHA REACH Guidance: default factor. The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

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:

0.5 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):

80

Dose descriptor starting point:

NOAEL

Value:

40 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

40 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The general population-DNEL long-term for the oral route - systemic is derived from the oral NOAEL of 40 mg/kg bw/day, obtained in the key "Extended One-generation reproduction toxicity study, rats, oral administration (gavage)" (OECD TG 443).

Modification of the dose descriptor starting point was not required, as no differences in the absorption rate and exposure between experimental animals and humans are expected.

AF for dose response relationship:

1

Justification:

ECHA REACH Guidance: starting point for the DNEL calculation is a NOAEL, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

ECHA REACH Guidance: The recommended AF for the extrapolation from sub-chronic to chronic exposure is applied.

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA REACH Guidance: The default allometric scaling factor for the differences between rats and humans is applied.

AF for other interspecies differences:

1

Justification:

At the lowest effect level of 40 mg/kg bw/d, a microsomal liver enzyme induction (clinical chemistry parameters, increased liver weights, hepatocellular hypertrophy) was observed in both sexes as the main systemic toxic effect. Altered thyroid hormone levels, increased thyroid weights in combination with histopathologic findings in the thyroid are indicative for a secondary hypothyroidism by
increased clearance of T4 levels via the liver and a compensatory increase of the TSH levels. In F1 animals these effects were observed at the high dose (600 mg/kg bw/d) only. Hepatic enzyme induction is generally an adaptive response not showing cell death or severe organ toxicity. Therefore, a factor of 2.5 for ‘remaining‘ interspecies differences does not need to be applied.

In general, although ‘residual’ interspecies variability may remain following allometric scaling, this is largely accounted for in the assessment factors proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies assessment factors (see also Calabrese et al., 1993, Regul. Toxicol. Pharmacol. 17: 44-51). Furthermore, within the ERASM project, it was found, that species are on average equally sensitive to equipotent doses, if doses are related to energy turnover. An animal to human interspecies extrapolation distribution with a geometric mean identical to the allometric scaling factor (e.g. 4 rat/human, 7 mouse/human) was identified, without an additional factor of 2.5 for putative toxicodynamic differences. Therefore, a factor of 2.5 for ‘remaining‘ interspecies differences may be questionable as a standard procedure (see also Escher et al., 2013, Toxicology Letters 218; 159-165). 

AF for intraspecies differences:

10

Justification:

ECHA REACH Guidance: The default value for the relatively heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

ECHA REACH Guidance: The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

ECHA REACH Guidance: default factor. The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)