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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
26.1 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:
296 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
260.9 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 296 mg/kg bw/day, obtained in the key "Repeated-dose 90-day oral toxicity study in Wistar rats, Administration via the diet" (OECD TG 408). 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) = 296 mg/kg bw/day * (1/0.38 m³/kg/d) * (6.7 m³ (8h)/10 m³ (8h)) * (50%/100%) = 260.9 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:
The absence of test substance releated signs of general systemic and specific organ toxicity in Wistar rats in all tested doses (even in females tested above the limit dose (1000 mg/kg bw/d) does not indicate a potential for any toxikodynamic difference of the test substance between species including humans. Therefore the interspecies factor was assumed as "1".
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:
14.8 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:
296 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
592 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 296 mg/kg bw/day, obtained in the key "Repeated-dose 90-day oral toxicity study in Wistar rats, Administration via the diet" (OECD TG 408). The NOAELcorr. is calculated as follows:

- absorption oral animal = 100%

- absorption dermal human = 50%

--> modified dose descriptor (corrected dermal NOAEL) = 296 mg/kg bw/day * (100% rat oral / 50% human dermal) = 592 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:
The absence of test substance releated signs of general systemic and specific organ toxicity in Wistar rats in all tested doses (even in females tested above the limit dose (1000 mg/kg bw/d) does not indicate a potential for any toxikodynamic difference of the test substance between species including humans. Therefore the interspecies factor was assumed as "1".
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)

Additional information - workers

The present DNELs are considered as interim values, since further relevant studies are currently ongoing ( see ECHA final decision CCH-D-2114359360-53-01/F)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.4 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:
296 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
128.7 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 296 mg/kg bw/day, obtained in the key "Repeated-dose 90-day oral toxicity study in Wistar rats, Administration via the diet" (OECD TG 408). 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) = 296 mg/kg bw/day * (1/1.15 m³/kg/d) * (50%/100%) = 128.7 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:
The absence of test substance releated signs of general systemic and specific organ toxicity in Wistar rats in all tested doses even in females tested above the limit dose (1000 mg/kg bw/d) does not indicate a potential for any toxikodynamic difference of the test substance between species including humans. Therefore the interspecies factor was assumed as "1".
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:
7.4 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:
296 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
592 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 296 mg/kg bw/day, obtained in the key "Repeated-dose 90-day oral toxicity study in Wistar rats, Administration via the diet" (OECD TG 408). The NOAELcorr. is calculated as follows:

- absorption oral animal = 100%

- absorption dermal human = 50%

--> modified dose descriptor (corrected dermal NOAEL) = 296 mg/kg bw/day * (100% absorption oral animal / 50% absorption dermal human) = 592 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:
The absence of test substance releated signs of general systemic toxicity in Wistar rats in all tested doses (even in females tested up to the limit dose and the highest tolerated concentration tested in males), eliminated any possibility of a toxikodynamical potential of the test substance. Therefore the interspecies factor was assumed as "1".
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:
3.7 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:
296 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
296 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 296 mg/kg bw/day, obtained in the key "Repeated-dose 90-day oral toxicity study in Wistar rats, Administration via the diet" (OECD TG 408).

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:
The absence of test substance releated signs of general systemic toxicity in Wistar rats in all tested doses (even in females tested up to the limit dose and the highest tolerated concentration tested in males), eliminated any possibility of a toxikodynamical potential of the test substance. Therefore the interspecies factor was assumed as "1".
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)

Additional information - General Population

The present DNELs are considered as interim values, since further relevant studies are currently ongoing ( see ECHA final decision CCH-D-2114359360-53-01/F)

The Consumer is exposed to methyl ionone in food, cosmetics and some household products like cleaning agents (flavoring compound, aroma additive). Generally, the use levels are low, i.e.less than 1% in household products, up to 1% in biocidal products and up to 8% in air care products. Potential local effects due to its eye and skin irritating potential are considered unlikely based on the final concentrations and exposure conditions when using methyl ionone in final products. The major components of methyl ionone, namely α-iso-methylionone (CAS-No. 127-51-5), methyl-α-ionone (CAS-No. 7779-30-8), and methyl-β-ionone (CAS-No. 127-43-5) – together constituting an average of 91% of methyl ionone - were evaluated by JECFA in 1999 and recognized as safe for use in food products. Further, they are granted GRAS status for use in food by the US FDA (CFR 172.515) (cited in US EPA Test Plan for Ionone Derivatives 2002). The maximum skin level was determined to be 5.64%, assuming up to 20% use of fragrance oil in consumer products (IFRA 2001). According to Lalkoet al.(2007): “The 97.5th percentile use level in formulae for use in cosmetics in general has been reported to be 9.82% (IFRA, 2001), which would result in a conservative calculated maximum daily exposure on the skin of 0.25 mg/kg for high end users of these products.”