Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 942-741-0 | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Toxicological Summary
- Administrative data
- Workers - Hazard via inhalation route
- Workers - Hazard via dermal route
- Workers - Hazard for the eyes
- Additional information - workers
- General Population - Hazard via inhalation route
- General Population - Hazard via dermal route
- General Population - Hazard via oral route
- General Population - Hazard for the eyes
- Additional information - General Population
Administrative data
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)
Additional information - workers
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)
Additional information - General Population
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.