Registration Dossier
Registration Dossier
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EC number: 404-800-4 | CAS number: 118832-72-7 IRGANOX L 118
Toxicological Summary
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 1.47 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 30
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 44.1 mg/m³
- Explanation for the modification of the dose descriptor starting point:
- No data for the inhalation route were available; a route to route extrapolation was performed according to ECHA guidance.
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:
- 0.42 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 120
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 50 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
- No data for the dermal route were available; a route to route extrapolation was performed according to ECHA guidance.
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
Workers - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- no hazard identified
Additional information - workers
Identification of relevant dose descriptor
For the derivation of the DNELs, the 28-day repeated dose toxicity study in rats was qualified as the most relevant study. The dose descriptor chosen was the NOAEL of 50 mg/kg/day. The NOAEL is based on slight retardation in bodyweight gain, slight decrease in food consumption, changes in hematology and biochemistry parameters, increase in liver weights, liver enlargement and centrilobular hepatic cell hypertrophy. Further biochemical and ultrastructural investigations revealed that the test substance was a “mixed-type inducer” in the liver with peroxisome proliferator properties. The increased liver weights and the biochemical and ultramorphological changes observed at the highest dose level of 500 mg/kg bw/day can be considered as an adaptation of the liver to a functional load on the investigated parameters. The hepatic peroxisome proliferation of the test substance may reflect a rodent specific response.
To summarize, treatment with the test substance was well tolerated and did not produce any toxicologically relevant changes in male and female rats. Most of th effects observed were either adaptive in nature or rat specific, therefore the NOAEL might as well be considered at the high dose of 500 mg/kg body weight. However, to account for the remaining uncertainties i.e. the observed retardation of the body weight gain, blood chemistry parameters and lethal effects observed in the pre-study at higher doses, the NOAEL was chosen to be kept at 50 mg/kg.
Calculation of DNELs
Systemic, long-term, inhalative
Because no inhalation study is available, a route to route extrapolation was performed. The NOAEL (oral) is converted into a NOAEC (corrected) in accordance to guidance on information requirements and chemical safety assessment, Chapter R.8, ECHA, May 2008. The NOAEL (oral) has to be divided by a factor of 0.38 m3/kg body weight and corrected for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3). In addition, a default factor of 2 is applied to account for differences in oral and inhalative absorption properties. The corrected starting point is therefore:
NOAEC (corrected) = 50 mg/kg / 0.38 m3/kg x 0.5 x (6.7 m3/10m3) = 44.1 mg/m3
The DNEL is calculated as follows: NOAEL (corrected) / Sum of assessment factors applicable.
The following assessment factors according to "ECHA guidance on information requirements and chemical safety assessment, Chapter R8" were chosen:
Intraspecies differences (worker): 5
Interspecies variations: 1
Exposure duration: 6
Dose-response factor: 1
Quality of whole database factor: 1
The overall assessment factor employed for the inhalation route is therefore 30.
DNEL = 44.1 mg/m3/ 30 = 1.47 mg/m3
Systemic, long-term, dermal:
DNEL = NOAEL (oral) / Sum of assessment factors applicable
The dermal route is typically covered by oral route information in the absence of data for this administration route. Since no data on skin penetration is available a worst case approach was chosen and an absorption of 100% is assumed. The following assessment factors according to "ECHA guidance on information requirements and chemical safety assessment, Chapter R8" were chosen:
Intraspecies differences (worker): 5
Interspecies variations: 1
Allometric scaling (rat to human): 4
Exposure duration: 6
Dose-response factor: 1
Quality of whole database factor: 1
Overall, an assessment factor of 120 was employed for the dermal route.
DNEL= 50 mg/kg body weight / 120 = 0.42 mg/kg body weight.
Rationale for omitting "Factor 2.5"
According to ECETOC’s “guidance on Assessment Factors to derive a DNEL, Technical Report No. 110”, the application of a factor of 2.5 for ‘remaining uncertainties’ is unjustified. There is evidence that multiplicative association between inter- and intraspecies assessment factors is overly conservative and that the inclusion of a factor for remaining differences is unnecessary. ECETOC further recommends using allometric scaling and the 5th percentile of the human distribution of intraspecies variability. Consequently, the ‘remaining uncertainty’ for interspecies variability is already accounted for by the intraspecies AF (Calabrese, 1985; Hattis et al 1987). This is further supported by results of the ongoing ERASM project which examines studies in rats and mice to determine interspecies differences based on a probabilistic approach. In their recent publication (Escher, 2013), the authors confirmed the ECETOC position regarding the factor of 2.5 for remaining uncertainties (i. e. the factor does not apply). Therefore, the factor of 2.5 for remaining uncertainties is omitted for this risk assessment.
Literature:
- Calabrese EJ, Uncertainty factors and interindividual variation, Regul Toxicol Pharmacol. 1985 Jun;5(2):190-6.
- Hattis D et al, Human variability in susceptibility to toxic chemicals-a preliminary analysis of pharmacokinetic data from normal volunteers, Risk Anal. 1987 Dec;7(4):415-26.
- Escher SE et al, Interspecies extrapolation based on the RepDose database—A probabilistic approach, Toxicology Letters 218 (2013) 159– 165
Systemic, short-term, dermal and by inhalation
According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose[concentration]-response for human health", a DNEL for acute systemic toxicity should only be derived if an acute systemic toxicity hazard leading to classification is identified. Therefore, because the substance is not classified for acute toxicity according to Directive 67/548/EEC and Regulation 1272/2008/EC, no systemic DNELs for short-term exposures were calculated.
Local, long-term and short-term, dermal and by inhalation
Based on the available key toxicological information, the test item is not subject to classification for irritation and sensitization (according to 67/548/EEC and EC/1272/2008). Accordingly, no DNELs for local effects following acute/short-term or long-term exposure are derived. This is in line with the ECHA guidance document (Chapter R.8).
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.36 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):
- 60
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 21.7 mg/m³
- Explanation for the modification of the dose descriptor starting point:
- No data for the inhalation route were available; a route to route extrapolation was performed according to ECHA guidance.
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:
- 0.21 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):
- 240
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 50 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
- No data for the dermal route were available; a route to route extrapolation was performed according to ECHA guidance.
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
General Population - Hazard via oral route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.21 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):
- 300
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 50 mg/kg bw/day
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
Identification of relevant dose descriptor
For the derivation of the DNELs, the 28-day repeated dose toxicity study in rats was qualified as the most relevant study. The dose descriptor chosen was the NOAEL of 50 mg/kg/day.
Calculation of DNELs
Systemic, long-term, inhalative
Because no inhalation study is available, a route to route extrapolation was performed. The NOAEL (oral) has to be modified into a NOAEC (corrected) in accordance to guidance on information requirements and chemical safety assessment, Chapter R.8, ECHA, May 2008. Here, the NOAEL has to be divided by a factor of 1.15 m3/kg body weight. In addition, a default factor of 2 is applied to account for differences in oral and inhalative absorption properties. The corrected starting point is therefore:
NOAEC (corrected) = 50 mg/kg / 1.15 m3/kg x 0.5 = 21.7 mg/m3
The DNEL is calculated as follows: NOAEC (corrected) / Sum of assessment factors applicable.
The following assessment factors according to "ECHA guidance on information requirements and chemical safety assessment, Chapter R8" were chosen:
Intraspecies differences (general population): 10
Interspecies variations: 1
Exposure duration: 6
Dose-response factor: 1
Quality of whole database factor: 1
The overall assessment factor employed for the inhalation route is therefore 60.
DNEL = 21.7 mg/m3/ 60 = 0.36 mg/m3
Systemic, long-term, dermal:
DNEL = NOAEL (oral) / Sum of assessment factors applicable
The dermal route is typically covered by oral route information in the absence of data for this administration route. Since no data on skin penetration is available a worst case approach was chosen and an absorption of 100% is assumed. The following assessment factors according to "ECHA guidance on information requirements and chemical safety assessment, Chapter R8" were chosen:
Intraspecies differences (worker): 10
Interspecies variations: 1
Allometric scaling (rat to human): 4
Exposure duration: 6
Dose-response factor: 1
Quality of whole database factor: 1
Overall, an assessment factor of 240 was employed for the dermal route.
DNEL= 50 mg/kg body weight / 240 = 0.21 mg/kg body weight.
Systemic, long-term, oral:
The following assessment factors according to "ECHA guidance on information requirements and chemical safety assessment, Chapter R8" were chosen:
Intraspecies differences (worker): 10
Interspecies variations: 1
Allometric scaling (rat to human): 4
Exposure duration: 6
Dose-response factor: 1
Quality of whole database factor: 1
The overall assessment factor employed for the oral route is therefore 240.
DNEL= 50 mg/kg body weight / 240 = 0.21 mg/kg body weight.
Rationale for omitting "Factor 2.5"
According to ECETOC’s “guidance on Assessment Factors to derive a DNEL, Technical Report No. 110”, the application of a factor of 2.5 for ‘remaining uncertainties’ is unjustified. There is evidence that multiplicative association between inter- and intraspecies assessment factors is overly conservative and that the inclusion of a factor for remaining differences is unnecessary. ECETOC further recommends using allometric scaling and the 5th percentile of the human distribution of intraspecies variability. Consequently, the ‘remaining uncertainty’ for interspecies variability is already accounted for by the intraspecies AF (Calabrese, 1985; Hattis et al 1987). This is further supported by results of the ongoing ERASM project which examines studies in rats and mice to determine interspecies differences based on a probabilistic approach. In their recent publication (Escher, 2013), the authors confirmed the ECETOC position regarding the factor of 2.5 for remaining uncertainties (i. e. the factor does not apply). Therefore, the factor of 2.5 for remaining uncertainties is omitted for this risk assessment.
Literature:
- Calabrese EJ, Uncertainty factors and interindividual variation, Regul Toxicol Pharmacol. 1985 Jun;5(2):190-6.
- Hattis D et al, Human variability in susceptibility to toxic chemicals-a preliminary analysis of pharmacokinetic data from normal volunteers, Risk Anal. 1987 Dec;7(4):415-26.
- Escher SE et al, Interspecies extrapolation based on the RepDose database—A probabilistic approach, Toxicology Letters 218 (2013) 159– 165
Systemic, short-term, dermal, oral and by inhalation
According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose[concentration]-response for human health", a DNEL for acute systemic toxicity should only be derived if an acute systemic toxicity hazard leading to classification is identified. Therefore, because the substance is not classified for acute toxicity according to Directive 67/548/EEC and Regulation 1272/2008/EC, no systemic DNELs for short-term exposures were calculated.
Local, long-term and short-term, dermal and by inhalation
Based on the available key toxicological information, the test item is not subject to classification for irritation and sensitization (according to 67/548/EEC and EC/1272/2008). Accordingly, no DNELs for local effects following acute/short-term or long-term exposure are derived. This is in line with the ECHA guidance document (Chapter R.8).
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