Registration Dossier
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EC number: 265-512-0 | CAS number: 65140-91-2
Toxicological Summary
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 3 mg/m³
DNEL related information
- DNEL derivation method:
- other: The general exposure limit for inhalable dust is applied
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 1 mg/m³
DNEL related information
- DNEL derivation method:
- other: see discussion
Acute/short term exposure
- Hazard assessment conclusion:
- hazard unknown (no further information necessary)
DNEL related information
Workers - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 6 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):
- 14
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 84.1 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
The test substance was analyzed in several repeated dose toxicity studies by the oral route. The 90-day toxicity study performed in Beagle dogs was chosen as the most relevant for safety assessment. In this study, groups of six male and female dogs were treated with the test article continuously in feed. No treatment-related adverse effects have been observed up to the highest dose tested, thus a NOAEL of 84.1 (males) and 90.2 mg/kg body weight per day (females), was established. For derivation of DNELs, the lower value of 84.1 mg/kg was selected as calculation starting point.
Calculation of DNELs
Systemic, long-term, inhalative
According to "ECHA guidance on information requirements and chemical safety assessment, Chapter R8", the systemic DNEL for the inhalation route is derived by route to route extrapolation if no data for the inhalation exposure is available. Calculation of the DNEL following the method and assessment factors described, would result in a DNEL above the general exposure limit for dust. For such cases the ECHA guideline suggests that the general exposure limit shall be applied, especially for non-soluble dusts. For significantly soluble dusts this limit might be relevant as well. The test substance is fairly soluble in water, however no data on absorption after inhalation is available. Therefore toxicological effects related to lung clearance overload (as caused by non-soluble dusts) cannot be completely ruled out and consequently the general exposure limit for dust is applied. Since particle size distribution analysis revealed that the test article is in the respirable range, the general exposure limit of 3 mg/m3 for inhalable dust is applied. However, the test substance is classified for respiratory irritation. The threshold dose for this local effect is not known, it is possible that threshold might be rather low, thereby limiting the systemic dose. To protect against, the DNEL for this effect was set at 1 mg/m3(see below).
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 penetration through skin are available, 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 (dog to human): 1.4
Exposure duration: 2
Oral to dermal route extrapolation factor: 1
Dose-response factor: 1
Quality of whole database factor: 1
Overall, an assessment factor of 14 was employed for the dermal route.
DNEL= 84.1 mg/kg body weight / 14 = 6 mg/kg body weight.
Factor 2.5 rationale
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 inhalative
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, inhalative
The test article was found to be not irritating to skin and eyes in animal studies. In addition, no respiratory irritation potential was observed in an acute inhalation study. However, some isolated cases of respiratory irritation were reported in human workers in the production facility. As a result, risk management measures were implemented and exposure to the substance was strictly controlled at 1 mg/m3. Recent measurements at the industrial site confirmed that the concentration of substance is below this internal exposure level. Since no further cases of respiratory irritation have been reported after these safety measure were in place, the level of 1 mg/m3 is considered as sufficient to protect from this effect and considered as the DNEL for further risk assessment.
Local, short-term, inhalative
It is not known what level of short-term exposure might trigger respiratory irritation in humans. However, since the long-term exposure limit of 1mg/m3 is protective of this local effect (see above), it is concluded that this limit should also protect for short term exposure, given that extreme peak exposures can be avoided.
Local, long-term and short-term, dermal
Based on the available key toxicological information, the test item is not subject to classification for skin and eye irritation and skin 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:
- no hazard identified
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:
- 3 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):
- 28
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 84.1 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
- Since no data for the dermal route was available, a route to route extrapolation was performed
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:
- 3 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):
- 28
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 84.1 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
The dose descriptor chosen is the same as for workers (see above). The NOAEL of 84.1 mg/kg observed in the oral 90-day repeated dose study in dogs was used as starting point to derive the DNELs.
Calculation of DNELs
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 penetration through skin are available, 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): 1.4
Exposure duration: 2
Oral to dermal route extrapolation factor: 1
Dose-response factor: 1
Quality of whole database factor: 1
Overall, an assessment factor of 28 was employed for the dermal route.
DNEL= 84 mg/kg body weight / 28 = 3 mg/kg body weight.
Systemic, long-term, oral:
The NOAEL of 84.1 mg/kg body weight observed in the oral 90-day repeated dose study in dogs was used as starting point to derive the DNELs. 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): 1.4
Exposure duration: 2
Dose-response factor: 1
Quality of whole database factor: 1
The overall assessment factor employed for the inhalation route is therefore 28.
DNEL = 84 mg/kg body weight / 28 = 3 mg/kg body weight
Factor 2.5 rationale
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 and Local, short term and long-term, inhalative
The pure, dusty product is neither intended for use by the general population nor are there any possible use scenarios that might be of interest to the general population. The chemical is embedded in polymer and plastic materials at low concentrations. Based on the very low vapor pressure, evaporation from these materials is not possible. Therefore, no inhalative DNELs for the general population need to be derived.
Systemic, short-term, dermal and oral
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
Based on the available key toxicological information, the test item is not subject to classification for skin and eye irritation and skin 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).
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.
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