Registration Dossier
Registration Dossier
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EC number: 220-150-2 | CAS number: 2643-07-4
Toxicological Summary
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Acute/short term exposure
DNEL related information
Local effects
Acute/short term exposure
DNEL related information
Workers - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DMEL (Derived Minimum Effect Level)
- Value:
- 10 µg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 300
- Modified dose descriptor starting point:
- NOAEL
Acute/short term exposure
DNEL related information
Local effects
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 20 µg/cm²
- Most sensitive endpoint:
- sensitisation (skin)
DNEL related information
- Overall assessment factor (AF):
- 10
Workers - Hazard for the eyes
Additional information - workers
Due to the toxicological profile and the physico-chemical properties of the test substance, only the dermal route is a relevant route of exposure for human workers. Therefore, the dermal DNEL for local effects derived from a skin sensitisation study in mice (LLNA) and the dermal DNEL for systemic effects derived from a 28-day oral repeated dose study in rats are considered sufficient to ensure the safety of human workers.
Acute / short-term exposure - local effects:
An induction-specific DNEL was derived for skin sensitisation based on the EC3 value from a LLNA study (BASF SE, 2010). The sensitisation threshold (EC3 value) was reported to be 0.8% w/w, indicative of a sensitiser of strong potency. According to the Guidance on information requirements and chemical safety assessment, Chapter R.8, the EC3 value (in mg/cm²) can be used as a surrogate for the NOAEL for induction.
Therefore the EC3 (%) was converted to the EC3 (µg/cm²) using the formula
EC3 (%) x 250 (µg/cm²/%) = EC3 (µg/cm²) = 0.8 x 250 = 200 µg/cm².
EC3 data generally correlate well with human skin sensitisation thresholds. However, there are cases where this correlation is poor and the two values may differ by 10-fold or more. Therefore, using the default AF of 10 for interspecies variation, the acute dermal DNEL was calculated to be 20 µg/cm² = 0.020 mg/cm².
Long-term exposure – systemic effects:
Due to the severe toxic effects of the substance (mutagenic in all available in vitro genotoxicity tests, potentially carcinogenic) a DMEL has been derived. Due to the physicochemical properties of the substance the dermal route is the only relevant exposure route for workers.
Due to the existing database for this substance (lack of a carcinogenicity study) the dermal DMEL after long-term exposure was derived based on the NOAEL value in female rats from a subacute (28 days) repeated dose toxicity study by oral application (BASF SE, 2010). In this study,the oral administration ofthe test substanceby gavage over a period of 4 weeks caused incipient signs of general systemic toxicity at dose levels of 10 mg/kg bw/d in female animals (clinicochemical parameters:decreased total protein and calcium levels) and 40 mg/kg bw/d in both genders.Therefore,under the conditions of the present studytheNOAEL was2.5 mg/kg bw/din female and 10 mg/kg bw/d in male Wistar rats.
The NOAEL of 2.5 mg/kg body weight in female animals which was taken as relevant dose descriptor for systemic effects after long-term exposure has been modified in order to get the correct starting point for dermal DNEL derivation:
In the first step, a route-to-route extrapolation within the species rat was performed. The oral rat NOAEL was converted into the dermal rat NOAEL on the assumption that, in general, dermal absorption will not be higher than oral absorption (i.e. factor 1). The resulting corrected starting point for dermal DNEL derivation is equal to 2.5 mg/kg body weight.
The following assessment factors (AF) were applied to the correct starting point:
Interspecies variation:
An allometric scaling factor of 4 for interspecies extrapolation (rat to man) was recognised by default. Since incipient signs of general systemic toxicity at dose levels as low as 10 mg/kg bw/d in female animals (clinicochemical parameters) and 40 mg/kg bw/d in both genders were the relevant adverse clinical finding in this study, and due to the otherwise severe toxicological profile of the substance (toxic if swallowed, harmful in contact with skin, irritating to skin, may cause sensitisation by skin contact, danger of serious damage to health by prolonged exposure if swallowed, mutagenic) an additional assessment factor of 2.5 for remaining differences in interspecies variation was applied.
Intraspecies variation:
The intraspecies variation among human workers was recognised by an assessment factor of 5 by default.
Exposure duration:
An assessment factor of 6 was used for extrapolation of exposure duration from sub-acute (28-day study) to chronic by default.
Dose-response:
An assessment factor of 1 was used by default.
Quality of whole database:
An assessment factor of 1 was used by default.
Accordingly, an overall assessment factor of 300 was calculated based on the recommendations given in the Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, May 2008, Figure R.8-6, p. 38) and based on the above mentioned arguments. Thus, the dermal DMEL for long-term exposure was calculated as follows:
Dermal DMEL long-term exposure – systemic effects = corrected dermal NOAEL / Overall AF = 2.5 mg/kg body weight / 300 = 0.0083 = approx. 0.01 mg/kg body weight.
General Population - Hazard via inhalation route
Systemic effects
Acute/short term exposure
DNEL related information
Local effects
Acute/short term exposure
DNEL related information
General Population - Hazard via dermal route
Systemic effects
Acute/short term exposure
DNEL related information
General Population - Hazard via oral route
Systemic effects
Acute/short term exposure
DNEL related information
General Population - Hazard for the eyes
Additional information - General Population
Exposure to the general population is not expected, and therefore a DNEL and/or DMEL has not been established.
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