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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3 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):
50
Modified dose descriptor starting point:
NOAEC
Value:
151.1 mg/m³
Explanation for the modification of the dose descriptor starting point:
No data by inhalation is available, therefore, 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
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.6 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):
17.5
Modified dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No data by the dermal route is available, therefore, 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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Identification of relevant dose descriptor

The most relevant study for hazard assessment was considered to be the one-generation study in mice. The subacute oral toxicity study in rats was not considered adequate because of the rat-specific effects on the liver-thyroid axis (for more details see also chapter 7.5). Mice proved to be much less sensitive and showed adaptive effects on liver with a NOAEL of 150 mg/kg body weight for exposure for 12-18 weeks. Both liver and thyroid, the target organs identified in the rat study, were investigated in the one-generation study, therefore adequate information for assessment is provided. Consequently, the NOAEL of 150 mg/kg body weight obtained in the one-generation study was used as point of departure for DNEL calculations. This is in line with the results obtained with the structurally related compound CAS 2082-79-3. Here, chronic treatment resulted in increases in liver and thyroid weights in rats but not in mice, with NOAELs of 64 and 54 mg/kg body weight, respectively. These studies do not only confirm the rat specific mode of action of this substance class, they also confirm the level of toxicity with NOAELs in the same range, taking the longer exposure period into account. The NOAEL of 150 mg/kg obtained in the 1-gen study in mice is therefore considered adequate for hazard assessment.

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. Based on the available dermal absorption data, only minimal amounts of test substance penetrate the skin (4.42 % after 6 h dermal exposure). For further risk assessment, an additional factor of 0.1 is applied. 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: 2.5

Allometric scaling (mouse to human): 7

Exposure duration: 2 (12 -18 weeks)

Oral to dermal route extrapolation factor: 0.1

Dose-response factor: 1

Overall, an assessment factor of 17.5 was employed for the dermal route.

DNEL= 150 mg/kg body weight / 17.5 = 8.57 mg/kg body weight.

 

Systemic, long-term, inhalative

According to ECHA guidelines, a route to route extrapolation is performed if no information by inhalation is available. Following ECHA guidance document Chapter R.8 the NOAEL (oral) has to be adjusted for differences in respiratory volume for test animals (mice) and humans and corrected for activity driven differences of respiratory volumes in workers compared to workers in rest, resulting in a corrected starting point of 151.1 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: 2.5

Exposure duration: 2 (12 -18 weeks)

Default factor to account for differences in oral and inhalative absorption properties: 2

Dose-response factor: 1

The overall assessment factor employed for the inhalation route is therefore 50.

DNEL = 151.1 mg/m3/ 50 = 3.0 mg/m3

 

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 and short-term, inhalative and 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:
DNEL (Derived No Effect Level)
Value:
0.74 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):
100
Modified dose descriptor starting point:
NOAEC
Value:
74.4 mg/m³
Explanation for the modification of the dose descriptor starting point:
No data by inhalation is available, therefore, 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
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.3 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):
35
Modified dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No data by the dermal route is available, therefore, 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:
0.43 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):
350
Modified dose descriptor starting point:
NOAEL
Value:
150 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 NOAEL of 150 mg/kg obtained in the 1-generation study was used as point of departure for DNEL calculations (see above).

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. Based on the available dermal absorption data, only minimal amounts of test substance penetrate the skin (4.42 % after 6 h dermal exposure). For further risk assessment, an additional factor of 0.1 for dermal absorption is applied. 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: 2.5

Allometric scaling (mouse to human): 7

Exposure duration: 2 (12-18 weeks)

Oral to dermal route extrapolation factor: 0.1

Dose-response factor: 1

Overall, an assessment factor of 35 was employed for the dermal route.

DNEL= 150 mg/kg body weight / 35 = 4.3 mg/kg body weight.

Systemic, long-term, inhalative

Because no inhalation study is available, a route to route extrapolation was performed. The NOAEL (oral) has to be adjusted into a NOAEL (corrected) based on differences in respiratory volumes for test animals (mice) and humans in accordance to guidance on information requirements and chemical safety assessment, Chapter R.8, ECHA, May 2008. The corrected starting point here is 74.4 mg/m3 per day. 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 (general population): 10

Interspecies variations: 2.5

Exposure duration: 2 (12-18 weeks)

Dose-response factor: 1

Default factor to account for differences in oral and inhalative absorption properties: 2

The overall assessment factor employed for the inhalation route is therefore 100.

DNEL = 74.4 mg/m3/ 100 = 0.74 mg/m3

Systemic, long-term, oral:

The NOAEL of 150 mg/kg body weight observed in the 1-gen study in rats was used as starting point for DNEL derivation. 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: 2.5

Allometric scaling (mouse to human): 7

Exposure duration: 2 (12-18 weeks)

Dose-response factor: 1

Overall, an assessment factor of 350 was employed for the dermal route.

DNEL= 150 mg/kg body weight / 350 = 0.43 mg/kg body weight.

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 and short-term, inhalative and 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).