Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.35 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):
75
Modified dose descriptor starting point:
NOAEC
Value:
176 mg/m³
Explanation for the modification of the dose descriptor starting point:
No long-term study on inhalation is available. Thus route-to-route extrapolation has been performed. There is no data available that would indicate a specific concern for the inhalation route, that would invalidate this approach.
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
Difference in duration subacute to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable (accounted for by respiratory volumes)
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
5
Justification:
default for worker
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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:
0.67 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:
200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No dermal long-term study is available. Thus route-to-route extrapolation has been performed. There is no data available that would indicate a specific concern for the dermal route, that would invalidate this approach.
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
Difference in duration subacute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Default (rat)
AF for other interspecies differences:
2.5
Justification:
Default
AF for intraspecies differences:
5
Justification:
Default (worker)
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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

Repeated dose toxicity & systemic effects:

Base for deriving systemic long-term DNELs is a 28 day oral toxicity study in SD rats (Kauffmann, 2003). The test item was well tolerated and resulted in no deaths or severe clinical symptoms. Neurotoxicological examination, hematology and clinical chemistry values as well as urinalysis and histopathological investigation showed no substance related or biologically relevant alterations in all dose groups. Animals in the high dose group (800 mg/(kg/d) showed squatting posture and/or stilted gait at the end of the treatment period. Female animals of the high dose group showed additionally slightly reduced body weight gains during the treatment period (14 %), slightly decreased absolute liver weights as well as slightly increased relative spleen weights. However, these changes were reversible and normalized after the recovery period. The NOAEL is 200 mg/kg bw/day, the LOAEL is 800 mg/kg/d.

There is no data available that would indicate a specific concern for the inhalation and dermal route. Thus, route-to-route extrapolation is justified. ECHA guidance values have been used for accounting possible differences in the route-specific absorption rates (dermal = oral and inhalation = 200% oral).

The test item is considered not to have any sensitizing properties in a GLP guideline study in guinea pigs.

Acute toxicity & local effects:

According to ECHA guidance there is no established accepted methodology to derive no-effect-levels for acute toxicity. It is considered not only cumbersome and resource-intensive but probably unnecessary, as the long-term DNEL is normally sufficient to ensure that effects do not occur. It is proposed that a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential for high peak exposures. The test item is not classified for acute toxicity based on a LD50> 2000 mg/kg/d for the oral and dermal route.

Data on skin irritation/corrosion and eye irritation in vivo suggest a low hazard potential with regards to local effects.

The test substance led to persistent discoloration of conjunctivae, which resulted in classification of "potential risk of serious damage to eyes" according to the classification criteria of Directive 2001/59/EC. However, the irreversible discoloration of the conjunctiva is not considered an adverse effect according to Regulation (EC) 1272/2008, as this discoloration does not lead to an impaired sight

Overall, a low hazard potential is concluded for the test item. 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.58 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):
150
Modified dose descriptor starting point:
NOAEC
Value:
86.96 mg/m³
Explanation for the modification of the dose descriptor starting point:
No long-term study on inhalation is available. Thus route-to-route extrapolation has been performed. There is no data available that would indicate a specific concern for the inhalation route, that would invalidate this approach.
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
Difference in duration subacute to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable (accounted for by respiratory volumes)
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
Justification:
Default (general population)
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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:
0.33 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):
600
Modified dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No dermal long-term study is available. Thus route-to-route extrapolation has been performed. There is no data available that would indicate a specific concern for the dermal route, that would invalidate this approach.
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
Difference in duration subacute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Default (rat)
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
Justification:
Default (general population)
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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:
0.33 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):
600
Modified dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
Difference in duration subacute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Default (rat)
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
Justification:
Default (general population)
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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

Repeated dose toxicity & systemic effects:

Base for deriving systemic long-term DNELs is a 28 day oral toxicity study in SD rats (Kauffmann, 2003). The test item was well tolerated and resulted in no deaths or severe clinical symptoms. Neurotoxicological examination, hematology and clinical chemistry values as well as urinalysis and histopathological investigation showed no substance related or biologically relevant alterations in all dose groups. Animals in the high dose group (800 mg/(kg/d) showed squatting posture and/or stilted gait at the end of the treatment period. Female animals of the high dose group showed additionally slightly reduced body weight gains during the treatment period (14 %), slightly decreased absolute liver weights as well as slightly increased relative spleen weights. However, these changes were reversible and normalized after the recovery period. The NOAEL is 200 mg/kg bw/day, the LOAEL is 800 mg/kg/d.

There is no data available that would indicate a specific concern for the inhalation and dermal route. Thus, route-to-route extrapolation is justified. ECHA guidance values have been used for accounting possible differences in the route-specific absorption rates (dermal = oral and inhalation = 200% oral).

The test item is considered not to have any sensitizing properties in a GLP guideline study in guinea pigs.

Acute toxicity & local effects:

According to ECHA guidance there is no established accepted methodology to derive no-effect-levels for acute toxicity. It is considered not only cumbersome and resource-intensive but probably unnecessary, as the long-term DNEL is normally sufficient to ensure that effects do not occur. It is proposed that a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential for high peak exposures. The test item is not classified for acute toxicity based on a LD50> 2000 mg/kg/d for the oral and dermal route.

Data on skin irritation/corrosion and eye irritation in vivo suggest a low hazard potential with regards to local effects.

The test substance led to persistent discoloration of conjunctivae, which resulted in classification of "potential risk of serious damage to eyes" according to the classification criteria of Directive 2001/59/EC. However, the irreversible discoloration of the conjunctiva is not considered an adverse effect according to Regulation 1272/2008, as this discoloration does not lead to an impaired sight

Overall, a low hazard potential is concluded for the test item.