Registration Dossier

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):
75
Modified dose descriptor starting point:
NOAEC
Value:
110.2 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. No data are 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 for remaining interspecies differences
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:
0.42 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):
300
Modified dose descriptor starting point:
NOAEL
Value:
125 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. No data are 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 for remaining interspecies differences
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:

The basis for deriving systemic long-term DNELs is a 28 day oral toxicity study in Wistar rats (Schladt, 1991).

Adverse effects were reported for body weight gain in the 625 mg/kg bw male dose group. In the 625 mg/kg bw dose group significant haematological effects were observed, and increased liver weights together with hypertrophy of hepatocytes were noted for both female and male rats.

The NOAEL is 125 mg/kg/d.

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

The test item is considered not to exhibit any sensitising properties according to a guideline-compliant study under GLP in guinea pigs (Diesing, 1991).

Acute toxicity/local effects:

According to ECHA guidance there is no established accepted methodology to derive no-effect-levels for acute toxicity. Under these prerequisites derivation of acute DNELs is considered not only to be cumbersome and resource-intensive but probably unnecessary, as the long-term DNEL is normally sufficient to safeguard against any acute effects. It is proposed that a DNEL for acute toxicity should be derived only if an acute toxicity hazard (leading to C&L) is identified and there is a potential for high peak exposures. However, the test item is not classified for acute toxicity based on LD50 > 2000 mg/kg for the oral and dermal route (Bomhard, 1990/1991).

Data on skin irritation/corrosion and eye irritation in vivo suggest a low hazard potential with regard to local effects (Märtins, 1991).

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:
0.36 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):
150
Modified dose descriptor starting point:
NOAEC
Value:
54.35 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. No data are 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 for remaining interspecies differences
AF for intraspecies differences:
10
Justification:
Default for 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:
0.21 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):
600
Modified dose descriptor starting point:
NOAEL
Value:
125 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. No data are 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 for remaining interspecies differences
AF for intraspecies differences:
10
Justification:
Default for 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:
no hazard identified
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:

The basis for deriving systemic long-term DNELs is a 28 day oral toxicity study in Wistar rats (Schladt, 1991).

Adverse effects were reported for body weight gain in the 625 mg/kg bw male dose group. In the 625 mg/kg bw dose group significant haematological effects were observed, and increased liver weights together with hypertrophy of hepatocytes were noted for both female and male rats.

The NOAEL is 125 mg/kg/d.

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

The test item is considered not to exhibit any sensitising properties according to a guideline-compliant study under GLP in guinea pigs (Diesing, 1991).

Acute toxicity/local effects:

According to ECHA guidance there is no established accepted methodology to derive no-effect-levels for acute toxicity. Under these prerequisites derivation of acute DNELs is considered not only to be cumbersome and resource-intensive but probably unnecessary, as the long-term DNEL is normally sufficient to safeguard against any acute effects. It is proposed that a DNEL for acute toxicity should be derived only if an acute toxicity hazard (leading to C&L) is identified and there is a potential for high peak exposures. However, the test item is not classified for acute toxicity based on LD50 > 2000 mg/kg for the oral and dermal route (Bomhard, 1990/1991).

Data on skin irritation/corrosion and eye irritation in vivo suggest a low hazard potential with regard to local effects (Märtins, 1991).

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