Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.3 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):
75
Dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
22.1 mg/m³
Explanation for the modification of the dose descriptor starting point:

Most sensitive endpoint: the NOAEL for a combined repeated dose oral toxicity study with the reproduction/developmental toxicity screening test was considered to be 25 mg/kg/day for males and females.

The NOAEL for repeated dose toxicity was considered to be 25 mg/kg/bw.

--> correct to worker, 8h inhalation:

NOAEC = 25 * (1/ 0.38) * (6.7 / 10) = 44.1 mg/m3

--> in the absence of information on gastro-intestinal absorption an assessment factor of 2, default value for oral-to-inhalation extrapolation has to be applied:

NOAEC = 44.1/ 2 = 22.1 mg/m3

AF for dose response relationship:
1
Justification:
No assessment factor required
AF for differences in duration of exposure:
6
Justification:
ECHA REACH standard AF for sub-acute to chronic extrapolation
AF for interspecies differences (allometric scaling):
1
Justification:
Not used for inhalation results
AF for other interspecies differences:
2.5
Justification:
ECHA standard AF for "differences not related to calorimetric differences"
AF for intraspecies differences:
5
Justification:
ECHA REACH standard AF for intraspecies differences to workers (ECHA Guidance R8)
AF for the quality of the whole database:
1
Justification:
No additional assessment factor required, sufficient data of good quality available
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.8 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):
12.5
DNEL extrapolated from long term DNEL
Dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
22.1 mg/m³
Explanation for the modification of the dose descriptor starting point:

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 (ECHA R.8).

The median lethal dose of the test item after a single oral administration to female rats, observed

over a period of 14 days is a LD50 cut-off (rat) of 200 mg/kg bw and the test substance has an obligatory labelling requirement for toxicity and is classified into Category 3.

However the LD50 does not provide sufficient information on sub-lethal toxicity at lower doses. Therefore as a starting point the most sensitive endpoint, the NOAEL for a combined repeated dose oral toxicity study with the reproduction/developmental toxicity screening test with 25 mg/kg/day for males and females, was considered.

--> time scaling needed ?(correct to worker, 15 min inhalation)

NOAEC = 25 * (1/ 0.38) * (6.7 / 10) = 44.1 mg/m3

--> in the absence of information on gastro-intestinal absorption an assessment factor of 2, default value for oral-to-inhalation extrapolation has to be applied:

NOAEC = 44.1/ 2 = 22.1 mg/m3

AF for dose response relationship:
1
Justification:
No assessment factor required
AF for interspecies differences (allometric scaling):
1
Justification:
No assessment factor required
AF for other interspecies differences:
2.5
Justification:
ECHA standard AF for "differences not related to calorimetric differences"
AF for intraspecies differences:
5
Justification:
ECHA REACH standard AF for intraspecies differences to workers (ECHA Guidance R8)
AF for the quality of the whole database:
1
Justification:
No additional assessment factor required, sufficient data of good quality available
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties

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:
0.08 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
Dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

25 mg/kg bw/d taken from the combined repeated oral dose toxicity study with the reproduction/

developmental toxicity screening in rats (oral administration).

Assuming 50% oral absorption according to R.7.12.2.4 (p. 179).

Assuming 50% dermal absorption.

AF for dose response relationship:
1
Justification:
No assessment factor required.
AF for differences in duration of exposure:
6
Justification:
ECHA REACH standard AF for sub-acute to chronic extrapolation
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA REACH standard AF for rat to human extrapolation
AF for other interspecies differences:
2.5
Justification:
ECHA REACH standard AF for "differences not related to calorimetric differences"
AF for intraspecies differences:
5
Justification:
ECHA REACH standard AF for intraspecies differences to workers
AF for the quality of the whole database:
1
Justification:
No issues with the quality of the data base
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.07 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
Dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
10.87 mg/m³
Explanation for the modification of the dose descriptor starting point:

25 mg/kg bw/d taken from the combined repeated oral dose toxicity study with the reproduction/

developmental toxicity screening in rats (oral administration).

In the absence of information on oral absorption the assessment factor of 2, default value for oral-to inhalation

extrapolation is considered.

AF for dose response relationship:
1
Justification:
No assessment factor required
AF for differences in duration of exposure:
6
Justification:
ECHA REACH standard AF for sub-acute to chronic extrapolation
AF for interspecies differences (allometric scaling):
1
Justification:
Not used for oral results
AF for other interspecies differences:
2.5
Justification:
ECHA REACH standard AF for "differences not related to calorimetric differences"
AF for intraspecies differences:
10
Justification:
ECHA REACH standard AF for the general population
AF for the quality of the whole database:
1
Justification:
no remaining uncertainties identified
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties 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:
0.042 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
Dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

25 mg/kg bw/d taken from the combined repeated oral dose toxicity study with the reproduction/

developmental toxicity screening in rats (oral administration).

Assuming 50% oral absorption according to R.7.12.2.4 (p. 179).

Assuming 50% dermal absorption.

AF for dose response relationship:
1
Justification:
No assessment factor required
AF for differences in duration of exposure:
6
Justification:
ECHA REACH standard AF for sub-acute to chronic extrapolation
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA REACH standard AF for rat to human extrapolation
AF for other interspecies differences:
2.5
Justification:
ECHA REACH standard AF for "differences not related to calorimetric differences"
AF for intraspecies differences:
10
Justification:
ECHA REACH default AF for the general population
AF for the quality of the whole database:
1
Justification:
no issues with the quality of the database
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

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 (ECHA R.8). However, the substance does not need to be classified.

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.042 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
Dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No modification ot the dose descriptor required.

AF for dose response relationship:
1
Justification:
No assessment factor required
AF for differences in duration of exposure:
6
Justification:
ECHA REACH standard AF for sub-acute to chronic extrapolation
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA REACH standard AF for rat to human extrapolation
AF for other interspecies differences:
2.5
Justification:
ECHA REACH standard AF for "differences not related to calorimetric differences"
AF for intraspecies differences:
10
Justification:
ECHA REACH default AF for the general population
AF for the quality of the whole database:
1
Justification:
no issues with the quality of the database
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties identified
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population