Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
944.55 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA factors in combination with recent scientific literature
Overall assessment factor (AF):
8.4
Modified dose descriptor starting point:
NOAEC
DNEL value:
7 934 mg/m³
Explanation for the modification of the dose descriptor starting point:
A key oral 90-day toxicity study is available; there was no repeated-dose inhalation toxicity study.
AF for dose response relationship:
1
Justification:
Different doses were tested in the various studies, therefore no additional factor is used.
AF for differences in duration of exposure:
1.4
Justification:
Extrapolation from subchronic to chronic; see justification attached.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is already applied in route-to-route extrapolation.
AF for other interspecies differences:
1
Justification:
No toxicodynamic differences between species; see justification attached.
AF for intraspecies differences:
2.4
Justification:
Refined assessment of population differences; see justification attached.
AF for the quality of the whole database:
1
Justification:
Results were based on key Klimisch 1-2 studies (and possible supporting studies).
AF for remaining uncertainties:
2.5
Justification:
For remaining uncertainties that would result from the above assessment factors.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
669.64 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA factors in combination with recent scientific literature
Overall assessment factor (AF):
33.6
Modified dose descriptor starting point:
NOAEL
DNEL value:
22 500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
A key oral 90-day toxicity study is available; there was no repeated-dose dermal toxicity study.
AF for dose response relationship:
1
Justification:
Different doses were tested in the various studies, therefore no additional factor is used.
AF for differences in duration of exposure:
1.4
Justification:
Extrapolation from subchronic to chronic; see justification attached.
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
No toxicodynamic differences between species; see justification attached.
AF for intraspecies differences:
2.4
Justification:
Refined assessment of population differences; see justification attached.
AF for the quality of the whole database:
1
Justification:
Results were based on key Klimisch 1-2 studies (and possible supporting studies).
AF for remaining uncertainties:
2.5
Justification:
For remaining uncertainties that would result from the above assessment factors.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

Source information for DNELS:

- A key oral 28-day dietary toxicity with registered substance (test item containing 35% active ingredient) in rats was performed at systemic dose levels of 0.05, 0.25 and 1.25% in the diet (as solids), corresponding to 48, 254 and 1225 mg act.ingr./kg bw/day. There were no adverse effects observed, therefore the dose of 1225 mg/kg can be considered as NOAEL.

- Oral 90-day dietary toxicity studies with registered substance (test item containing 35% active ingredient) were performed in rats at systemic dose levels of 0.5, 2 and 8 (reduced to 4) g act. ingr./kg bw/day (key study) and in dogs at 0.062, 0.250 and 1 g act. ingr. /kg bw/day (supporting study) . In rats, 2 and 8 (4) g act.ingr./kg bw/day were toxic, as demonstrated by decreased body weight and food consumption, serum changes, organ-to-body weight decreases and renal disease; the dose of 500 mg/kg bw/day can be considered as NOAEL. The dog study was considered to be less appropriate as the animals were very young and sensitive to gastro-intestinal irritation, although the study did not show systemic toxicity up to 1000 mg/kg bw/day.

- A justification for calculation of DNELs is attached.

Qualitative assessment
Only systemic long term exposure values for worker and general population were calculated, because no concrete values (like NOAEL, LOAEL etc) are available from acute or irritation studies. The study design of the test conducted assessing the acute and local toxicity does not allow in general the derivation of local or acute DNELs, as most of the tests were, for example, conducted as limit tests due to animal welfare. Therefore a qualitative risk assessment for irritation is performed.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
279.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA and ERASM factors
Overall assessment factor (AF):
14
Modified dose descriptor starting point:
NOAEC
DNEL value:
3 913 mg/m³
Explanation for the modification of the dose descriptor starting point:
A key oral 90-day toxicity study is available; there was no repeated-dose inhalation toxicity study.
AF for dose response relationship:
1
Justification:
Different doses were tested in the various studies, therefore no additional factor is used.
AF for differences in duration of exposure:
1.4
Justification:
Extrapolation from subchronic to chronic; see justification attached.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is already applied in route-to-route extrapolation.
AF for other interspecies differences:
1
Justification:
No toxicodynamic differences between species; see justification attached.
AF for intraspecies differences:
4
Justification:
Refined assessment of population differences; see justification attached.
AF for the quality of the whole database:
1
Justification:
Results were based on key Klimisch 1-2 studies (and possible supporting studies).
AF for remaining uncertainties:
2.5
Justification:
For remaining uncertainties that would result from the above assessment factors.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
401.79 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA factors in combination with recent scientific literature
Overall assessment factor (AF):
56
Modified dose descriptor starting point:
NOAEL
DNEL value:
22 500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
A key oral 90-day toxicity study is available; there was no repeated-dose dermal toxicity study.
AF for dose response relationship:
1
Justification:
Different doses were tested in the various studies, therefore no additional factor is used.
AF for differences in duration of exposure:
1.4
Justification:
Extrapolation from subchronic to chronic; see justification attached.
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
No toxicodynamic differences between species; see justification attached.
AF for intraspecies differences:
4
Justification:
Refined assessment of population differences; see justification attached.
AF for the quality of the whole database:
1
Justification:
Results were based on key Klimisch 1-2 studies (and possible supporting studies).
AF for remaining uncertainties:
2.5
Justification:
For remaining uncertainties that would result from the above assessment factors.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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:
8.93 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA factors in combination with recent scientific literature
Overall assessment factor (AF):
56
Modified dose descriptor starting point:
NOAEL
DNEL value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Not applicable
AF for dose response relationship:
1
Justification:
Different doses were tested in the various studies, therefore no additional factor is used.
AF for differences in duration of exposure:
1.4
Justification:
Extrapolation from subchronic to chronic; see justification attached.
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
No toxicodynamic differences between species; see justification attached.
AF for intraspecies differences:
4
Justification:
Refined assessment of population differences; see justification attached.
AF for the quality of the whole database:
1
Justification:
Results were based on key Klimisch 1-2 studies (and possible supporting studies).
AF for remaining uncertainties:
2.5
Justification:
For remaining uncertainties that would result from the above assessment factors.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

Source information for DNELS:

- A key oral 28-day dietary toxicity with registered substance (test item containing 35% active ingredient) in rats was performed at systemic dose levels of 0.05, 0.25 and 1.25% in the diet (as solids), corresponding to 48, 254 and 1225 mg act.ingr./kg bw/day. There were no adverse effects observed, therefore the dose of 1225 mg/kg can be considered as NOAEL.

- Oral 90-day dietary toxicity studies with registered substance (test item containing 35% active ingredient) were performed in rats at systemic dose levels of 0.5, 2 and 8 (reduced to 4) g act. ingr./kg bw/day (key study) and in dogs at 0.062, 0.250 and 1 g act. ingr. /kg bw/day (supporting study) . In rats, 2 and 8 (4) g act.ingr./kg bw/day were toxic, as demonstrated by decreased body weight and food consumption, serum changes, organ-to-body weight decreases and renal disease; the dose of 500 mg/kg bw/day can be considered as NOAEL. The dog study was considered to be less appropriate as the animals were very young and sensitive to gastro-intestinal irritation, although the study did not show systemic toxicity up to 1000 mg/kg bw/day.

- A justification for calculation of DNELs is attached.

Qualitative assessment
Only systemic long term exposure values for worker and general population were calculated, because no concrete values (like NOAEL, LOAEL etc) are available from acute or irritation studies. The study design of the test conducted assessing the acute and local toxicity does not allow in general the derivation of local or acute DNELs, as most of the tests were, for example, conducted as limit tests due to animal welfare. Therefore a qualitative risk assessment for irritation is performed.