Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.05 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
DNEL value:
78.95 mg/m³
Explanation for the modification of the dose descriptor starting point:
The oral NOAEL of 30 mg/kg bw/d is converted to a NOAEC by dividing by 0.38 according to ECHA Guidance
AF for dose response relationship:
1
Justification:
NOAEC is used as a starting point
AF for differences in duration of exposure:
6
Justification:
based on an oral 28 days oral study
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is not applied in the derivation of inhalation
AF for other interspecies differences:
2.5
Justification:
no substance specific data are available.
AF for intraspecies differences:
5
Justification:
for workers the default factor of 5 is used
AF for the quality of the whole database:
1
Justification:
Available data from substance fulfilling scientific principle is used
AF for remaining uncertainties:
1
Justification:
No further uncertainties to be taken into account
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.05 mg/m³
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:
0.1 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
DNEL value:
30 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
oral to dermal
AF for dose response relationship:
1
Justification:
NOAEL is used as a starting point.
AF for differences in duration of exposure:
6
Justification:
based on an oral 28-day study
AF for interspecies differences (allometric scaling):
4
Justification:
rats are used in the animal test.
AF for other interspecies differences:
2.5
Justification:
no substance-specific data are available.
AF for intraspecies differences:
5
Justification:
for worker, a default AF of 5 is to be used.
AF for the quality of the whole database:
1
Justification:
Available data from substance fulfilling scientific principle is used . AF for remaining uncertainties 1 Justification no other uncertainties needed to be considered.
AF for remaining uncertainties:
1
Justification:
no other uncertainties needed to be considered.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.1 mg/kg bw/day
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

Though it is not conclusive if inhalation is a likely route of exposure to workers, the corresponding DNEL has been derived.

As there is no quantitative data available for dermal absorption of test article, a worst case scenario is assumed in which the absorption rate from dermal route is considered to be same as oral route, and for both routes assumed to be 100%.

As basis for DNEL derivation the result from a 28 -day oral toxicity study with rats was used, performed by Chemicals Evaluation and Research Institute, Japan, Hita Laboratory in 2014. The study has been completed in the course of registration to the US EPA.

This study was a confirmatory test based on previous same 28-day oral study (study number B11-0836) in which toxic effect was observed at 25 mg/kg/day dosage. The aim was to confirm the presence or absence of the toxic effects at 30 mg/kg/day and reproducibility of the test results.

The confirmatory study was carried out according to OECD guideline and GLP principles. Control: CD(SD) rats were orally administrated at doses of 0, 30, and 120 mg/kg/day for 28 consecutive days. The NOAEL of test item was 30 mg/kg/day under the conditions tested since adverse effects were not noted in the 30 mg/kg/day group.

Based on the above description, the basis for the DNEL therefore is this oral NOAEL (30 mg/kg bw/day), and NOAELcorr for the dermal route is still 30 mg/kg.bw/day. According to ECHA guidance document the oral NOAEL is converted to an inhalative NOAECWorker by dividing through 0.38 m3/kg resulting in a NOAEC of 78.95 mg/m3.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.17 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
DNEL value:
26.09 mg/m³
Explanation for the modification of the dose descriptor starting point:
The oral NOAEL of 30 mg/kg bw/d is converted to a NOAEC by dividing by 1.15 according to ECHA Guidance
AF for dose response relationship:
1
Justification:
NOAEC is used as a starting point
AF for differences in duration of exposure:
6
Justification:
based on an oral 28 days feeding study
AF for interspecies differences (allometric scaling):
1
Justification:
allometric scaling is not applied to inhalation
AF for other interspecies differences:
2.5
Justification:
no substance specific data are available.
AF for intraspecies differences:
10
Justification:
for general population the default factor of 10 is used
AF for the quality of the whole database:
1
Justification:
Available data from substance fulfilling scientific principle is used .
AF for remaining uncertainties:
1
Justification:
No further uncertainties to be taken into account
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.17 mg/m³
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:
0.05 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
DNEL value:
30 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
oral to dermal
AF for dose response relationship:
1
Justification:
NOAEL is used as starting point
AF for differences in duration of exposure:
6
Justification:
based on oral 28 days study
AF for interspecies differences (allometric scaling):
4
Justification:
rats had been used as test animals
AF for other interspecies differences:
2.5
Justification:
no substance-specific data are available.
AF for intraspecies differences:
10
Justification:
default value for general population
AF for the quality of the whole database:
1
Justification:
Available data fromsubstance fulfilling scientific principle is used
AF for remaining uncertainties:
1
Justification:
No other uncertainties needed to be considered.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.05 mg/kg bw/day
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:
0.05 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
DNEL value:
30 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no route to route
AF for dose response relationship:
1
Justification:
NOAEL is used as a starting point.
AF for differences in duration of exposure:
6
Justification:
DNEL is based on an oral 28-day study.
AF for interspecies differences (allometric scaling):
4
Justification:
Rats were used in the animal study.
AF for other interspecies differences:
2.5
Justification:
No substance-specific data is available.
AF for intraspecies differences:
10
Justification:
For general population, a default AF of 10 is to be used.
AF for the quality of the whole database:
1
Justification:
Available data from substance fulfilling scientific principle.
AF for remaining uncertainties:
1
Justification:
No other uncertainties needed to be considered.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.05 mg/kg bw/day
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Though it is not conclusive if inhalation is a likely route of exposure to population, the corresponding DNEL has been derived.

As there is no quantitative data available for dermal absorption of test article, a worst case scenario is assumed in which the absorption rate from dermal route is considered to be same as oral route, and for both routes assumed to be 100%.

As basis for DNEL derivation the result from a 28-day oral toxicity study with rats was used, performed by Chemicals Evaluation and Research Institute, Japan, Hita Laboratory in 2014. The study has been completed in the course of registration to the US EPA.

This study was a confirmatory test based on previous same 28-day oral study (study number B11-0836) in which toxic effect was observed at 25 mg/kg/day dosage. The aim was to confirm the presence or absence of the toxic effects at 30 mg/kg/day and reproducibility of the test results.

The confirmatory study was carried out according to OECD guideline and GLP principles. Control: CD(SD) rats were orally administrated at doses of 0, 30, and 120 mg/kg/day for 28 consecutive days. The NOAEL of test item was 30 mg/kg/day under the conditions tested since adverse effects were not noted in the 30 mg/kg/day group.

Based on the above description, the basis for the DNEL therefore is this oral NOAEL (30 mg/kg bw/day), and NOAELcorr for the dermal route is still 30 mg/kg.bw/day.

According to ECHA guidance document the oral NOAEL is converted to an inhalative NOAECpopulation by dividing through 1.15

m3/kg, resulting in a NOAEC of 26.09 mg/m3 .