Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
35.2 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):
25
Modified dose descriptor starting point:
NOAEC
DNEL value:
88 mg/m³
Explanation for the modification of the dose descriptor starting point:
The oral NOAEL of 50 mg/kg bw/d is converted to a NOAEC according to ECHA Guidance: 50/0.38*6.7/10=88
AF for dose response relationship:
1
Justification:
NOAEC is used as a starting point
AF for differences in duration of exposure:
2
Justification:
based on an oral 90 days feeding study
AF for interspecies differences (allometric scaling):
1
Justification:
allometric scaling not used for 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:
35.2 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:
0.5 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):
100
Modified dose descriptor starting point:
NOAEL
DNEL value:
50 mg/kg bw/day
AF for dose response relationship:
1
Justification:
NOAEL is used as a starting point.
AF for differences in duration of exposure:
2
Justification:
based on an oral 90-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.
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

According to the results of toxicokinetics assessment, due to the physical-chemical properties of test substance, inhalation of exposure is irrelevant routeand will not be a concern for safety assessment purpose.

As there is no quantitative data available for dermal adsorption 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 sub-chronic feeding study with rats was used, performed by Central Institute for Nutrition and Food Research. In this study, test material was administered at levels of 0, 0.075, 0.1, 0.15 and 1% in stock diet to groups of ten males and ten females each.

Mean body weight, food intake and food efficiency were decreased at 1% in males, Alkaline phosphatase activity in blood plasma was increased at 1 % in both sexes. Relative liver weights were statistically significantly increased in both sexes at 1% only. Histopathological examination revealed minimal, though clearly treatment related, changes in the liver of animals at the 1% level. It was concluded that 0.1 % was a no-effect level, which is approximately equivalent with a daily intake of 50 mg /kg body weight.

Hence this study is chosen as basis for DNEL derivation, applying the higher applied dose as NOAEL value (50 mg/kg bw/d) in this study in line with a worst case approach. This result obtained in the key study was supported by another supportive study (Report number: R 5228). From the combined results of the two experiments in this study it was concluded that a more conservative no-effect level 0.1 % test article is a no-effect level, approximately equivalent with an intake of 50 mg/kg body weight/day. Based on the above description, the basis for the DNEL therefore is this oral NOAEL (50 mg/kg bw/day), and NOAEL corr for the dermal route is still 50 mg/kg.bw/day. According to ECHA guidance document the oral NOAEL is converted to ainhalative NOAECWorkerby dividing through 0.38 m3/kg resulting in a NOAEC of 88 mg/m3.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.87 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):
50
Modified dose descriptor starting point:
NOAEC
DNEL value:
43.48 mg/m³
Explanation for the modification of the dose descriptor starting point:
The oral NOAEL 0f 50 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:
2
Justification:
based on an oral 90 days feeding study
AF for interspecies differences (allometric scaling):
1
Justification:
allometric scaling not used for inhalation
AF for other interspecies differences:
2.5
Justification:
no substance specific data are available.
AF for intraspecies differences:
10
Justification:
for 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:
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:
0.25 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):
200
Modified dose descriptor starting point:
NOAEL
DNEL value:
50 mg/kg bw/day
AF for dose response relationship:
1
Justification:
NOAEL is used as starting point
AF for differences in duration of exposure:
2
Justification:
based on oral 90 days 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 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:
no hazard identified
DNEL related information
DNEL extrapolated from long term DNEL

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:
0.25 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):
200
Modified dose descriptor starting point:
NOAEL
DNEL value:
50 mg/kg bw/day
AF for dose response relationship:
1
Justification:
NOAEL is used as a starting point.
AF for differences in duration of exposure:
2
Justification:
DNEL is based on an oral 90-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.
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:
0.25 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

According to the results of toxicokinetics assessment, due to the physical-chemical properties of test substance, inhalation of exposure isirrelevant routeand will not be a concern for safety assessment purpose.

As there is no quantitative data available for dermal adsorption 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 sub-chronic feeding study with rats was used, performed by Central Institute for Nutrition and Food Research. In this study,test material was fed at levels of 0, 0.075, 0.1, 0.15 and1% in stock diet to groups of ten males andten females each.

Mean body weight, food intake and food efficiency were decreased at 1% in males,Alkaline phosphatase activity in blood plasma was increased at I % in both sexes. Relative liver weights were statistically significantly increased in both sexes at 1% only. Histopathological examination revealed minimal, though clearly treatment related,changes in the liver of animals at the I % level. It was concluded that 0.1 % was a no-effect level, which is approximately equivalent with a daily intake of 50 mg /kg body weight.

Hence this study is chosen as basis for DNEL derivation, applying the higherapplied dose as NOAEL value (50 mg/kg bw/d) in this study in line with a worst case approach. This result obtained in the key study was supported by another supportive study (Report number: R 5228). From the combined results of the two experiments in this study it was concluded that a more conservative no-effect level 0.1 % test article is a no-effect level, approximately equivalent with an intake of 50mg/kg body weight/day. Based on the above description, the basis for the DNEL therefore is this oral NOAEL (50 mg/kg bw/day), and NOAELcorr for the dermal route is still 50 mg/kg.bw/day. According to ECHA guidance document the oral NOAEL is converted to ainhalative NOAECgeneral population by dividing through 1.15 m3/kg resulting in a NOAEC of 43.48 mg/m3.