Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.099 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):
13
Dose descriptor starting point:
NOAEL
Value:
1 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
1.2 mg/m³
Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on an oral NOAEL observed in a combined oral chronic toxicity and carcinogenicity study in rats (OECD 453). To convert the rat oral NOAEL into a corrected inhalatory NOAEC to assess human inhalatory exposure, the NOAEL has to be corrected as follows:

Corrected inhal NOAEC = NOAEL(oral) × (1 ÷ sRVrat) × (ABSoral-rat ÷ ABSinh-human) × (sRVhuman ÷ wRV) × (Fstudy ÷ Fworker)

= 1 mg/kg bw/day × (1 ÷ 0.38 m³/kg bw) × (1 ÷ 2) × (6.7 m³ ÷ 10 m³) × (7 ÷ 5) = 1.2 mg/m³

sRV = standard respiratory volume; wRV = respiratory volume light activity for worker (8 h); ABS = absorption; Fstudy = frequency of exposure in study; Fworker = frequency of exposure worker

As worst case as recommended in the ECHA Guidance R.8 (2012), it is assumed that oral absorption rate is 50% of that of inhalation absorption.

Thus, the corrected starting point for workers is 1.2 mg/m³ for inhalation.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL.
AF for differences in duration of exposure:
1
Justification:
The DNEL is based on a chronic study.
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation route.
AF for other interspecies differences:
2.5
Justification:
Default value according to ECHA REACH Guidance.
AF for intraspecies differences:
5
Justification:
Default value for workers according to ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
The DNEL is based on a high-quality study.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.033 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on a dermal NOAEL observed in a repeated dose toxicity study in rats (OECD 410). The frequency of treatment in the dermal repeated dose toxicity study was 5 days/week for the first three weeks and 7 days/week thereafter. As the animals were mainly exposed 5 days/week, the frequency of exposure is identical to the exposure frequnency of the worker and no correction factor for the frequency was applied. Therefore, no modification of the dose descriptor starting point is neccessary.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL.
AF for differences in duration of exposure:
6
Justification:
The DNEL is based on a subacute study.
AF for interspecies differences (allometric scaling):
4
Justification:
Default value according to ECHA REACH Guidance.
AF for other interspecies differences:
2.5
Justification:
Default value according to ECHA REACH Guidance.
AF for intraspecies differences:
5
Justification:
Default value for workers according to ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
The DNEL is based on a high-quality study.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.017 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
Dose descriptor starting point:
NOAEL
Value:
1 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
0.4 mg/m³
Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on an oral NOAEL observed in a combined oral chronic toxicity and carcinogenicity study in rats (OECD 453). To convert the rat oral NOAEL into a corrected inhalatory NOAEC to assess human inhalatory exposure, the NOAEL has to corrected as follows:

Corrected inhal NOAEC = NOAEL(oral) × (1 ÷ sRVrat) × (ABSoral-rat ÷ ABSinh-human)

= 1 mg/kg bw/day × (1 ÷ 1.15 m³/kg bw) × (1 ÷ 2) = 0.4 mg/m³

As worst case as recommended in the ECHA Guidance R.8 (2012), it is assumed that oral absorption rate is 50% of that of inhalation absorption (ABS = absorption).

Thus, the corrected starting point for the general population is 0.4 mg/m³ for inhalation.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL.
AF for differences in duration of exposure:
1
Justification:
The DNEL is based on a chronic study.
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation route.
AF for other interspecies differences:
2.5
Justification:
Default value according to ECHA REACH Guidance.
AF for intraspecies differences:
10
Justification:
Default value for general population according to ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
The DNEL is based on a high-quality study.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.012 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
7.1 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on a dermal NOAEL observed in a repeated dose toxicity study in rats (OECD 410). As the frequency of treatment in this study was predominantly 5 days/week, and the exposure frequnecy of the general population is 7 days/week, the dose descriptor starting point is modified with the factor 5/7 to 7.1 mg/kg bw/day.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL.
AF for differences in duration of exposure:
6
Justification:
The DNEL is based on a subacute study.
AF for interspecies differences (allometric scaling):
4
Justification:
Default value according to ECHA REACH Guidance.
AF for other interspecies differences:
2.5
Justification:
Default value according to ECHA REACH Guidance.
AF for intraspecies differences:
10
Justification:
Default value for the general population according to ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
The DNEL is based on a high-quality study.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.01 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
Dose descriptor starting point:
NOAEL
Value:
1 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on an oral NOAEL observed in a combined oral chronic toxicity and carcinogenicity study in rats (OECD 453). As the frequency of treatment in the study (7 days/week) was identical to the exposure frequency of the general population no correction factor for the frequency was applied. Therefore, no modification of the dose descriptor starting point is necessary.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL.
AF for differences in duration of exposure:
1
Justification:
The DNEL is based on a chronic study.
AF for interspecies differences (allometric scaling):
4
Justification:
Default value according to ECHA REACH Guidance.
AF for other interspecies differences:
2.5
Justification:
Default value according to ECHA REACH Guidance.
AF for intraspecies differences:
10
Justification:
Default value for the general population according to ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
The DNEL is based on a high-quality study.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population