Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.94 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
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:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
88.2 mg/m³
Explanation for the modification of the dose descriptor starting point:

Long-term inhalatory DNEL(developmental) based on NOAEL (OECD 414, oral) in rats:
- NOAEC(inhalation) derived according to “Guidance on information requirements and chemical safety assessment”, Chapter R.8.4.2, Figure R. 8-3 (p. 21).
corrected NOAEC(inhalation)

 = NOAEL(oral, rat) x 1/sRVratxABS(oral-rat)/ABS(inh-human) x sRVhuman/wRV
 = 100 mg/kg x 1/0.38 m3/kg/d x 50%/100% x 6.7 m3/10 m3
 = 88.2 mg/m3
with sRV: standard respiratory volume; ABS: Absorption; wRV: worker respiratory volume

AF for dose response relationship:
1
Justification:
NOAEL is the starting point for DNEL derivation. According to Guidance on information Chapter R.8, p. 30, the assessment factor is 1.
AF for differences in duration of exposure:
6
Justification:
relevant NOAEL is derived from a developmental toxicity study (14 days dosing)
AF for interspecies differences (allometric scaling):
1
Justification:
interspecies difference is included in the calculation by correcting the respiratory volumes of rat and man (for details refer to "explanation for the modification of the dose descriptor starting point")
AF for other interspecies differences:
1
Justification:
It can be assumed that workers are trained in handling chemicals and according to general occupational health regulations an exposure of pregnant workers to the substance at the production site is excluded. However, for precautionary reasons the DNEL is based on the NOAEL derived on develpomental effects exclusively. This situation is very unlikely to occur in the occupational environment. Therefore, the assessment factor 1 is considered to be sufficient.
AF for intraspecies differences:
5
Justification:
according to Guidance on information Chapter R.8, Table 8-6, p. 32
AF for the quality of the whole database:
1
Justification:
Original study is reliable without restriction
AF for remaining uncertainties:
1
Justification:
no further uncertainties assumed
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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.83 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
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:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Workers:Long-term dermal systemic DNEL(developmental) based on NOAEL (OECD 414, oral) in rats:
- NOAEL(dermal) derived according to “Guidance on information requirements and chemical safety assessment”, Appendix R. 8-2, Example B.5 (p. 63).
corrected NOAEL(dermal)
   

= NOAEL(oral, rat) x Absorption(oral-rat)/Absorption(dermal-human)

= 100 mg/kg bw x 100%/100%
= 100 mg/kg bw

AF for dose response relationship:
1
Justification:
The orginal study is reliable without restrictions. The route to route extrapolation was performed by applying the equation as cited in Guidance on information requirements and chemical safety assessment, Chapter R.8 (by ECHA) with all recommended assessment factors.
AF for differences in duration of exposure:
6
Justification:
relevant NOAEL is derived from a developmental toxicity study (14 days dosing)
AF for interspecies differences (allometric scaling):
4
Justification:
according to Guidance on information Chapter R.8, Table 8-3, p. 24
AF for other interspecies differences:
1
Justification:
It can be assumed that workers are trained in handling chemicals and according to general occupational health regulations an exposure of pregnant workers to the substance at the production site is excluded. However, for precautionary reasons the DNEL is based on the NOAEL derived on develpomental effects exclusively. This situation is very unlikely to occur in the occupational environment. Therefore, the assessment factor 1 is considered to be sufficient.
AF for intraspecies differences:
5
Justification:
according to Guidance on information Chapter R.8, Table 8-6, p. 32
AF for the quality of the whole database:
1
Justification:
Original study is reliable without restriction
AF for remaining uncertainties:
1
Justification:
no further uncertainties assumed
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

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.29 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
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:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
43.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

Long-term inhalatory DNEL(developmental) based on NOAEL (OECD 414, oral) in rats:
- NOAEC(inhalation) derived according to “Guidance on information requirements and chemical safety assessment”, Chapter R.8.4.2, Figure R. 8-3 (p. 21).
corrected NOAEC(inhalation)
        

= NOAEL(oral, rat) x 1/sRVratxABS(oral-rat)/ABS(inh-human)

= 100 mg/kg x 1/1.15 m3/kg/d x 50%/100%
= 43.5 mg/m3
with sRV: standard respiratory volume; ABS: Absorption; wRV: worker respiratory volume

AF for dose response relationship:
1
Justification:
NOAEL is the starting point for DNEL derivation. According to Guidance on information Chapter R.8, p. 30, the assessment factor is 1.
AF for differences in duration of exposure:
6
Justification:
relevant NOAEL is derived from a developmental toxicity study (14 days dosing)
AF for interspecies differences (allometric scaling):
4
Justification:
according to Guidance on information Chapter R.8, Table 8-3, p. 24
AF for other interspecies differences:
10
Justification:
according to Guidance on information Chapter R.8, Table 8-6, p. 32
AF for intraspecies differences:
2.5
Justification:
according to Guidance on information Chapter R.8, Table 8-6, p. 32
AF for the quality of the whole database:
1
Justification:
Original study is reliable without restriction
AF for remaining uncertainties:
1
Justification:
no further uncertainties assumed
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:
0.17 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
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:
100 mg/m³
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Long-term dermal systemic DNEL(developmental) based on NOAEL (OECD 414, oral) in rats:
- NOAEL(dermal) derived according to “Guidance on information requirements and chemical safety assessment Appendix R. 8-2, Example B.5 (p. 63).
corrected NOAEL(dermal)
  

= NOAEL(oral, rat) x Absorption(oral-rat)/Absorption(dermal-human)
= 100 mg/kg bw x 100%/100%
= 100 mg/kg bw

AF for dose response relationship:
1
Justification:
The orginal study is reliable without restrictions. The route to route extrapolation was performed by applying the equation as cited in Guidance on information requirements and chemical safety assessment, Chapter R.8 (by ECHA) with all recommended assessment factors.
AF for differences in duration of exposure:
6
Justification:
relevant NOAEL is derived from a developmental toxicity study (14 days dosing)
AF for interspecies differences (allometric scaling):
4
Justification:
according to Guidance on information Chapter R.8, Table 8-3, p. 24
AF for other interspecies differences:
2.5
Justification:
according to Guidance on information Chapter R.8, Table 8-6, p. 32
AF for intraspecies differences:
10
Justification:
according to Guidance on information Chapter R.8, Table 8-6, p. 32
AF for the quality of the whole database:
1
Justification:
Original study is reliable without restriction
AF for remaining uncertainties:
1
Justification:
no further uncertainties assumed
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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.17 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
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:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

n.a., relevant study was performed using the oral route

AF for dose response relationship:
1
Justification:
NOAEL is the starting point for DNEL derivation. According to Guidance on information Chapter R.8, p. 30, the assessment factor is 1.
AF for differences in duration of exposure:
6
Justification:
relevant NOAEL is derived from a developmental toxicity study (14 days dosing)
AF for interspecies differences (allometric scaling):
4
Justification:
according to Guidance on information Chapter R.8, Table 8-3, p. 24
AF for other interspecies differences:
2.5
Justification:
according to Guidance on information Chapter R.8, Table 8-6, p. 32
AF for intraspecies differences:
10
Justification:
according to Guidance on information Chapter R.8, Table 8-6, p. 32
AF for the quality of the whole database:
1
Justification:
Original study is reliable without restriction
AF for remaining uncertainties:
1
Justification:
no further uncertainties assumed
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

none