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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
66.1 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):
10
Dose descriptor starting point:
NOAEL
DNEL value:
375 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
661 mg/m³
Explanation for the modification of the dose descriptor starting point:

To correct the interspecies difference between rat and human the no observed effect level has to be corrected as follows:

Corrected starting point for the inhalative route for workers:

= NOAEL(oral) * (1/0.38 m³/kg bw/day) * (ABSoral-rat/ABSinh-human) * 6.7 m³ (8h) /10 m³ (8h)

= 375 mg/kg bw/day * (1/0.38 m³/kg bw/day) * (1/1) * 0.67 m³ = 661 mg/m³

Based on the toxicokinetic data, it can be assumed that the systemic bioavailability will be high both after oral and inhalation exposure; oral absorption rate in rats and inhalation absorption rate in humans is assumed to be the same.

(ABSoral-rat = oral absorption in rats, ABSinh-human = inhalation absorption rate in humans)

Thus, the corrected starting point for workers was 661.2 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:
1
Justification:
(factor 1 was used for remaining interspecies differences, because 375 mg/kg bw/d was the highest dose tested in the chronic study and did not cause any effects, suggesting that the NOAEL would have been higher, and the level did also not cause any effects on other species, namely in the mouse at the highest tested dose of 667 mg/kg bw/d in a chronic study, in the hamster at the highest tested dose of 405 mg/kg bw/d in a teratogenicity study, and in the rabbit at the highest tested dose of 425 mg/kg bw/d in a teratogenicity study, which does not indicate any relevant species differences in susceptibility.
AF for intraspecies differences:
5
Justification:
Default value for workers according to ECHA REACH Guidance.
AF for the quality of the whole database:
2
Justification:
The available studies are pre/GLP and non-guideline studies.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/m³
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
other: VCI document "Ableitung von DNEL für lokal reizende Stoffe mit guter Datenlage zur systemischen Toxizität, aber limitierter Datenlage zur Inhalationstoxizität" see attachment
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/m³
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
other: VCI document "Ableitung von DNEL für lokal reizende Stoffe mit guter Datenlage zur systemischen Toxizität, aber limitierter Datenlage zur Inhalationstoxizität" see attachment

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9.4 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):
40
Dose descriptor starting point:
NOAEL
DNEL value:
375 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
375 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Dermal NOAEL = oral NOAEL*ABS(oral)/ABS(dermal) = 375 mg/kg bw/day *(1/1) = 375 mg/kg bw/day. It is assumed that oral and dermal absorption rates are equal.

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:
The experimental animal was a rat.
AF for other interspecies differences:
1
Justification:
factor 1 was used for remaining interspecies differences, because 375 mg/kg bw/d was the highest dose tested in the chronic study and did not cause any effects, suggesting that the NOAEL would have been higher, and the level did also not cause any effects on other species, namely in the mouse at the highest tested dose of 667 mg/kg bw/d in a chronic study, in the hamster at the highest tested dose of 405 mg/kg bw/d in a teratogenicity study, and in the rabbit at the highest tested dose of 425 mg/kg bw/d in a teratogenicity study, which does not indicate any relevant species differences in susceptibility.
AF for intraspecies differences:
5
Justification:
Default value for workers according to ECHA REACH Guidance.
AF for the quality of the whole database:
2
Justification:
The available studies are pre-GLP and non-guideline studies.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
16.3 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):
20
Dose descriptor starting point:
NOAEL
DNEL value:
375 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
326 mg/m³
Explanation for the modification of the dose descriptor starting point:
NOAECcorr = NOAELoral*(1/1.15 m³/kg bw/day (24h)) *(ABSoral-rat/ABSinh-human) = 375 mg/kg bw/day*(1/1.15 m³/kg bw/day)*(1/1) = 326 mg/m³. It is assumed that oral and inhalation absorption rates are equal. ABS(oral/rat)=oral absorption rate in rats, ABS(inh./human)=inhalation absorption rate in humans.
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:
1
Justification:
factor 1 was used for remaining interspecies differences, because 375 mg/kg bw/d was the highest dose tested in the chronic study and did not cause any effects, suggesting that the NOAEL would have been higher, and the level did also not cause any effects on other species, namely in the mouse at the highest tested dose of 667 mg/kg bw/d in a chronic study, in the hamster at the highest tested dose of 405 mg/kg bw/d in a teratogenicity study, and in the rabbit at the highest tested dose of 425 mg/kg bw/d in a teratogenicity study, which does not indicate any relevant species differences in susceptibility.
AF for intraspecies differences:
10
Justification:
Default value for general population according to ECHA REACH Guidance.
AF for the quality of the whole database:
2
Justification:
The available studies are pre-GLP and non-guideline studies.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
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:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.7 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):
80
Dose descriptor starting point:
NOAEL
DNEL value:
375 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
375 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Dermal NOAEC=oral NOAEL*ABS(oral)/ABS(dermal) = 375 mg/kg bw/day *(1/1) = 375 mg/kg bw/day. It is assumed that oral and dermal absorption rates are equal.

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:
The experimental animal was rat.
AF for other interspecies differences:
1
Justification:
factor 1 was used for remaining interspecies differences, because 375 mg/kg bw/d was the highest dose tested in the chronic study and did not cause any effects, suggesting that the NOAEL would have been higher, and the level did also not cause any effects on other species, namely in the mouse at the highest tested dose of 667 mg/kg bw/d in a chronic study, in the hamster at the highest tested dose of 405 mg/kg bw/dy in a teratogenicity study, and in the rabbit at the highest tested dose of 425 mg/kg bw/d in a teratogenicity study, which does not indicate any relevant species differences in susceptibility.
AF for intraspecies differences:
10
Justification:
Default value for general population according to ECHA REACH Guidance.
AF for the quality of the whole database:
2
Justification:
The available studies are pre-GLP and non-guideline studies.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.7 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):
80
Dose descriptor starting point:
NOAEL
DNEL value:
375 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
375 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

no route to route extrapolation 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:
The experimental animal was rat.
AF for other interspecies differences:
1
Justification:
factor 1 was used for remaining interspecies differences, because 375 mg/kg bw/d was the highest dose tested in the chronic study and did not cause any effects, suggesting that the NOAEL would have been higher, and the level did also not cause any effects on other species, namely in the mouse at the highest tested dose of 667 mg/kg bw/d in a chronic study, in the hamster at the highest tested dose of 405 mg/kg bw/d in a teratogenicity study, and in the rabbit at the highest tested dose of 425 mg/kg bw/d in a teratogenicity study, which does not indicate any relevant species differences in susceptibility.
AF for intraspecies differences:
10
Justification:
Default value for general population according to ECHA REACH Guidance.
AF for the quality of the whole database:
2
Justification:
The available studies are old and not guideline studies.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population