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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9.8 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC (acc. to ECETOC, Technical Report No. 86, 2003)
Overall assessment factor (AF):
18
Modified dose descriptor starting point:
NOAEC
Value:
176.32 mg/m³
Explanation for the modification of the dose descriptor starting point:

Instructions of IGHRC Guideline on route-to-route extrapolation are considered applicable.

AF for dose response relationship:
1
Justification:
No correction needed as a NOAEL has been used.
AF for differences in duration of exposure:
6
Justification:
standard AF for 28-day subacute study
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed.
AF for other interspecies differences:
1
Justification:
No AF for other differences was considered.
AF for intraspecies differences:
3
Justification:
ECETOC AF for workers
AF for the quality of the whole database:
1
Justification:
All available information indicate no toxicity so that the a high quality can be assumed
AF for remaining uncertainties:
1
Justification:
No remainig uncertainties to be considered.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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:
13.89 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):
72
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

IHGRC guidance has been applied. As no information on dermal or oral adsorption is available, equal adsorption is assumed.

AF for dose response relationship:
1
Justification:
No correction needed as a NOAEL has been used.
AF for differences in duration of exposure:
6
Justification:
standard AF for 28-day subacute study
AF for interspecies differences (allometric scaling):
4
Justification:
standard AF
AF for other interspecies differences:
1
Justification:
No AF for other differences was considered.
AF for intraspecies differences:
3
Justification:
ECETOC AF for workers
AF for the quality of the whole database:
1
Justification:
All available information indicate no toxicity so that the a high quality can be assumed.
AF for remaining uncertainties:
1
Justification:
No remainig uncertainties to be considered.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Although no hazard have been identified, long term DNEL havebeen derived.However, the ECETOC assessment factors have been used to avoid overly conservtaive DNEL for a non-hazarsous substance.

The only study included in this dossier with a robust study summary that qualifies for DNEL derivation is a developmental study (OECD 414). Furthermore, it is known that a 28-day study exists, which ECHA has not requested to be included in the dossier. Both studies did not show any effects at the maximum dose of 1000 mg/kg/day. Although no hazard have been identified, long term DNEL has been derived. As the OECD 414 covers the relevant life cycle, no assessment factor for exposure duration would be applied. Therefore, DNEL would be less conservative than those derived from the 28-day study, which requires the application of an assessment factor of 6 for exposure duration. Consequently, all DNEL will be derived from the 28-day study, as this will result in more conservative values.

Long-term systemic inhalation DNEL for workers

Step 1: NOAEL based on a 28-day study (EU Method B.7) = 1000 mg/kg/day

Step 2: Modification into a correct starting point:

Conversion into an inhalatory rat NOAEC by dividing by 0.38 m3/kg (8-hour respiratory volume in the rat)

Correction for activity driven differences in respiratory volume in workers compared to individuals at rest (6.7 m3/10 m3)

Correction for inhalation and oral absorption rates: 10 (acc. to IGHRC guidance)

In conclusion, inhalation NOAEC = (oral NOAEL/0.38) * (6.7/10) =176.32 mg/m³

Step 3: Use of assessment factors: 18

Interspecies: no allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed (acc. to ECETOC, Technical Report No. 86, 2003).

Intraspecies:3(acc. to ECETOC, Technical Report No. 86, 2003)

Exposure duration:6

Dose-response relationship:1

In conclusion long-term systemic inhalation DNEL for workers is DNEL= 9.8 mg/m3


Long-term systemic dermal DNEL for workers

Step 1: NOAEL based on a 28-day study (EU Method B.7) = 1000 mg/kg/day

Step 2: Modification into a correct starting point:

Conversion into a dermal rat NOAEL

Correction for dermal and oral absorption rates: dermal adsorption is assumed to be the same as oral absorption

corrected starting point is 1000 mg/kg/day.

Step 3: Use of assessment factors: 72

Interspecies:4for allometric scaling factor (acc. to ECETOC, Technical Report No. 86, 2003)

Intraspecies:3(acc. to ECETOC, Technical Report No. 86, 2003)

Exposure duration:6

Dose-response relationship: a factor of1is applied due to the use of a NOAEL

In conclusion long-term systemic dermal DNEL for workers is 13.89 mg/kg

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.9 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):
30
Modified dose descriptor starting point:
NOAEC
Value:
86.96 mg/m³
Explanation for the modification of the dose descriptor starting point:

Instructions of IGHRC Guideline on route-to-route extrapolation are considered applicable.

AF for dose response relationship:
1
Justification:
No correction needed as a NOAEL has been used.
AF for differences in duration of exposure:
6
Justification:
standard AF for 28-day subacute study
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed.
AF for other interspecies differences:
1
Justification:
No AF for other differences was considered.
AF for intraspecies differences:
5
Justification:
ECETOC AF for general population
AF for the quality of the whole database:
1
Justification:
All available information indicate no toxicity so that the a high quality can be assumed.
AF for remaining uncertainties:
1
Justification:
No remainig uncertainties to be considered.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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:
8.33 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):
120
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

IHGRC guidance has been applied. As no information on dermal or oral adsorption is available, equal adsorption is assumed.

AF for dose response relationship:
1
Justification:
No correction needed as a NOAEL has been used.
AF for differences in duration of exposure:
6
Justification:
standard AF for 28-day subacute study
AF for interspecies differences (allometric scaling):
4
Justification:
standard AF
AF for other interspecies differences:
1
Justification:
No AF for other differences was considered.
AF for intraspecies differences:
5
Justification:
ECETOC AF for general population
AF for the quality of the whole database:
1
Justification:
All available information indicate no toxicity so that the a high quality can be assumed.
AF for remaining uncertainties:
1
Justification:
No remainig uncertainties to be considered.
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:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.33 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):
120
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

not applicable

AF for dose response relationship:
1
Justification:
No correction needed as a NOAEL has been used.
AF for differences in duration of exposure:
6
Justification:
standard AF for 28-day subacute study
AF for interspecies differences (allometric scaling):
4
Justification:
standard AF
AF for other interspecies differences:
1
Justification:
No AF for other differences was considered.
AF for intraspecies differences:
5
Justification:
ECETOC AF for general population
AF for the quality of the whole database:
1
Justification:
All available information indicate no toxicity so that the a high quality can be assumed.
AF for remaining uncertainties:
1
Justification:
No remainig uncertainties to be considered.
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

Although no hazard have been identified, long term DNEL have been derived. However, the ECETOC assessment factors have been used to avoid overly conservtaive DNEL for a non-hazarsous substance.

The only study included in this dossier with a robust study summary that qualifies for DNEL derivation is a developmental study (OECD 414). Furthermore, it is known that a 28-day study exists, which ECHA has not requested to be included in the dossier. Both studies did not show any effects at the maximum dose of 1000 mg/kg/day. Although no hazard have been identified, long term DNEL has been derived. As the OECD 414 covers the relevant life cycle, no assessment factor for exposure duration would be applied. Therefore, DNEL would be less conservative than those derived from the 28-day study, which requires the application of an assessment factor of 6 for exposure duration. Consequently, all DNEL will be derived from the 28-day study, as this will result in more conservative values.

Long term inhalation toxicity

Step 1: NOAEL based on a 28-day study (EU Method B.7) = 1000 mg/kg/day

Step 2: Modification into a correct starting point:

Conversion into an inhalatory rat NOAEC by dividing by 1.15 m3/kg d

Correction for inhalation and oral absorption rates: 10 (acc. to IGHRC guidance)

In conclusion, inhalation NOAEC = (oral NOAEL/1.15) /10 =86.96mg/m³

Step 3: Use of assessment factors: 30

Interspecies: no allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed (acc. to ECETOC, Technical Report No. 86, 2003)

Intraspecies:5(acc. to ECETOC, Technical Report No. 86, 2003)

Exposure duration:1

Dose-response relationship:6

In conclusion, long-term systemic inhalation DNEL= 2.90 mg/m3


Long term dermal exposure toxicity

Step 1: NOAEL based on a 28-day study (EU Method B.7) = 1000 mg/kg/day

Step 2: Modification into a correct starting point:

Conversion into a dermal rat NOAEL

Correction for dermal and oral absorption rates: dermal adsorption is assumed to be the same as oral absorption

corrected starting point is 1000 mg/kg/day.

Step 3: Use of assessment factors: 120

Interspecies:4for allometric scaling factor (acc. to ECETOC, Technical Report No. 86, 2003)

Intraspecies:5(acc. to ECETOC, Technical Report No. 86, 2003)

Exposure duration:6

Dose-response relationship: a factor of1is applied due to the use of a NOAEL

In conclusion, long-term systemic dermal DNEL = 8.33 mg/kg/day


Long term oral exposure toxicity

Step 1: NOAEL based on a 28-day study (EU Method B.7) = 1000 mg/kg/day

Step 2: Modification into a correct starting point

Not required

Step 3: Use of assessment factors: 120

Interspecies:4for allometric scaling factor (acc. to ECETOC, Technical Report No. 86, 2003)

Intraspecies:5(acc. to ECETOC, Technical Report No. 86, 2003)

Exposure duration:6

Dose-response relationship: a factor of1is applied due to the use of a NOAEL

In conclusion, long-term systemic oral DNEL = 8.33 mg/kg/day.