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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.41 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Technical Report No. 110
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
DNEL value:
44.08 mg/m³
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated exposure by inhalation. The recommended approach using oral data and assuming the same absorption for inhalation and oral route is used.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
AF for other interspecies differences:
1
Justification:
The effects observed at the next higher dose of 150 mg/kg were slight and without histological correlate
AF for intraspecies differences:
5
Justification:
Intraspecies differences of worker are considered to be fully covered by the selected factor.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
DNEL related information

Local effects

Long term exposure
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Technical Report No. 110
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
DNEL value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No route to route extrapolation is necessary since a repeated dose dermal toxicity study is available.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
The effects observed at the next higher dose of 150 mg/kg were slight and without histological correlate
AF for intraspecies differences:
5
Justification:
Intraspecies differences of worker are considered to be fully covered by the selected factor.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

General

DNEL derivation for the test substance is performed under consideration of the recommendations of ECHA REACH Guidance (2012) and ECETOC (2010). In view of the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

Long-term exposure – systemic effects, Inhalation exposure:

In order to derive a long-term inhalation DNEL, an inhalation NOEC was derived from NOEL oral value (determined in a combined repeated dose and reproductive/developmental toxicity test with rats), as no repeated dose inhalation study was available. Oral NOEL of 50 mg/kg bw/day was converted to an inhalation NOEC, assuming 100% absorption via the lung and 50 % absorption via the oral route.

The oral NO(A)EL was converted into an inhalation NO(A)EC according to the following formula assuming a daily exposure period of 8 hours during light activity:

- Modification of the starting point

Relevant dose descriptor (NOAEL): 50 mg/kg bw/day

Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m³/kg bw/day

Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 0.5

Standard respiratory volume of humans (sRVhuman) for 8 hours: 6.7 m³

Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m³

Corrected inhalatory NOAEC for workers

= 50 mg/kg bw/day × (1 / 0.38 m³/kg bw/day) × 0.5 × (6.7 m³/10 m³)

= 44.08 mg/m³

- Calculation of the worker DNEL

Corrected inhalatory NOAEC for workers: 44.08 mg/m³

Assessment factor for exposure duration (subchronic to chronic): 2

Assessment factor for other interspecies differences: 1 (The effects observed at the next higher dose of 150 mg/kg were slight and without histological correlate)

Assessment factor for intraspecies differences (worker): 5

Worker DNEL (long-term inhalation exposure) 4.41 mg/m³

Long-term exposure – systemic effects, dermal exposure:

In order to derive a long-term dermal DNEL, an dermal NOEL was derived from NOEL oral value (determined in a combined repeated dose and reproductive/developmental toxicity test with rats), as no repeated dose dermal study was available. Oral NOEL of 50 mg/kg bw/day was converted to an dermal NOEL, considering a conservative 10 % absorption through the skin (ECHA document R.7C, 2008, 7.12)

NOEL (long-term dermal) = 50 mg/kg bw /d x 100 : 10 = 500 mg/kg bw/d

Taking in account the appropriate modification and assessment factors, the worker DNEL (long-term dermal exposure) is calculated as follows:

Relevant dose descriptor (NOAEL): 500 mg/kg bw/day

Exposure duration factor (subchronic to chronic): 2

Allometric scaling factor (rat-to-human): 4

Assessment factor for other interspecies differences: 1 (The effects observed at the next higher dose of 150 mg/kg were slight and without histological correlate)

Assessment factor for intraspecies differences (worker): 5

Worker DNEL (long-term dermal exposure): 12.5 mg/kg bw/day

References

- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.09 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Technical Report No. 110
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEC
DNEL value:
21.74 mg/m³
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated exposure by inhalation. The recommended approach using oral data and assuming the same absorption for inhalation and oral route is used.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
AF for other interspecies differences:
1
Justification:
The effects observed at the next higher dose of 150 mg/kg were slight and without histological correlate
AF for intraspecies differences:
10
Justification:
Intraspecies differences of general population are considered to be fully covered by the selected factor.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.25 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Technical Report No. 110
Overall assessment factor (AF):
80
Modified dose descriptor starting point:
NOAEL
DNEL value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No route to route extrapolation is necessary since a repeated dose dermal toxicity study is available.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
The effects observed at the next higher dose of 150 mg/kg were slight and without histological correlate
AF for intraspecies differences:
10
Justification:
Intraspecies differences of general population are considered to be fully covered by the selected factor.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.625 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Technical Report No. 110
Overall assessment factor (AF):
80
Modified dose descriptor starting point:
NOAEL
DNEL value:
50 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No route to route extrapolation is necessary since a combined repeat dose and reproductive/developmental toxicity screening test is available.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
The effects observed at the next higher dose of 150 mg/kg were slight and without histological correlate
AF for intraspecies differences:
10
Justification:
Intraspecies differences of general population are considered to be fully covered by the selected factor.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population

General

DNEL derivation for the test substance is performed under consideration of the recommendations of ECHA REACH Guidance (2012) and ECETOC (2010). In view of the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

Long-term exposure – systemic effects, inhalation exposure:

In order to derive the general population DNEL (long-term inhalation exposure), the NOEL assessed in combined repeated dose and reproductive/developmental toxicity test with rats was identified as the relevant dose descriptor (NOEL = 50 mg/kg bw/d). Considering the appropriate modification and assessment factors, the general population DNEL (long-term, inhalation exposure) is calculated as follows:

- Modification of the starting point

Relevant dose descriptor (NOEL): 50 mg/kg bw/ day

Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.15 m³/kg bw/day

Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 0.5  

Corrected inhalatory LOAEC for the general population

= 50 mg/kg bw/day x (1 / 1.15 m³/kg bw/day) x 0.5 =  21.74 mg/m³  

- Calculation of the general population DNEL

Corrected inhalatory NOEC for general population: 21.74 mg/m³

Assessment factor for other interspecies differences: 1 (The effects observed at the next higher dose of 150 mg/kg were slight and without histological correlate)

Assessment factor for intraspecies differences (general population): 10

Assessment factor for duration of exposure (subchronic to chronic): 2

General Population DNEL (long-term inhalation exposure) : 1.09 mg/m3

 

Long-term exposure – systemic effects, dermal exposure:

In order to derive a long-term dermal DNEL, an dermal NOEL was derived from NOEL oral value (determined in a combined repeated dose and reproductive/developmental toxicity test with rats), as no repeated dose dermal study was available. Oral NOEL of 50 mg/kg bw/day was converted to an dermal NOEL,considering a conservative 10 % absorption through the skin (ECHA document R.7C, 2008, 7.12)

NOEL (long-term dermal) = 50 mg/kg bw/d x 100 : 10 = 500 mg/kg bw/d

Taking in account the appropriate modification and assessment factors, the worker DNEL (long-term dermal exposure) is calculated as follows:

Relevant dose descriptor (NOAEL): 500 mg/kg bw/day

Exposure duration factor (subchronic to chronic): 2

Allometric scaling factor (rat-to-human): 4

Assessment factor for other interspecies differences: 1 (The effects observed at the next higher dose of 150 mg/kg were slight and without histological correlate)

Assessment factor for intraspecies differences (general population): 10

 

General Population DNEL (long-term dermal exposure) : 6.25 mg/kg

Long-term exposure – systemic effects, oral exposure:

In order to derive the general population DNEL (long-term oral exposure), the NOEL assessed in a combined repeated dose and reproductive/developmental toxicity test with rats was identified as the relevant dose descriptor (NOEL = 50 mg/kg bw/day). Considering the appropriate modification and assessment factors, the general population DNEL (long-term dermal exposure) is calculated as follows: .

Dose descriptor of relevant study: 50 mg/kg bw/day (NOEL)

Assessment factor of duration of exposure (subchronic to chronic): 2

Assessment factor for interspecies (allometric scaling): 4

Assessment factor for other interspecies differences: 1 (The effects observed at the next higher dose of 150 mg/kg were slight and without histological correlate)

Assessment factor for intraspecies differences (general population): 10

General Population DNEL (long-term dermal exposure) 0.625 mg/kg

 

References

- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health.