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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.88 mg/m³
Most sensitive endpoint:
effect on fertility
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:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
881.6 mg/m³
Explanation for the modification of the dose descriptor starting point:

Dose descriptor starting point (oral rat NOAEL = 1000 mg/kg bw) has been determined as a result of an oral test performed according to OECD 422 Guideline. In this test negative results have been obtained (i.e. NOAEL has been set equal to maximum dose of 1000 mg/kg bw); however, according to ECHA Guidance R.8, a negative result in OECD 422 test may lower the concerns for reproductive toxicity, but can not provide reassurance of the absence of this hazardous property.

According to ECHA Guidance Chapter R.8: Characterisation of dose [concentration]-response for human health, negative result in a OECD 422 test can provide the basis for deriving a DNELfertility and/or DNELdevelopment from the highest dose level tested and by application of an additional assessment factor of 2 to 5, decided on a case-by-case basis, that should account for the limitations of the study.

No adequate experimental effect data are available on the inhalation route of exposure for workers; therefore, route-to-route extrapolation has been performed for systemic effects. It is not possible to quantify differences in metabolism, excretion and distribution, so only differences between the different routes as determined by the percentages of absorption into the systemic circulation has been considered.

Default absorption values have been used for the different routes of exposure; therefore, for both the starting route and the end route (the route to which the extrapolation is being made), worst case assumptions have been applied. Worst case, in this context, has been obtained assuming a limited absorption for the starting route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL a maximum absorption has been assumed for the end route, leading to a low external NOAEL.

This approach is proposed by ECHA Guidance Chapter R.8: Characterisation of dose [concentration]-response for human health in the absence of route-specific information on the starting route, to include a default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) in the case of oral-to inhalation extrapolation. The inclusion of this factor 2 means for example that 50% (instead of 100%) absorption is assumed for oral absorption, and 100% for inhalation.

Modification of the starting point

Conversion of the oral rat NOAEL into a corrected inhalatory NOAEC to assess human inhalatory exposure for workers (in case of 8h exposure/d).

corrected inhalatory NOAEC = oral NOAEL x 1/sRVrat x ABSoral-rat/ABSinh-human x sRVhuman/wRV

corrected inhalatory NOAEC = 1000 mg/kg bw x 1/0.38 m3/kg bw x 50/100 x 6.7 m3 (8h)/ 10 m3 (8h) = 881.6 mg/m3

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation is a NOAEL.
AF for differences in duration of exposure:
6
Justification:
The dose descriptor starting point has been determined in OECD 422 test. The combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD TG 422) is a combination of a sub-acute toxicity study and the screening study for reproductive/developmental toxicity; therefore, the extrapolation applied is from subacute to chronic.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling factor has been set to 1.
According to ECHA Guidance Chapter R.8: Characterisation of dose [concentration]-response for human health (version 2.1, 2010 - p. 62) interspecies differences factor for allometric scaling have not to be applied when starting point has been converted from oral NOAEL rat into inhalatory NOAEC rat (Example B.3, p. 62), since the value has been calculated using a default respiratory volume for the rat corresponding to the daily duration of human exposure, followed by a correction for differences in absorption between routes, and a correction for differences in ihalation absorption between rats and humans. Moreover, for workers an additional correction has been applied for the difference between respiratory rates under standard conditions and under conditions of light activity.
AF for other interspecies differences:
2.5
Justification:
An additional factor of 2.5 for other interspecies differences has been applied.
AF for intraspecies differences:
5
Justification:
For workers, as standard procedure for threshold effects a default assessment factor of 5 is to be used, based on the fact that this sub population does not cover the very young, the very old, and the very ill.
AF for the quality of the whole database:
2
Justification:
A negative result in OECD 421/422 test may lower the concerns for reproductive toxicity, but can not provide reassurance of the absence of this hazardous property. However, it can provide the basis for deriving a DNELfertility and/or DNELdevelopment from the highest dose level tested and by application of an additional assessment factor of 2 to 5, decided on a case-by-case basis that should account for the limitations of this study.
AF for remaining uncertainties:
1
Justification:
No others uncertainties identified.
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:
1.67 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
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:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Dose descriptor starting point (oral rat NOAEL = 1000 mg/kg bw) has been determined as a result of an oral test performed according to OECD 422 Guideline. In this test negative results have been obtained (i.e. NOAEL has been set equal to maximum dose of 1000 mg/kg bw); however, according to ECHA Guidance R.8, a negative result in OECD 422 test may lower the concerns for reproductive toxicity, but can not provide reassurance of the absence of this hazardous property.

According to ECHA Guidance Chapter R.8: Characterisation of dose [concentration]-response for human health, negative result in a OECD 422 test can provide the basis for deriving a DNELfertility and/or DNELdevelopment from the highest dose level tested and by application of an additional assessment factor of 2 to 5, decided on a case-by-case basis, that should account for the limitations of the study.

No adequate experimental effect data are available on the dermal route of exposure for workers; therefore, route-to-route extrapolation has been performed for systemic effects. It is not possible to quantify differences in metabolism, excretion and distribution, so only differences between the different routes as determined by the percentages of absorption into the systemic circulation has been considered.

Modification of the starting point

Conversion of the oral rat NOAEL into dermal NOAEL rat (in mg/kg bw day) by correcting for differences in absorption between routes as well as for differences in dermal absorption between rats and humans.

corrected dermal NOAEL = oral NOAEL x ABSoral-rat/ABSderm-human

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e. factor 1) has been introduced for oral-to-dermal extrapolation.

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation is a NOAEL.
AF for differences in duration of exposure:
6
Justification:
The dose descriptor starting point has been determined in OECD 422 test. The combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD TG 422) is a combination of a sub-acute toxicity study and the screening study for reproductive/developmental toxicity; therefore, the extrapolation applied is from subacute to chronic.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling factor for rat is 4.
AF for other interspecies differences:
2.5
Justification:
An additional factor of 2.5 for other interspecies differences has been applied; therefore, the overall value is 10.
AF for intraspecies differences:
5
Justification:
For workers, as standard procedure for threshold effects a default assessment factor of 5 is to be used, based on the fact that this sub population does not cover the very young, the very old, and the very ill.
AF for the quality of the whole database:
2
Justification:
A negative result in OECD 421/422 test may lower the concerns for reproductive toxicity, but can not provide reassurance of the absence of this hazardous property. However, it can provide the basis for deriving a DNELfertility and/or DNELdevelopment from the highest dose level tested and by application of an additional assessment factor of 2 to 5, decided on a case-by-case basis that should account for the limitations of this study.
AF for remaining uncertainties:
1
Justification:
No others uncertainties identified.
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:
high hazard (no threshold derived)

Additional information - workers

General Population - Hazard via inhalation route

Systemic 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

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:
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

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

General Population - Hazard via oral route

Systemic 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 for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

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