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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
23.5 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):
75
Modified dose descriptor starting point:
NOAEC
Value:
1 763 mg/m³
Explanation for the modification of the dose descriptor starting point:
No local or systemic toxicity was observed in a subacute repeated dose toxicity study after oral application; consequently route-to-route extrapoation is appropriate
AF for dose response relationship:
1
Justification:
No toxicity was observed at the limit dose, a NOAEL is = 1000 mg/kg is conservative since no LOAEL can be established.
AF for differences in duration of exposure:
6
Justification:
default sub-acute to chronic extrapolation
AF for interspecies differences (allometric scaling):
1
Justification:
included in the derivation of the dose desciptor starting point.
AF for other interspecies differences:
2.5
Justification:
There is no indication that this "additional uncertainty" is appropriate for this compound. Nevertheless the default factor is applied.
AF for intraspecies differences:
5
Justification:
Default factor for worker
AF for the quality of the whole database:
1
Justification:
No toxicity was observed at the limit dose, a NOAEL is = 1000 mg/kg is conservative since no LOAEL can be established.
AF for remaining uncertainties:
1
Justification:
No toxicity was observed at the limit dose, a NOAEL is = 1000 mg/kg is conservative since no LOAEL can be established.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
188 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: Limit for peak exposure is based on the long-term DNEL and a peak-exposure factor; see justification

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:
3.3 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):
300
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No local or systemic toxicity was observed in a subacute repeated dose toxicity study after oral application; consequently route-to-route extrapoation is appropriate
AF for dose response relationship:
1
Justification:
No toxicity was observed at the limit dose, a NOAEL is = 1000 mg/kg is conservative since no LOAEL can be established.
AF for differences in duration of exposure:
6
Justification:
default sub-acute to chronic extrapolation
AF for interspecies differences (allometric scaling):
4
Justification:
extrapolation from rats to humans
AF for other interspecies differences:
2.5
Justification:
There is no indication that this "additional uncertainty" is appropriate for this compound. Nevertheless the default factor is applied.
AF for intraspecies differences:
5
Justification:
Default factor for worker
AF for the quality of the whole database:
1
Justification:
No toxicity was observed at the limit dose, a NOAEL is = 1000 mg/kg is conservative since no LOAEL can be established.
AF for remaining uncertainties:
1
Justification:
No toxicity was observed at the limit dose, a NOAEL is = 1000 mg/kg is conservative since no LOAEL can be established.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
27 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: Limit for peak exposure is based on the long-term DNEL and a peak-exposure factor; see justification

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

The derived DNEL cover also the endpoints fertility and development.

Fertility: The sub-acute toxicity study with Vulcuren (99.7%) (Bayer AG 2000d) did not reveal any evidence of an adverse effect to the reproductive organs up to the highest dose tested (1000 mg/kg body weight and day). As confirmed by literature (Mangelsdorf et al. 2003, Ulbrich & Palmer 1995, Janer et al. 2007 and Dent 2007) histopathological examinations in repeated dose toxicity are of high value and high sensitivity for the evaluation of reproductive toxicity. Therefore at least for fertility assessment a repeated dose toxicity study showing no adverse effect should be taken into account. Also it is agreed that histopathological changes on the reproductive organs in repeated dose studies (subacute or longer exposure, see e.g. Ulbrich & Palmer 1995, Mangelsdorf et al. 2003) are indicative of effects on fertility. Therefore repeated dose toxicity studies is considered as sufficient information for a DNEL calculation for fertility if histological examination of the reproductive organs is covered by repeated dose toxicity studies and the mode of action of the test substance does not give evidence for a specific toxicity (which is not the case with Vulcuren (purity: 99.7%)). It is proposed by the group of researchers that in the absence of a two-generation study the NOAEL obtained from a subchronic study (or the lowest available studies) could be used as a reference point for deriving the DNEL (Janer at. al. 2007). Therefore, for Vulcuren (purity: 99.7%) the NOAEL (1000 mg/kg body weight and day) from the subacute toxicity study (Bayer AG 2000) could be used for DNEL derivation. No adverse effects on the reproduction organs were seen up to the highest dose group evaluated in male and female rats (1000 mg/kg body weight). Since the long-term DNEL is calculated from this study it covers systemic and fertility endpoints.

Development: A developmental toxicity study according to OECD TG 414 was conducted in rats. NOEL appearance of placentas: 300 mg/kg bw/day; an increased incidence of engorged placentas occurred at the 1000 mg/kg level in one litter, for which a treatment related effect cannot be excluded; NOAEL remaining developmental toxicity: 1000 mg/kg bw/day. Taking 300 mg/kg as a conservative and not necessarily adverse starting point for DNEL calculation and applying the default factors for a developmental toxicity study (interspecies differences: 4; additional uncertainty: 2.5; intra-species difference worker: 5; overall assessment factor of 50) a DNEL of 6 mg/kg could be derived for oral and dermal exposure. The corresponding inhalation DNEL would be 47 mg/m³. These DNEL are higher than the corresponding DNEL derived for systemic toxicity.

Therefore, for Vulcuren the DNELs derived for long-term exposure cover systemic toxicity, fertility and development.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.8 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):
150
Modified dose descriptor starting point:
NOAEC
Value:
870 mg/m³
Explanation for the modification of the dose descriptor starting point:
No local or systemic toxicity was observed in a subacute repeated dose toxicity study after oral application; consequently route-to-route extrapoation is appropriate.
AF for dose response relationship:
1
Justification:
No toxicity was observed at the limit dose, a NOAEL is = 1000 mg/kg is conservative since no LOAEL can be established.
AF for differences in duration of exposure:
6
Justification:
default sub-acute to chronic extrapolation
AF for interspecies differences (allometric scaling):
1
Justification:
included in the derivation of the dose desciptor starting point.
AF for other interspecies differences:
2.5
Justification:
There is no indication that this "additional uncertainty" is appropriate for this compound. Nevertheless the default factor is applied.
AF for intraspecies differences:
10
Justification:
Default factor for general population
AF for the quality of the whole database:
1
Justification:
No toxicity was observed at the limit dose, a NOAEL is = 1000 mg/kg is conservative since no LOAEL can be established.
AF for remaining uncertainties:
1
Justification:
No toxicity was observed at the limit dose, a NOAEL is = 1000 mg/kg is conservative since no LOAEL can be established.
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:
1.7 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):
600
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No local or systemic toxicity was observed in a subacute repeated dose toxicity study after oral application; consequently route-to-route extrapoation is appropriate
AF for dose response relationship:
1
Justification:
No toxicity was observed at the limit dose, a NOAEL is = 1000 mg/kg is conservative since no LOAEL can be established.
AF for differences in duration of exposure:
6
Justification:
default sub-acute to chronic extrapolation
AF for interspecies differences (allometric scaling):
4
Justification:
extrapolation from rats to humans
AF for other interspecies differences:
2.5
Justification:
There is no indication that this "additional uncertainty" is appropriate for this compound. Nevertheless the default factor is applied.
AF for intraspecies differences:
10
Justification:
Default factor for general population
AF for the quality of the whole database:
1
Justification:
No toxicity was observed at the limit dose, a NOAEL is = 1000 mg/kg is conservative since no LOAEL can be established.
AF for remaining uncertainties:
1
Justification:
No toxicity was observed at the limit dose, a NOAEL is = 1000 mg/kg is conservative since no LOAEL can be established.
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:
1.7 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: DNEL were derived similar as dermal DNEL
Overall assessment factor (AF):
600
Modified dose descriptor starting point:
NOAEL
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

The derived DNEL covers also the endpoints fertility and development.

Fertility: The sub-acute toxicity study with Vulcuren (purity: 99.7%) (Bayer AG 2000d) did not reveal any evidence of an adverse effect to the reproductive organs up to the highest dose tested (1000 mg/kg body weight and day). As confirmed by literature (Mangelsdorf et al. 2003, Ulbrich & Palmer 1995, Janer et al. 2007 and Dent 2007) histopathological examinations in repeated dose toxicity are of high value and high sensitivity for the evaluation of reproductive toxicity. Therefore at least for fertility assessment a repeated dose toxicity study showing no adverse effect should be taken into account. Also it is agreed that histopathological changes on the reproductive organs in repeated dose studies (subacute or longer exposure, see e.g. Ulbrich & Palmer 1995, Mangelsdorf et al. 2003) are indicative of effects on fertility. Therefore repeated dose toxicity studies is considered as sufficient information for a DNEL calculation for fertility if histological examination of the reproductive organs is covered by repeated dose toxicity studies and the mode of action of the test substance does not give evidence for a specific toxicity (which is not the case with Vulcuren (purity: 99.7%)). It is proposed by the group of researchers that in the absence of a two-generation study the NOAEL obtained from a subchronic study (or the lowest available studies) could be used as a reference point for deriving the DNEL (Janer at. al. 2007). Therefore, for Vulcuren (purity: 99.7%) the NOAEL (1000 mg/kg body weight and day) from the subacute toxicity study (Bayer AG 2000) could be used for DNEL derivation. No adverse effects on the reproduction organs were seen up to the highest dose group evaluated in male and female rats (1000 mg/kg body weight). Since the long-term DNEL is calculated from this study it covers systemic and fertility endpoints.

Development: A developmental toxicity study according to OECD TG 414 was conducted in rats. NOEL appearance of placentas: 300 mg/kg bw/day; an increased incidence of engorged placentas occurred at the 1000 mg/kg level in one litter, for which a treatment related effect cannot be excluded; NOAEL remaining developmental toxicity: 1000 mg/kg bw/day. Taking 300 mg/kg as a conservative and not necessarily adverse starting point for DNEL calculation and applying the default factors for a developmental toxicity study (interspecies differences: 4; additional uncertainty: 2.5; intra-species difference worker: 10; overall assessment factor of 100) a DNEL of 3 mg/kg could be derived for oral and dermal exposure. The corresponding inhalation DNEL would be 23.5 mg/m³ These DNEL are higher than the corresponding DNEL derived for systemic toxicity.

Therefore, for Vulcuren the DNELs derived for long-term exposure cover systemic toxicity, fertility and development.

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