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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.76 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:
264.5 mg/m³
Explanation for the modification of the dose descriptor starting point:
For converting the oral NOAEL (rat) to an inhalation NOAEC for worker the oral NOAEL (rat) is multiplied with 1/0.38 m³/kg bw/8h (default respiratory volume in rat, Table R.8.2 of CSR guidance) to give the corresponding rat inhalation 8h-NOAEC (no-observed adverse effect concentration). Due to the absence of route specific information a default factor of 2 is included by assuming 50 % for oral absorption (ABS oral-rat) and 100 % absorption after inhalation (ABS inh-human). To obtain the starting point for workers, a factor of 0.67 is applied to account for the differences in inhalation rates between animals at rest and humans involved in light activity. For workers the corrected inhalation NOAEC is calculated according to the following equation: corrected inhalation NOAEC = oral NOAEL x 1/sRV ratx ABS oral-rat/ ABS inh-human x sRV human/ wRV1 = 300 x 1/0.38 x50/100 x 6.7/10
AF for dose response relationship:
1
Justification:
In a reliable, adequate and relevant subchronic study in rats there were no toxicological effects relevant to humans up to and including the highest administered dose of 300 mg/kg bw/d. The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
Default assessment factor for extrapolation from sub acute to chronic.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling rat to humans as inhalation; differences in respiratory volume already included in route-to-route extrapolation (ECHA 2008).
AF for other interspecies differences:
2.5
Justification:
Default AF for remaining interspecies differences
AF for intraspecies differences:
5
Justification:
Default AF for workers.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. The tested dose range included the highest administered dose of 300 mg/kg bw/day. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
2
Justification:
To account for a lower sensitivity and the limited scope of the repeated dose toxicity studies for detecting effects on reproductive organs an additional assessment factor of 2 was applied.
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:
0.5 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:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The dermal NOAEL is determined to be equal to the oral NOAEL. Based on the assumption, that dermal absorption will not be higher than oral absorption, no additional assessment factor deemed necessary for oral-todermal extrapolation.
AF for dose response relationship:
1
Justification:
In a reliable, adequate and relevant subchronic study in rats there were no toxicological effects relevant to humans up to and including the highest administered dose of 300 mg/kg bw/d. The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
Default assessment factor for extrapolation from sub-acute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (ECHA 2008).
AF for other interspecies differences:
2.5
Justification:
Default AF for remaining interspecies differences
AF for intraspecies differences:
5
Justification:
Default AF for workers
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. The tested dose range included the highest administered dose of 300 mg/kg bw/day. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
2
Justification:
To account for a lower sensitivity and the limited scope of the repeated dose toxicity studies for detecting effects on reproductive organs an additional assessment factor of 2 was applied.
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:
no hazard identified

Additional information - workers

Selection of the relevant dose descriptors:

Oral:

NOAEL 300 mg/kg bw/day: 28-day gavage study rat; highest dose tested

 

Modification to the correct starting point:

No data exist on differences in bioavailability following oral or dermal exposure between experimental

animals and humans, and a similar bioavailability is assumed by default.

 

Route-to-route extrapolations:

Oral to dermal:

The dermal NOAEL is determined to be equal to the oral NOAEL. Based on the assumption, that dermal absorption will not be higher than oral absorption, no additional assessment factor deemed necessary for oral-to dermal extrapolation.

 

The dermal NOAEL is therefore:

NOAEL 300 mg/kg bw/day: 28-day gavage study rat; highest dose tested

 

Oral to inhalatory

For inhalatory exposure as a worst case assumption a 100% absorption is assumed in absence ofany experimental data (TGD R85).

For workers the corrected inhalatory NOEC is calculated according to the following equation(TGD on information requirements R8, Figure R. 8-3):

corrected inhalatory NOEC = oral NOEL x 1/sRVrat x ABSoral-rat / ABSinh-human x sRVhuman / wRV

= 300 x 1/0.38 x 50/100 x 6.7/10

 

The corrected inhalatory NOECworker (8h) is therefore:

= 264.5 mg/m³ (8h-TWA)

 

DNELs local effects

DNELs acute and long-term - local effects are not established because the substance does not meetthe classification criteria for irritation, corrosion and sensitisation.

DNELs systemic effects

DNEL acute, systemic effects:

A DNEL acute systemic effects (inhalation, dermal and oral route) was not derived as no acutefindings were observed in either acute or the long-term studies and there is no potential for highpeak exposures. The DNEL long-term is also protective for acute exposures.

 

DNEL long term, systemic effects:

DNELs long-term, systemic effects for workers have been derived for the dermal and inhalationroute. Inhalation is not a relevant route of exposure for this substance (please refer to the exposure scenarios in chapter 9 and 10). The DNEL for the inhalation route has only been derived to run a tier 1 exposure assessment since the recommended tools also calculate aninhalation exposure by default.

Strictly conservative DNELs have been derived from results of the available test data, which is sub-acute a study (for a compilation of all long-term DNELs derived please refer to Annex I).

No substance-related adverse effects were found in any of the tests conducted and the NOAEL used to derive the DNEL corresponds to the maximum doses tested. To account for a lower sensitivity and the limited scope of the repeated dose toxicity study for detecting effects on reproductive organs an additional assessment factor of 2 was applied. The additional assessment factor of 2 was chosen in accordance with the REACH TGD (Chapter R8).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.44 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):
300
Modified dose descriptor starting point:
NOAEC
Value:
130.4 mg/m³
Explanation for the modification of the dose descriptor starting point:
To assess consumer inhalation exposure, the oral NOAEL (rat) is multiplied with 1/1.15 m³/kg bw (Table R.8.2 of CSR guidance) to give the corresponding 24h-NOAEC (no-observed adverse effect concentration). Due to the absence of route specific information a default factor of 2 is included by assuming 50 % for oral absorption (ABS oral-rat) and 100 % absorption after inhalation (ABS inh-human). For consumers the corrected inhalation NOAEC is calculated according to the following equation: corrected inhalation NOAEC = oral NOAEL x 1/sRV rat x ABS oral-rat/ ABS inh-rat x ABS oral-human/ ABS inh-human = 300 x 1/1.15 x50/100
AF for dose response relationship:
1
Justification:
In a reliable, adequate and relevant sub-acute study in rats there were no toxicological effects relevant to humans up to and including the highest administered dose of 300 mg/kg bw/d. The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
Default assessment factor for extrapolation from sub-acute to chronic.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling rat to humans as inhalation; differences in respiratory volume already included in route-to-route extrapolation (ECHA 2008).
AF for other interspecies differences:
2.5
Justification:
Default AF for remaining interspecies differences
AF for intraspecies differences:
10
Justification:
Default AF for general population
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. The tested dose range included the highest administered dose of 300 mg/kg bw/day. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
2
Justification:
To account for a lower sensitivity and the limited scope of the repeated dose toxicity studies for detecting effects on reproductive organs an additional assessment factor of 2 was applied.
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:
0.25 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):
1 200
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The dermal NOAEL is determined to be equal to the oral NOAEL. Based on the assumption, that dermal absorption will not be higher than oral absorption, no additional assessment factor deemed necessary for oral-todermal extrapolation.
AF for dose response relationship:
1
Justification:
In a reliable, adequate and relevant subchronic study in rats there were no toxicological effects relevant to humans up to and including the highest administered dose of 300 mg/kg bw/d. The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
Default assessment factor for extrapolation from sub-acute to chronic.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (ECHA 2008).
AF for other interspecies differences:
2.5
Justification:
Default AF for remaining interspecies differences
AF for intraspecies differences:
10
Justification:
Default AF for general population
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. The tested dose range included the highest administered dose of 300 mg/kg bw/day. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
2
Justification:
To account for a lower sensitivity and the limited scope of the repeated dose toxicity studies for detecting effects on reproductive organs an additional assessment factor of 2 was applied.
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:
0.25 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):
1 200
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no route to route extrapolation required
AF for dose response relationship:
1
Justification:
In a reliable, adequate and relevant sub-acute study in rats there were no toxicological effects relevant to humans up to and including the highest administered dose of 300 mg/kg bw/d. The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
Default assessment factor for extrapolation from sub-acute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (ECHA 2008).
AF for other interspecies differences:
2.5
Justification:
Default AF for remaining interspecies differences
AF for intraspecies differences:
10
Justification:
Default AF for general population
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. The tested dose range included the highest administered dose of 300 mg/kg bw/day. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
2
Justification:
To account for a lower sensitivity and the limited scope of the repeated dose toxicity studies for detecting effects on reproductive organs an additional assessment factor of 2 was applied.
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

Selection of the relevant dose descriptors:

Oral:

NOAEL 300 mg/kg bw/day: 28-day gavage study rat; highest dose tested

 

Modification to the correct starting point:

No data exist on differences in bioavailability following oral or dermal exposure between experimental

animals and humans, and a similar bioavailability is assumed by default.

 

Route-to-route extrapolations:

Oral to dermal:

The dermal NOAEL is determined to be equal to the oral NOAEL. Based on the assumption, that dermal absorption will not be higher than oral absorption, no additional assessment factor deemed necessary for oral-to dermal extrapolation.

 

The dermal NOAEL is therefore:

NOAEL 300 mg/kg bw/day: 28-day gavage study rat; highest dose tested

 

Oral to inhalatory

For inhalatory exposure as a worst case assumption a 100% absorption is assumed in absence ofany experimental data (TGD R85).

For general population in case of 24 hours exposure/d  the corrected inhalatory NOEC is calculated according to the following equation(TGD on information requirements R8, Figure R. 8-3):

corrected inhalatory NOEC = oral NOEL x 1/sRVrat x ABSoral-rat / ABSinh-human x sRVhuman / wRV

= 300 x 1/1.15 x 50/100

 

The corrected inhalatory NOEC general population (24 h) is therefore:

= 130.4 mg/m³

 

DNELs local effects

DNELs acute and long-term - local effects are not established because the substance does not meetthe classification criteria for irritation, corrosion and sensitisation.

DNELs systemic effects

DNEL acute, systemic effects:

A DNEL acute systemic effects (inhalation, dermal and oral route) was not derived as no acutefindings were observed in either acute or the long-term studies and there is no potential for highpeak exposures. The DNEL long-term is also protective for acute exposures.

 

DNEL long term, systemic effects:

DNELs long-term, systemic effects for general population have been derived for the dermal and inhalation route. Inhalation is not a relevant route of exposure for this substance (please refer to the exposure scenarios in chapter 9 and 10). The DNEL for the inhalation route has only been derived to run a tier 1 exposure assessment since the recommended tools also calculate an inhalation exposure by default.

Strictly conservative DNELs have been derived from results of the available test data,which is sub-acute a study(for a compilation of all long-term DNELs derived please refer to Annex I).

No substance-related adverse effects were found in any of the tests conducted and the NOAEL used to derive the DNEL corresponds to the maximum doses tested. To account for a lower sensitivity and the limited scope of the repeated dose toxicity study for detecting effects on reproductive organs an additional assessment factor of 2 was applied. The additional assessment factor of 2 was chosen in accordance with the REACH TGD (Chapter R8).