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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: ECHA REACH Guidance and ECETOC Technical Report No. 110
Overall assessment factor (AF):
18
Modified dose descriptor starting point:
NOAEC
Value:
176.3
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. For details, please refer to the discussion.
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:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (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:
There is no evidence for species differences in the general mode of actions or kinetics.
AF for intraspecies differences:
3
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:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.8 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):
72
Modified dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated dermal exposure. The recommended approach using oral data assuming a two times lower absorption via the dermal route (end route) as compared to the oral route (starting route) is used. For details, please refer to the discussion.
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:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (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:
There is no evidence for species differences in the general mode of actions or kinetics.
AF for intraspecies differences:
3
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:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Acute/short-term exposure - systemic effects

According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health", a DNEL for acute systemic toxicity should only be derived if an acute systemic toxicity hazard leading to classification is identified.

Referring to the available data on acute toxicity, ureido methacrylate displays no acute toxicity up to 5000 mg/kg bw determined in rats for the oral and dermal route. No experimental data for the inhalation route are available. Therefore, ureido methacrylate is not subject to classification for acute toxicity according to Directive 67/548/EEC and Regulation No 1272/2008, and consequently the derivation of worker DNELs for acute/short-term exposure - systemic effects is not required.

 

Acute/short-term and long-term exposure - local effects

Reliable animal studies were available to assess the local effects of ureido methacrylate. In guideline conform in vivo studies, 0.5 g or 0.5 mL test substance caused no skin irritation after 4 hours of semiocclusive exposure (BASF AG 1986; Rohm & Haas 2002).

A serious risk for eye damage was provided by application of 0.1 mL test substance into the conjunctival sac of rabbit eyes in a guideline conform study without rinsing of the treated eyes (BASF AG 1986). Moderate conjunctivae redness and chemosis was reversible within at least 15 days, but iridal effects and corneal opacity were not reversible within 21 days. There are a few other in vivo studies available applying the same amount of test substance, therefore a quantitative approach of a No-effect-level could not be made based on these studies. In a study, ureido methacrylate was assessed to be a weak skin sensitizer.

The local hazard after acute and long-term exposure is thus covered with a qualitative assessment. Due to a low vapour pressure of 0.0051 Pa at 25°C, effects on the respiratory tract are not expected.

 

Long-term exposure - systemic effects

No studies were available for the assessment of the DNEL after dermal and inhalative exposure. Therefore, route-to-route extrapolations from relevant studies using oral application have to be conducted. As the most reliable source of information, a combined repeated dose study was performed with rats which received ureido methacrylate for 54 days per gavage (Rohm & Haas, 2002). More than 100 mg ureido methacrylate/kg bw/day caused increased liver weights in males. No corroborative findings were observed in necropsy and histopathology indicating an adverse effect, therefore this value is assessed as NOEL. The NOEL in females was assessed to be 300 mg ureido methacrylate/kg bw/day due to increased liver and kidney weights (again, without supporting effects in other observations). No recovery group was installed to check the effects for reversibility. However, as a worst case assumption the observed effects were considered as adverse and the lowest NOAEL is therefore 100 mg/kg bw/day in male rats.

This value was modified to get the correct starting point for the dermal and inhalative DNEL derivation. For the oral-dermal extrapolation, a default factor of 0.5 is used; the correct starting point was therefore 200 mg/kg bw/d for the dermal pathway.

For the inhalation route, the NO(A)EL of 100 mg/kg bw/day from the same subacute oral toxicity study (Rohm & Haas, 2002) is considered to represent the appropriate dose descriptor for systemic effects related to long-term dermal inhalation to ureido methacrylate. A factor of only 1 was assumed for route to route (oral to inhalation) extrapolation.

In order to derive a worker DNEL and under the assumption of a daily exposure period of 8 hours, the oral NO(A)EL is converted into an inhalation NO(A)EC according to the following formula:

inhalation NO(A)EC = oral NO(A)EL × 1/sRV(rat) × ABSoral(rat)/ABSinhalation(human) × sRV(human)/wRV(human)

with:

oral NO(A)EL: 100 mg/kg bw/day

sRV(rat): 0.38 m³/kg bw (8 hours) [standard respiratory volume of the rat]

ABSoral(rat)/ABSinhalation(human): 1 [ratio of oral absorption in the rat to inhalative absorption in the human]

sRV(human)/wRV(human): 6.7 m³/10 m³ [ratio of human standard respiratory volume to worker respiratory volume]

Accordingly, the oral NO(A)EL of 100 mg/kg bw/day is transformed in an inhalation NO(A)EC of 176.3 mg/m³.

 

The following assessment factors are used for the derivation of worker DNELs for dermal or inhalation exposure to ureido methacrylate:

Interspecies factor (rat to human): 4 [used for the dermal route only]

Intraspecies factor (worker): 3

Exposure duration factor: 6 (subacute to chronic) [for the dermal and inhalation route]

Quality of whole database factor: 1

The resulting worker DNELs are:

 

Worker DNEL (inhalation exposure) = 176.3 mg/m³ / (3 × 6 × 1 × 1) = 176.3 mg/m³ / 18 = 9.80 mg/m³

 

Worker DNEL (dermal exposure) = 200 mg/kg bw/day / (4 × 3 × 6 × 1 × 1) = 200 mg/kg bw/day /72 = 2.78 mg/kg bw/day

 

This is in line with ECETOC technical report no. 110, 2010 "Guidance on assessment factors to derive a DNEL" and ECETOC technical report no. 86, 2003 “Derivation of assessment factors for human health risk assessment”.

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:
other: ECHA REACH Guidance and ECETOC Technical Report No. 110
Overall assessment factor (AF):
30
Modified dose descriptor starting point:
NOAEC
Value:
86.9 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. For details, please refer to the discussion.
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:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (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:
There is no evidence for species differences in the general mode of actions or kinetics.
AF for intraspecies differences:
5
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:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
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:
other: ECHA REACH Guidance and ECETOC Technical Report No. 110
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated dermal exposure. The recommended approach using oral data assuming a two times lower absorption via the dermal route (end route) as compared to the oral route (starting route) is used. For details, please refer to the discussion.
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:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (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:
There is no evidence for species differences in the general mode of actions or kinetics.
AF for intraspecies differences:
5
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:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

Local effects

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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.83 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):
120
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No route to route extrapolation is necessary as a oral repeated dose 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:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (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:
There is no evidence for species differences in the general mode of actions or kinetics.
AF for intraspecies differences:
5
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:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

Acute/short-term exposure - systemic effects

According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health", a DNEL for acute systemic toxicity should only be derived if an acute systemic toxicity hazard leading to classification is identified. Referring to the available data on acute toxicity, ureido methacrylate displays no acute toxicity up to 5000 mg/kg bw determined in rats for the oral and dermal route. No experimental data for the inhalation route are available. Therefore, ureido methacrylate is not subject to classification for acute toxicity according to Directive 67/548/EEC and Regulation No 1272/2008, and consequently the derivation of worker DNELs for acute/short-term exposure - systemic effects is not required.

Acute/short-term and long-term exposure - local effects

Reliable animal studies were available to assess the local effects of ureido methacrylate. In guideline conform in vivo studies, 0.5 g or 0.5 mL test substance caused no skin irritation after 4 hours of semiocclusive exposure (BASF AG 1986; Rohm & Haas 2002).

A serious risk for eye damage was provided by application of 0.1 mL test substance into the conjunctival sac of rabbit eyes in a guideline conform study without rinsing of the treated eyes (BASF AG 1986). Moderate conjunctivae redness and chemosis was reversible within at least 15 days, but iridal effects and corneal opacity were not reversible within 21 days. There are a few other in vivo studies available applying the same amount of test substance, therefore a quantitative approach of a No-effect-level could not be made based on these studies. In a study, ureido methacrylate was assessed to be a weak skin sensitizer.

The local hazard after acute and long-term exposure is thus covered with a qualitative assessment. Due to a low vapour pressure of 0.0051 Pa at 25°C, effects on the respiratory tract are not expected.

 

Long-term exposure - systemic effects

No studies were available for the assessment of the DNEL after dermal and inhalative exposure. Therefore, route-to-route extrapolations from relevant studies using oral application have to be conducted. As the most reliable source of information, a combined repeated dose study was performed with rats which received ureido methacrylate for 54 days per gavage (Rohm & Haas, 2002). More than 100 mg ureido methacrylate/kg bw/day caused increased liver weights in males. No corroborative findings were observed in necropsy and histopathology indicating an adverse effect, therefore this value is assessed as NOEL. The NOEL in females was assessed to be 300 mg ureido methacrylate/kg bw/day due to increased liver and kidney weights (again, without supporting effects in other observations). No recovery group was installed to check the effects for reversibility. However, as a worst case assumption the observed effects were considered as adverse and the lowest NOAEL is therefore 100 mg/kg bw/day in male rats.

This value was modified to get the correct starting point for the dermal and inhalative DNEL derivation. For the oral-dermal extrapolation, a default factor of 0.5 is used; the correct starting point was therefore 200 mg/kg bw/d for the dermal pathway.

For the inhalation route, the NO(A)EL of 100 mg/kg bw/day from the same subacute oral toxicity study (Rohm & Haas, 2002) is considered to represent the appropriate dose descriptor for systemic effects related to long-term dermal inhalation to ureido methacrylate. A factor of 1 was assumed for route to route (oral to inhalation) extrapolation.

In order to derive a general population DNEL and under the assumption of a daily exposure period of 24 hours, the oral NO(A)EL is converted into an inhalation NO(A)EC according to the following formula:

Inhalation NO(A)EC = oral NO(A)EL × 1/sRV(rat) × ABSoral(rat)/ABSinhalation(human)

with:

oral NO(A)EL: 100 mg/kg bw/day

sRV(rat): 1.15 m³/kg bw/day [standard respiratory volume of the rat]

ABSoral(rat)/ABSinhalation(human): 1 [ratio of oral absorption in the rat to inhalative absorption in the human]

Accordingly, the oral NO(A)EL of 100 mg/kg bw/day is transformed in an inhalation NO(A)EC of 86.9 mg/m³.

 

For the oral route, the NO(A)EL of 100 mg/kg bw/day from the same subacute oral toxicity study (Rohm & Haas, 2002) is considered to represent the appropriate dose descriptor for systemic effects related to long-term exposure to ureido methacrylate.

 

The following assessment factors are used for the derivation of general population DNELs for dermal, inhalation or oral exposure to ureido methacrylate:

Interspecies factor (rat to human): 4 [used for the oral and dermal route only]

Intraspecies factor (general population): 5

Exposure duration factor: 6 (subacute to chronic) [for the dermal, inhalation and oral route]

Quality of whole database factor: 1

 

The resulting general population DNELs are:

 

General population DNEL (inhalation exposure) = 86.9 mg/m³ / (5 × 6 × 1 × 1) = 86.9 mg/m³ / 30 = 2.90 mg/m³

 

General population DNEL (dermal exposure) = 200 mg/kg bw/day / (4 × 5 × 6 × 1 × 1) = 200 mg/kg bw/day / 120 = 1.67 mg/kg bw/day

 

General population DNEL (oral exposure) = 100 mg/kg bw/day / (4 × 5 × 6 × 1 × 1) = 100 mg/kg bw/day / 120 = 0.83 mg/kg bw/day

 

This is in line withECETOC technical report no. 110, 2010 "Guidance on assessment factors to derive a DNEL". and ECETOC technical report no. 86, 2003 “Derivation of assessment factors for human health risk assessment”.