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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.81 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):
25
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
370.26 mg/m³
Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. For details on calculations please refer to 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:
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:
2.5
Justification:
Recommended AF for other interspecies differences.
AF for intraspecies differences:
5
Justification:
The default value for the relatively homogenous group "worker" is used.
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
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.2 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):
100
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
420 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 and assuming the same absorption for dermal 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:
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:
2.5
Justification:
Recommended AF for other interspecies differences.
AF for intraspecies differences:
5
Justification:
The default value for the relatively homogenous group "worker" is used.
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
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

General
DNEL derivation for the test item is performed under consideration of the recommendations of ECHA (2012).
 
Acute, systemic DNEL
The test substance is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral, inhalation and dermal toxicity. Thus, the derivation of a DNEL for acute/short term exposure is not required.
 
Acute/long term DNEL for local effects
Respiratory irritation: Cyclohexyl methacrylate is classified as respiratory irritant (STOT SE 3, H335) according to Regulation (EC) No 1272/2008 (CLP) and will therefore be qualitatively assessed.

Skin irritation/corrosion: The test substance is not classified for skin irritation/corrosion according to Regulation (EC) No 1272/2008 (CLP) based on the available experimental data. Therefore, no qualitative assessment is conducted.
 
Eye irritation: The test substance is not classified for eye irritation according to Regulation (EC) No 1272/2008 (CLP) based on the available experimental data.Therefore, no qualitative assessment is conducted.

Skin sensitisation: The test substance is classified as skin sensitising cat. 1 according to Regulation (EC) No 1272/2008 (CLP).Although data from a local lymph node assay is available, the derivation of an EC3 was not possible. The available LLNA data showed that the threshold concentration for sensitization induction was < 3%. Based on the available data, Cyclohexylmethacrylate is a skin sensitizer of strong potency. However, taking into account the observed irritating effects on the ears, and the missing dose-dependency of the lymph node proliferation, the sensitising effect cannot be clearly discriminated from at least partly possible lymph node proliferation based on skin irritancy.

In the animal and in vitro studies cyclohexyl methacrylate and methyl methacrylate did not show a skin or eye irritating effect, nevertheless monoalkyl esters of metharcylic acid are classified as irritating to skin, eyes and respiratory tract.
 
Long term, systemic DNEL
Occupational exposure to the test substance occurs mainly by inhalation and dermal route. Therefore two long-term DNELs are calculated for workers. In view of the data used for evaluation, the "quality of whole database factor", "dose-response factor" and remaining “uncertainties” and are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.
 
Exposure by inhalation
Step 1: Selection of the relevant dose descriptor (starting point):
No repeated dose inhalation toxicity studies are available for cyclohexyl methacrylate. Therefore the DNEL long term, systemic (inhalation) is derived by route-to route extrapolation from the repeated dose oral toxicity study.

The modified combined repeated dose oral toxicity study according to OECD 422 and OECD 408 is selected for DNEL derivation. This study is the relevant repeated dose study performed using cyclohexyl methacrylate in accordance to OECD guideline and GLP. In this study, the oral NOAEL is 300 mg/kg bw/day.
 
Step 2: Modification into a correct starting point:
Using a conservative approach, a worker DNEL (long term inhalation exposure) is derived considering a two times higher absorption via inhalation than oral absorption.

 

Relevant dose descriptor (NOAEL): 300 mg/kg bw/day

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

Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat 50 %/ ABSinh-human 100 %): 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

Frequency of exposure in study: 7 days/week

Frequency of worker exposure: 5 days/week

 

Corrected inhalatory NOAEC for workers

= 300 mg/kg bw/day * 0.5 * (1 / 0.38 m³/kg bw/day) * (6.7 m³/10 m³) * (7/5)

= 370.26 mg/m³
 
Step 3: Use of assessment factors: 25
Interspecies: Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
Interspecies AF, remaining differences: 2.5
Intraspecies AF (worker): 5
Exposure duration AF: 2

In conclusion, long term systemic inhalation DNEL, workers = 14.81 mg/m³
 
Dermal exposure
Step 1: Selection of the relevant dose descriptor (starting point):
No repeated dose dermal toxicity studies are available for cyclohexyl methacrylate. Therefore the DNEL long term, systemic (dermal) is derived by route-to route extrapolation from the repeated dose oral toxicity study.

The modified combined repeated dose oral toxicity study according to OECD 422 and OECD 408 is selected for DNEL derivation. This study is the relevant repeated dose study performed using cyclohexyl methacrylate in accordance to OECD guideline and GLP. In this study, the oral NOAEL is 300 mg/kg bw/day.


 
Step 2: Modification of the starting point:
A worker DNEL (long-term dermal exposure) is derived. Based on physico-chemical (MW = 168.23 g/mol, log Kow = 3.13) and toxic properties of the test substance dermal absorption is favorable. The test substance is further classified as skin sensitiser and therefore some penetration has to be assumed. Thus, a dermal absorption equal to oral absorption is assumed as worst case.

Factor for dermal NOAEL= 100 % oral / 100 % dermal= 1

Frequency of exposure in study: 7 days/week

Frequency of worker exposure: 5 days/week

 

oral NOAEL 300 mg/kg bw/day * 1 * (7/5) = 420 mg/kg bw/day dermal NOAEL

Step 3: Use of assessment factors: 100
Interspecies AF, allometric scaling (rat to human): 4
Interspecies AF, remaining differences: 2.5
Intraspecies AF (worker): 5
Exposure duration AF: 2

In conclusion, long term systemic dermal DNEL, workers = 4.2 mg/kg bw/day

References
(not included as endpoint study record) 
- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2.1 ECHA-2010-G-19 –EN. 
- ECHA (2014). Guidance on information requirements and chemical safety assessment.Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. Version 2. ECHA-14 -G-06 -EN. 
- ECHA (2012) Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard 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

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard 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

General Population - Hazard via oral route

Systemic 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 for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Cyclohexyl methacrylate is used as a monomer in industrial applications only. Therefore exposure to the general population is not expected.