4-(1,1-dimethylethyl)cyclohexyl methacrylate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.64 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):

50

Dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

132.24 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no relevant data for repeated exposure by inhalation. The systemic NOAEL of 150 mg/kg/day from OECD 422 repeat dose oral study with rats (6 - 8 weeks) was used for DNEL derivation. Assuming an oral /inhalation absorption of 0.5 a dose descriptor NOAEC of 132.24 mg/m3 was derived as the modified starting point. This study is a well conducted repeated dose study in rats and is of good quality (GLP, OECD guideline). For details, please see under "Additional information - Workers".

AF for dose response relationship:

1

Justification:

Based on REACH Guidance. The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

4

Justification:

Based on REACH Guidance. The default extrapolation factor for exposure duration is used: The OECD 422 study length is between asubacute to subchronic (6-8 weeks). Therefore, AF 4 was used.

AF for interspecies differences (allometric scaling):

1

Justification:

Not applicable for inhalation DNEL, per REACH Guidance. Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences:

2.5

Justification:

Based on REACH Guidance

AF for intraspecies differences:

5

Justification:

Based on REACH Guidance (default value for the relatively homogeneous group, "worker" is used.

AF for the quality of the whole database:

1

Justification:

Based on REACH Guidance - considered sufficient.

AF for remaining uncertainties:

1

Justification:

Based on REACH Guidance. The approach used is conservative. No further assessment factors are required.

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:

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:

1.5 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):

200

Dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no specific experimental data on repeated dermal exposure or on dermal absorption. The systemic NOAEL of 150 mg/kg bw/day from OECD 422 repeat dose oral study in rats was used. Assuming a dermal absorption of 50% (taking into account the physico-chemical properties of low molecular weight and water solubility and high logKow), a dose descriptor of 300 mg/kg bw/d was derived as the starting point.This study was used for DNEL derivation as it is of good quality (GLP, OECD). Details can be found under "Additional information - Workers"

AF for dose response relationship:

1

Justification:

per REACH Guidance

AF for differences in duration of exposure:

4

Justification:

Per REACH Guidance. (OECD 422 study duration was 6-8 weeks)

AF for interspecies differences (allometric scaling):

4

Justification:

per REACH Guidance (allometric scaling)

AF for other interspecies differences:

2.5

Justification:

per REACH Guidance

AF for intraspecies differences:

5

Justification:

per REACH Guidance. Default value

AF for the quality of the whole database:

1

Justification:

per REACH Guidance. Default value

AF for remaining uncertainties:

1

Justification:

per REACH Guidance. Default value.

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Route of original study:

Dermal

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

Table 1. Physchem properties of4-(1,1-dimethylethyl)cyclohexyl methacrylate (CAS 46729-07-1)

 

Physical state		Liquid
Mol. Wt	g/Mol	224.34
Water solubility	mg/L, in water (measured)	0.04 at 20^oC
Log Kow	OECD 117	6.07 at 22^oC
Vapor Pressure	Pa (measured)	2.88 at 25^oC
skin	In vivo	Non-Irritant
Eye	In vivo	Non-Irritant
Skin sensitization	In vivo, LLNA (OECD 429)	Sensitizer, Cat 1
NOAEL, oral, rat,	Mg/kg bw/day (OECD 422)	150

 

Since the vapor pressure is low (2.88 Pa), exposure through inhalation is considered low. Low water solubility (0.04 mg/L) and higher log Kow (6.07) may lower or limit the uptake through skin. Low molecular weight (224.34) and low vapor pressure may favor dermal uptake. Therefore, the dermal absorption was considered to be 50%. The substance is neither a skin irritant nor an eye irritant.

 

It is considered to be a skin sensitizer (Cat. 1) based on QSAR analysis and a read across with CAS# 101 -43 -9 having positive LLNA result. A qualitative assessment is made for dermal exposure under the "High hazard band" category. Two long-term systemic DNELs (dermal and inhalation) are calculated for workers.

 

In an OECD 422 (6-8 week repeated dose) study conducted under GLP conditions, the oral administration of 4-(1,1-dimethylethyl)cyclohexyl methacrylate (CAS 46729-07-1) toWistar Han™:RccHan™:WIST strainrats for a period of up to eight weeks (including two weeks pre-pairing, gestation and early lactation for females) at dose levels 50, 150 and 450 mg/kg bw/day resulted in treatment related effects in animals of either sex treated with 450 mg/kg bw/day and in males treated with 150 and 50 mg/kg bw/day. These included reduced initial body weight gains in either sex at 450 mg/kg bw/day, reduced food consumption in females at 450 mg/kg bw/day, organ weight changes in males at 450 mg/kg bw/day, macroscopic changes in males at 450 mg/kg bw/day and microscopic changes in males at 450, 150 and 50 mg/kg bw/day. A No Observed Effect Level (NOEL) for systemic toxicity was therefore not established for males but was considered to be 150 mg/kg bw/day for females. NOAEL for systemic toxicity in females is considered to be 150 mg/kg bw/day.

 

Although the kidney findings of tubular basophilia and proteinaceous casts in male kidneys could be considered an adverse effect, these findings were considered to be associated with alpha 2u-globulin and formation of hyaline droplets, an effect recognized as being both species and sex specific and not relevant for humans. In terms of risk assessment, these findings observed on this study would suggest that a No Observed Adverse Effect Level (NOAEL) can be established at 150 mg/kg bw/day for males because the findings do not reflect true systemic toxicity. The ‘No Observed Adverse Effect Level’ (NOAEL) for reproductive toxicity was considered to be 150 mg/kg bw/day based on reduced offspring body weight gain and litter weights from Day 4post partumat 450 mg/kg bw/day.

Therefore, for DNEL calculation purposes, the NOAEL value of 150 mg/k bw/day was used.

 

DNEL inhalation-systemic-worker for 4 -(1,1 -dimethylethyl)cyclohexyl methacrylate:

 

Corrected inhalatory NOAEC: Oral NOAELx(1/sRVrat)x(ABSoral-rat/ABSinh-human)x(sRVhuman/wRV)

Correction for inhalation and oral absorption rates: Assume ABSoral-rat/ABSinh-human is 50/100 = 0.5 based on phys-chem properties and Endpoint Specific Guidance chapters 8 and 7c (R.7.12).

[ABS: absorption; sRV: standard Respiratory Volume; wRV: worker Respiratory Volume]

 

Conversion into an inhalatory rat NOAEC: dividing by 0.38 m3/kg (8-hour respiratory volume in the rat)

 

Correction for activity driven differences in respiratory volume in workers compared to individuals at rest: (6.7 m3/10 m3)

 

Therefore, Corrected NOAEC = 150 mg/kg/day x (1/0.38 m3/kg/day) x (0.5) x 6.7 m3/10m3 = 132.24 mg/m3 (Dose descriptor)

 

Applying remaining assessment factors in accordance with Endpoint Specific Guidance Chapter 8:

Correction for interspecies differences: 2.5

132.24 mg/m3/2.5 = 52.90 mg/m3

Correction for intraspecies differences: 5

52.90 mg/m3 /5 = 10.57 mg/m3

Correction for duration of exposure [between sub-acute-subchronic to chronic i.e., OECD 422]: 4

10.57 mg/m3/4 = 2.64 mg/m3

Correction for dose-response:1

2.64 mg/m3/1 = 2.64 mg/m3

Correction for whole database: 1 due to quality of study

2.64 mg/m3/1 = 2.64 mg/m3

Total AF = 50

 

DNEL, inhalation-systemic-worker = 2.64 mg/m3

 

DNEL dermal-systemic-worker for 4-(1,1-dimethylethyl)cyclohexyl methacrylate:

 

Corrections for dermal and oral absorption rates of 4-(1,1-dimethylethyl)cyclohexyl methacrylate based on Guidance on information reqirements

and chemical safety assessment, Chapter R 7.12: Dermal absorption is assumed to be moderate due to (1) the substance is a liquid but poorly soluble in water; and (2). High log Kow and low vapor pressure. The substance is a not a skin irritant but considered to be a skin sensitizer. The skin absorption is assumed to be 50% (correction factor= 0.5) as actual dermal absorption data are unavailable. The oral absorption factor is considered as100%.

 

Oral NOAEL (150 mg/kg/day) / 0.5 (50% dermal absorption) = 300 mg/kg/day = dermal dose descriptor.

Applying assessment factors in accordance with Endpoint Specific Guidance Chapter 8:

Correction for interspecies differences (applying allometric scaling factor of 4 for rat x 2.5 for additional factors): 10

300 mg/kg/day/10 = 30 mg/kg/d

Correction for intraspecies difference: 5

30 mg/kg/day/5 = 6 mg/kg/d

Correction for duration of exposure [between sub-acute/subchronic to chronic; OECD 422]: 4

6 mg/kg/day/4 = 1.5 mg/kg/d

Correction for dose-response: 1 (due to NOAEL)

1.5 mg/kg/day/1 = 1.5 mg/kg/d

Correction for whole database: 1 (due to quality of study)

1.5 mg/kg/day/1 = 1.5 mg/kg/d

 

Total AF = 200

 

DNEL, Dermal-worker-systemic = 1.5 mg/kg/day

 

There are no consumer uses of this substance. Human exposure, via the environment, is unlikely due to the general instability of the peroxide. The general population is not expected to be exposed to the substance by inhalation, dermal or oral exposures. Therefore no inhalation and dermal DNELs are derived for general population. Only DNELs for the relevant populations will have to be derived (Guidance on information requirements and chemical safety assessment R.8.1.2.3).  

 

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