4-(1,1-dimethylethyl)cyclohexyl methacrylate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: A combination of QSAR, indirect experimental study data etc

Adequacy of study:

weight of evidence

Reliability:

other:

Rationale for reliability incl. deficiencies:

other: No true toxicokinetic, metabplism, and distribution studies are available. a combination of QSAR, physchem properties, oral study data, and some analogue data are included.

Materials and methods

Principles of method if other than guideline:

Peredictions based on physchem properties, QSAR, and an in vivo (oral) study

GLP compliance:

yes (incl. QA statement)

Applicant's summary and conclusion

Conclusions:

Specific data are not available on the toxicokinetics, distribution, metabolism and excretion of the test substance. QSAR profile (Lipinski’s rule of bioavailability) suggests it may bioavailable. Hydrolysis of the registered substance, CAS No. 46729-07-1, could not be determined as a hydrolysis study was technically not feasible. Due to the low water solubility of the substance an analytical method of adequate accuracy could not be developed. Some of the available physico-chemical information may be useful to understand the potential for the absorption of the test item.

Absorption through Inhalation
The vapor pressure (2.88 Pa at 25oC) of the test item is low. Therefore, inhalation is not expected to be a major route of exposure / absorption.

Dermal absorption
The test item is not a skin irritant Low molecular weight (224.34) and low vapor pressure may favor dermal uptake. The substance is nor an eye irritant either. The QSAR result showed that the dermal absorption is 0.000808 mg/cm2/event (EPI DERMWIN). An indirect evidence of dermal absorption and distribution of the test item can be inferred from a read-across of the substance with an analogue, cyclohexyl methacrylate. The latter is classified as a skin sensitizer in mice. QSAR revealed some protein binding possibility, which is a first obligatory step required for skin sensitization. It may be a weak sensitizer. It is presumed that some uptake could occur to cause a positive immune system effect, which is a systemic response. Based on the physical properties (low molecular weight; low water solubility (0.04mg/L)), the test substance is expected to have a relatively moderate dermal absorption rate. It was assumed to be 50% absorbed for long term systemic DNEL calculations.

Absorption rate - oral (%)
100.0

Absorption rate - dermal (%)
50.0

Absorption rate - inhalation (%)
100.0

Oral Absorption.
Per QSAR, absorption from gastrointestinal tract could occur (90-100%). Some evidence of absorption and distribution of the test item can be inferred from the available in vivo study in rat (oral). The test substance, as tested, contained approximately 89.2% peroxide. Any lipophilic compound may be taken up by micellar solubilization but this mechanism may be of particular importance for highly lipophilic compounds (log P>4), particularly those that are poorly soluble in water (< 1mg/L) that would otherwise be poorly absorbed. Several systemic effects were noted in a 6-8 week OECD 422 oral gavage study in rats, as described below. The presence of Arachis oil in the gavage dose formulation may have had some influence on the test substance’s absorption from the digestive tract.

The oral administration of 4-(1,1-dimethylethyl)cyclohexyl methacrylate (CAS 46729-07-1) to Wistar Han™:RccHan™:WIST strain rats for a period of up to 8 weeks (including 2 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. The ‘No Observed Adverse Effect Level’ (NOAEL) for females was also 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). A NOAEL was established at 150 mg/kg bw/day for males because the findings do not reflect true systemic toxicity. The NOEL and the NOAEL for reproductive and developmental toxicity was considered to be 150 mg/kg bw/day.

These results clearly show the absorption of the test substance from the gastrointestinal tract of the rat, and distribution into internal organs at sufficient concentrations, of either the test substance or its potential metabolite(s), causing microscopic effects at tissue / cellular levels in a generally dose-dependent manner. However, this information does not provide quantitative data as to how much of the substance was absorbed or reached the target organ(s) or eliminated. No specific information is available on the metabolism or elimination of the test substance.

Ester hydrolysis is considered to be the only significant metabolic pathway for certain methacylates (Source: Disseminated dossier of the read across substance, CAS# 101-43-9). Accordingly, regarding the subsequent metabolism of the primary metabolites within the body and excretion, methacrylic acid and the corresponding alcohol are subsequently cleared predominantly via the liver (valine pathway and the TCA (TriCarboxylic Acid) cycle, respectively). It is generally accepted that methacrylic acid-coenzyme-A is a naturally occurring intermediate of the valine pathway. Methacrylic acid-COA is rapidly converted into (S3)-hydroxyisobutyryI-COA by the enzyme enoyI-CoA-hydratase. This pathway joins the citrate cycle, carbon dioxide and water being the final products (Rawn, 1983; Shimomura et 31., 1994; Boehringer, 1992).