2-(3,5-dimethylhex-3-en-2-yloxy)-2-methylpropyl cyclopropanecarboxylate

Endpoint summary

Description of key information

No specific toxicokinetic studies are required at this tonnage band but a toxicokinetic assessment was made based on the results of the toxicity studies (acute and repeated oral toxicity studies, skin irritation, eye irritation, skin sensitization, in vitro/in vivo genotoxicity and toxicity to reproduction (OECD 421)).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

No specific studies on the absorption, distribution, metabolism and elimination (ADME) of the substance are available and/or required at this tonnage band. 

A toxicokinetic assessment was made based on the results of the toxicity studies (acute and repeated oral toxicity studies, skin irritation, eye irritation, skin sensitization, in vitro/in vivo genotoxicity and toxicity to reproduction (OECD 421)).

 

The notified substance is a small organic molecule with a molecular weight of 268.39. It is a liquid and has a water solubility of 14 mg/L at 20°C and a log Kow of 4.4. 

 

Absorption:

Oral/GI absorption

The physical chemical characteristics described above suggest that the substance is of adequate molecular size (< 500 g/mol) to participate in endogenous absorption mechanisms within the mammalian gastrointestinal tract. The target substance is likely expected to cross gastrointestinal epithelial barriers. The absorption may be potentiated by the ability of the substance to dissolve into gastro-intestinal fluids and hence make contact with the mucosal surface.

These hypotheses are supported in the 28-day oral studies where evidence of liver and kidney changes were observed and indicate absorption from the GI tract and distribution within the body.

Dose levels >100 mg/kg/day were considered to have exceeded the no-adverse-effect-level due to test substance related and adverse effects on clinical biochemistry indicative of impaired kidney function and hepatocellular vacualation in the liver noted at this dose level.

The NOAEL was set to 50 mg/kg bw/day in the 28-day repeated dose toxicity study. 

Dermal absorption

The uptake of the substance into the stratum corneum is enhanced considering its potential to solubilize lipids allowing the transfer between the stratum corneum and the epidermis. The substance is sensitizing to the skin which may upon high-dose contact favour dermal penetration of the substance. Nevertheless, no evidence of bioavailability via dermal route was observed in the acute dermal toxicity study up to 2000 mg/kg bw.

 

Respiratory absorption

The potential for inhalation toxicity was not evaluated.

The vapour pressure of the target substance (VP = 0.459 Pa at 20°C) indicated a low volatility and inhalability and therefore no exposure by inhalation is anticipated. Thus, at ambient temperature, no respiratory absorption is expected under normal use and handling of the substance.

Based on the result of the physico-chemical properties, toxicological properties and pattern of use, e.g. potential human exposure, it has been determined that inhalation is not anticipated to be a potential route of exposure during the normal use(s) of this material.

 

Distribution:

Systemic distribution of the substance can be predicted from its physical chemical characteristics. Considering that the substance is highly lipophilic (log Pow >4) and slightly water soluble, it is suggested that, upon systemic absorption, the substance may be transported through the circulatory system in association with a carrier molecule such as a lipoprotein or other macromolecule. Afterwards, based on its lipophilic character, the substance will readily cross cellular barriers or will be distributed into fatty tissues with a potential to accumulate. Distribution of the substance via dermal route is supported by the positive response in the skin sensitisation test, which suggests that the test material binds to carrier proteins in the circulatory system.

Metabolism:

The results of the 28-day repeated dose toxicity study (OECD 407) performed in the rat with the substance showed liver changes that are consistent with the increased metabolism associated with detoxification of a xenobiotic. This liver induction confirmed that a non-negligible part of the substance is metabolised following gastrointestinal tract absorption.

 

Excretion:

The substance, having a molecular weight lower than 500 g/mol, is expected to be mainly excreted in urine unchanged or as glucuronide and sulfate conjugates following oral exposure and inhalation. A minor amount (< 10%) may be excreted in bile as such or as metabolites following metabolism. Any substance that is not absorbed from the gastro-intestinal tract, following oral ingestion, will be excreted in the faeces.

Following dermal exposure, highly lipophilic substances, such as the substance, that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with skin cells.

No other indications on the toxicokinetic behaviour could be derived from the results of the available studies and no specific studies on the absorption, distribution, metabolism and excretion are available.