Reaction mass of ethyl 2,6,6-trimethylcyclohexa-1,3-diene-1-carboxylate and ethyl 2,6,6-trimethylcyclohexa-2,4-diene-1-carboxylate and ethyl 6,6-dimethyl-2-methylenecyclohex-3-enecarboxylate

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 dose toxicity studies, skin irritation, eye irritation, skin sensitization, in vitro genotoxicity and reproductive toxicity study).

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 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 dose toxicity studies, skin irritation, eye irritation, skin sensitization, in vitro genotoxicity and reproductive toxicity study).

 

The notified substance is a small organic molecule with a molecular weight of 194.74. It is a liquid and has a water solubility of 143 mg/L at 20°C and a log Kow of 3.4 at 35°C. The physico-chemical properties of the test item would suggest the substance is likely to be absorbed via dermal, inhalation and gastric routes following exposure.

 

Absorption:

 

Oral/GI absorption

The physical chemical characteristics described above suggest that the target 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 Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (OECD 422) where evidence of liver and kidney changes were observed and indicate absorption from the GI tract and distribution within the body.

The NOAEL was set to 400 mg/kg bw/day in this 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. Furthermore, it is assumed that the dermal uptake of the substance in the blood is increased by its water solubility. Finally, the substance is irritating to the skin which may upon high-dose contact favour dermal penetration of the substance. No acute dermal toxicity study was available to discuss on the presence or absence of evidence of bioavailability via dermal route.

 

Respiratory absorption

The potential for inhalation toxicity was not evaluated.

The vapour pressure of the target substance (VP = 4.17 Pa at 20°C) indicated  a low of 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 can be predicted from its physical chemical characteristics. Considering that the substance is water soluble, it is suggested that, upon systemic absorption by oral and dermal routes or by inhalation, the substance may be transported through the circulatory system in association with a carrier molecule. Afterwards, based on its character, the substance may cross cellular barriers without potential to accumulate into fatty tissues.

 

Metabolism:

The results of Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (OECD 422) 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 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, any substance that has penetrated the stratum corneum is likely to be absorbed in the blood following excretion in urine unchanged or as glucuronide and sulfate conjugates if metabolisation in the liver occurs.

 

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.