Hexanoic acid, 3,5,5-trimethyl-, 1,1'-[2-ethyl-2-[[(3,5,5-trimethyl-1-oxohexyl)oxy]methyl]-1,3-propanediyl] ester

Endpoint summary

Description of key information

The toxicokinetic profile of the test item has been predicted using the physico-chemical properties of the substance, the data obtained from acute and repeated-dose toxicity studies, as well as information gained from genotoxicity assays. Read-across to the toxicokinetic properties of fatty acid polyols (Fatty acids, C5-9, esters with pentaerythritol (EC 270-290-3, CAS 68424-30-6) and Decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate (EC 234-392-1, CAS 11138-60-6)) and their analogues is also applicable based on the similarity in structure and physico-chemical properties.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Introduction

The toxicokinetic profile of the test item was predicted using the physico-chemical properties of the substance, the data obtained from acute and repeated-dose toxicity studies, as well as information gained from genotoxicity assays. Read-across to the toxicokinetic properties of fatty acid polyols (Fatty acids, C5-9, esters with pentaerythritol (EC 270-290-3, CAS 68424-30-6) and Decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate (EC 234-392-1, CAS 11138-60-6)) and their analogues is also applicable based on the similarity in structure and physico-chemical properties.

 

Physico-chemical properties

 

The test item is a UVCB, clear colorless liquid with the molecular weight of each of the four main isomers being 554.84 g/moL. The substance is poorly water soluble (≤2.04 x 10E-03 g/L) with a very high estimated octanol/water partition coefficient; Log Pow >9.4 (which is >4, the bioaccumulation limit), and a very low vapour pressure of 3.2 x 10E-06 Pa at 25 ^oC.

 

Absorption

 

Oral Route

 

The physico-chemical properties described above indicate that the test item has a molecular size (MW >500) greater than that which may be expected to be easily absorbed within the mammalian gastrointestinal tract, should that material be ingested. The substance, which has a low water solubility and is highly lipophilic with a Log P_ow>9.4) may be expected not to cross gastrointestinal epithelial barriers, and the high MW may also significantly restrict absorption. It may participate in micellar transport into the hepatic portal system along with other lipophilic substances (e.g., dietary fats). However, an acute oral gavage toxicity study identified no evidence of toxicity (LD50 >2000 mg/kg bw) and repeat dose and reproduction screening toxicology studies using the oral route gave a NOAEL of 1000 mg/kg bw/day. There was evidence of non-adverse, reversible effects in the liver and kidney, which supports a conclusion that some absorption does occur via the gastrointestinal tract. The lack of adverse findings following oral dosing may be due to limited gastrointestinal absorption of the test material after oral dosing, or a very low index of inherent toxicity for this substance, and/or its metabolite(s).

 

For the read-across substances, the absorbability of esterified alcohols containing one to eight ester groups given orally have been studied and there was little difference for polyol esters up to four ester groups. Esters of polyols (pentaerythritol, dipentaerythritol and 1,1,1-trimethylolpropane) have a common metabolic fate that involves stepwise hydrolysis to the carboxylic (e.g. fatty) acids and their polyols (pentaerythritol, dipentaerythritol or trimethylolpropane), respectively. This is supported by the action of ubiquitously distributed unspecific esterases and by site-specific and non-specific gastrointestinal lipases so only low and transient exposure to the parent compound is expected.

 

Dermal Route

 

Regarding the dermal absorption of the test item, its rate of uptake into the stratum corneum and its rate of transfer between the stratum corneum and the epidermis are likely to be very slow considering both the high MW, high Log P_owand low water solubility [1,2]. These assumptions were supported by the absence of observed systemic effects following dermal application of test material in an acute toxicity study at up to 2000 mg/kg bw and the absence of irritant effects to the skin.

 

Inhalation Route

 

The potential for inhalation toxicity was not studied directly in a toxicology study using the inhalation route. The test substance has been shown to have a low vapour pressure and high onset boiling point range (did not boil up to 400 °C at 101 kPa). As a result, the potential for generation of inhalable forms of the substance is low and exposure of humans via the respiratory route is predicted to be negligible under normal use conditions. Furthermore, the Log Pow value of >9.4 does not favour absorption directly across the respiratory tract epithelium by passive diffusion (Log10 Pow > 4) and the substance will not be readily soluble in blood because it is poorly water soluble (≤ 2.04 x 10^-3g/L at 20 °C).

 

Distribution

 

Systemic distribution of the test item can be predicted from physico-chemical properties. The high Log P_owand low water solubility suggests that this substance, upon systemic absorption, may be transported through the circulatory system in association with a carrier molecule such as a lipoprotein or other macromolecule. The lipophilic character but high Log P_owand MW >500 of the test material suggests that a major proportion of the substance will not readily traverse cellular barriers or distribute into fatty tissues. There is no evidence of systemic toxicity and/or adverse histopathological changes from the repeated dose study that may be taken as evidence of cumulative toxicity, as would be expected by an accumulation of test item, or its metabolites, in body tissues.

 

Metabolism

 

Acute and repeated-dose toxicity studies provided evidence that the test item was metabolised into non-toxic metabolites. Data from a bacterial mutagenicity test, a mammalian cell gene mutation assay and a chromosomal aberration in mammalian cells, in which test material was subjected to rat hepatic microsomal enzyme systems, did not show any evidence of genotoxic activity from the substance or from any potential metabolites. Furthermore, the in vitro toxicity of the substance to mammalian cells was equivalent in the presence and absence of metabolic enzymes. This may be taken to indicate either the absence of any significant level of metabolism, or that the metabolism that did occur gave rise to metabolites that were non-toxic.

 

Read-across to the toxicokinetic properties of fatty acid polyols (Fatty acids, C5-9, esters with pentaerythritol (EC 270-290-3, CAS 68424-30-6) and Decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate (EC 234-392-1, CAS 11138-60-6)) and their analogues is applicable based on the similarity in structure and physico-chemical properties. Esters of polyols (pentaerythritol, dipentaerythritol and 1,1,1-trimethylolpropane) have a common metabolic fate that involves stepwise hydrolysis to the carboxylic (e.g. fatty) acids and their polyols (pentaerythritol, dipentaerythritol or trimethylolpropane), respectively. This is supported by the action of ubiquitously distributed unspecific esterases and by site-specific and non-specific gastrointestinal lipases so only low and transient exposure to the parent compound is expected. Straight-chain fatty acids are normal dietary constituents and ubiquitous substrates for energy production by physiological pathways like the citric acid cycle, sugar synthesis, and lipid synthesis. Medium-chain fatty acids (MCFA) are readily absorbed from the small intestine directly into the bloodstream and transported to the liver for hepatic metabolism, while long-chain fatty acids (LCFA) are less readily absorbed, are incorporated into chylomicrons and enter the lymphatic system. It has been noted by several investigators that increasing fatty acid chain length slightly decreased their digestibility. MCFA are readily broken down to carbon dioxide and two-carbon fragments, while LCFA are re-esterified to triacylglycerols and either metabolized for energy or stored in adipose tissue. The natural occurrence of fatty acids and their specific metabolic fate imply that the exposure to small amounts is not a risk factor for human beings.

 

Excretion

 

Structural characteristics of the test item and the toxicological profile suggest that this substance may readily undergo phase I and phase II metabolic transformation. The resulting metabolic by-products are expected to undergo routine renal and or biliary excretion. Metabolites such as polyols are very polar and do not accumulate in the body but are readily excreted via urine. Alternatively one or more hydroxyl groups can be oxidised to a carboxylic acid moiety prior to urinary excretion.

 

References

 

[1] Derivation of assessment factors for human health risk assessment. ECETOC Technical Repot No. 86. ISBN-0773-6347-86, Brussels, February 2003, page 13, paragraph 1.

 

[2] Guidance document on dermal absorption. European Commission Sanco/222/2000 rev. 7. Page 7, paragraph 2.