2-Propenoic acid, 4-[[(4-benzoylphenoxy)carbonyl]oxy]butyl ester

Endpoint summary

Description of key information

Based on physico-chemical characteristics, particularly water solubility and octanol-water partition coefficient absorption via oral and dermal route is possible but most likely to occur on a small scale. Absorption via inhalation route is unlikely to take place due to the low vapour pressure of the compound. Intracellular concentration is likely to be higher than extracellular due to the moderate lipophilicity of the test substance. A conjugation reaction may increase hydrophilicity and metabolites are considered to be not more toxic than the parent molecule. Excretion of the metabolites may occur via the urine and the faeces, depending on their physicochemical properties. The logKow of the test item was determined to be 3.7. Thus the test substance has a low potential for biocaccumulation as the log Kow is below the threshold value of log Kow 4.5.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

There are no toxicokinetic studies available for the registered substance. The following assessment is based on the physico-chemical properties of the substance and results from available (eco)toxicological studies.

Toxicological profile of the test substance

An acute oral toxicity study following EEC Directive 84/449 revealed that the LD50 value was greater than 2200 mg/kg bw (applied as an emulsion in olive oil DAB 9) in Wistar rats.

In an acute dermal toxicity study (Limit Test) conducted in accordance to OECD guideline 402 and EU Method B.3 as well as EPA OPPTS 870.1200 and the Japan MAFF Testing guideline of 12 Nosan No 8147, young adult Wistar rats (5 males and 5 females) were dermally exposed to a single dose of 2000 mg/kg bw of the undiluted test item. No mortality occurred and no signs of systemic toxicity or skin effects such as erythema or edema were observed. The LD50 value for acute dermal toxicity was therefore found to be greater than 2000 mg/kg bw.

Additionally, the test substance did not give indication of an irritant property to the skin in an acute dermal irritation corrosion study on rabbits following OECD guideline 404 and EU Method B.4.

A sensitising effect was observed on the skin of guinea pigs in the Maximization Test (EU Method B.6).

The potential of the test substance to cause damage to the eyes was assessed in a study according to OECD guideline 405 in rabbits. Under the test concitions chosen and considering the described findings the test substance did not give indication of an irritant property to the eye.

In two bacterial reverse mutation assays no mutagenic effect was observed either with or without metabolic activation of the test substance. An in vitro mouse lymphoma cell mutation assay (OECD 476 and EEC Directive 87/302) gave no indication of a mutagenic property of the test substance as well. Also, no genetic toxicity was detected in an in vivo micronucleus test conducted on mice according to OECD 474 and EU Method B.12.

No data are available concerning repeated dose toxicity, toxicity to reproduction, or carcinogenicity of 2-Propenoic acid, 4-[[(4-benzoylphenoxy)carbonyl]oxy]butyl ester.

Toxicokinetic analysis of 2-Propenoic acid, 4-[[(4-benzoylphenoxy)carbonyl]oxy]butyl ester

2-Propenoic acid, 4-[[(4-benzoylphenoxy)carbonyl]oxy]butyl ester is a light brown, slightly turbid homogeneous liquid with a molecular weight of 368.39 g/mol. Its melting point and boiling point are -78 °C and 110 °C, respectively. Density is 1.124 g/m³ at 20 °C. The vapour pressure is determined to be 0.003 Pa at a temperature of 20 °C. The partition coefficient between octanol and water (log Kow) is 3.7 (at 23 °C). The substance is only slightly soluble in water (1.4 mg/L at 20 °C). The soil adsorption coefficient (log Koc) was calculated to be 2.8724. The half-life for hydrolysis was found to be 1089 min at a temperature of 50 °C and a pH value of 7.

 

Absorption

Generally, oral absorption is favoured for molecular weights below 500 g/mol. The test compound is only moderately lipophilic, which in general enables readily absorption through the GIT epithelium after oral intake. But, as in this case the water solubility is relatively low, oral absorption may be limited by the inability of the substance to dissolve in the gastro-intestinal fluids. Contact with the mucosal surface may thus be hindered. Besides the poor water solubility the relatively high molecular weight of the compound may inhibit direct uptake through aqueous pores or via carriage across the membrane. Micellular solubilisation may also be of little importance as the lipophilicity of the compound is not high enough to favour this mechanism.

Administered with olive oil as a vehicle in an acute oral toxicity study performed on Wistar rats, the single dose of 2200 mg/kg bw did not lead to any signs of toxicity. As no mortality occurred, the LD50 value was found to be greater than 2200 mg/kg bw for both male and female rats. Based on this result it can be assumed that only limited absorption of the substance across the epithelial lining of the gastro intestinal tract will occur.

Based on the low vapour pressure of 0.003 Pa the test substance is unlikely to become available for inhalation. If the substance would reach the lungs in its vapour or gaseous state, absorption directly across the respiratory tract epithelium by passive diffusion is assumed to be faciliated due to its log Kow value. But, as mentioned above, the low water solubility hinders contact with the mucus. These assumptions indicate only a low systemic availability after inhalation.

With regards to the physico–chemical properties of the test substance, it may be able to penetrate skin as the logPow value and water solubility allow dermal penetration. For substances with a log Kow between 1 and 4, both penetration into stratum corneum and partition into the epidermis are likely to occur. It is generally accepted that if a compound’s water solubility falls between 1-100 mg/L, absorption can be anticipated to be low to moderate. As the compound’s water solubility is 1.4 mg/L, it may be assumed that absorption takes place only to a very small extend. This assumption is supported by the results achieved from an acute dermal toxicity study performed on Wistar rats. In this study a single dose of 2000 mg/kg bw of the undiluted test substance revealed no signs of systemic toxicity. On the other hand the test substance was found to be sensitising to the skin after an intradermal and a percutaneous induction phase in a Maximization Test in guinea pigs. This result implies that some uptake must have occurred to initiate the immune response. It has to be mentioned that olive oil was used as a vehicle in this study during the challenge phase, which might have influenced dermal absorption.

Taken together, physico-chemical properties and experimental data indicate poor bioavailability of the test substance via oral, dermal and inhalation route.

 

Distribution

Assuming that the test substance is absorbed into the body following oral intake, it may be distributed into the interior part of cells due to its moderate lipophilic properties and in turn the intracellular concentration may be higher than extracellular concentration particularly in adipose tissues. As mentioned above, the physico-chemical properties, especially the low water solubility, inhibit systemic absorption. 

 

Metabolism

Based on the structure of the molecule it may be metabolized by Phase I enzymes while undergoing functionalization reactions aiming to increase the compound’s hydrophilicity. The substance is most likely not enzymatically activated (toxified) during metabolism. This assumption is supported by the result of an Ames test as well as an in vitro mammalian cell mutation assay in which cytotoxicity of the parent substance was not higher as compared to metabolic activated test substance.

Furthermore, Phase II conjugation reactions may covalently link an endogenous substrate to the parent compound or the Phase I metabolite in order to ultimately facilitate excretion.

 

Excretion

The substance is most likely excreted after metabolisation. Excretion of the metabolites is expected to occur via the urine and the faeces depending on the physicochemical characteristics of the degradation products.

Bioaccumulation

The log Kow of the test item was determined to be 3.7. Thus the test substance has a low potential for biocaccumulation as the log Kow is below the threshold value of log Kow 4.5.