Allyl phenoxyacetate

Endpoint summary

Description of key information

No studies are available. The molecular weight, physicochemical properties incl. water solubility and octanol-water partition coefficient of the substance suggest that oral, inhalative and dermal absorption can occur. Widely distribution within the water compartment of the body after systemic absorption is because of lipophilicity of the test substance not expected. However, the distribution into cells particularly in fatty tissues is likely. Based on its log Pow the test substance is not considered to accumulate. The test substance might be metabolized after absorption. Excretion is expected to be predominantly via the urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

40

Absorption rate - inhalation (%):

100

Additional information

In accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), assessment of the toxicokinetic behaviour of the test substance was conducted to the extent that can be derived from the relevant available information on physicochemical and toxicological characteristics. There are no studies available evaluating the toxicokinetic properties of the substance.

The test substance is a colourless to pale yellow clear liquid with a molecular weight of 192.21 g/mol and a water solubility of 0.559 g/L at 20 °C. The substance has a low vapour pressure of 0.07 hPa at 20 °C and the log Pow is 2.33 at 24.7 °C.

 

Absorption

The major routes by which the test substance can enter the body are via the lung, the gastrointestinal tract, and the skin. To be absorbed, the test substances must transverse across biological membranes either by active transport mechanisms or - as being the case for most compounds - by passive diffusion. The latter is dependent on compound properties such as molecular weight, lipophilicity, or water solubility (ECHA, 2017).

Oral

In general, low molecular weight (MW≤500) and moderate lipophilicity (log Pow values of -1 to +4) are favourable for membrane penetration and thus absorption. The molecular weight of the test substance is relatively low with 192.21 g/mol, favouring oral absorption of the compound. This is supported by the determined log Pow value of 2.33, being advantageous for oral absorption. In addition the moderate water solubility of 0.559 g/L leading to dissolving of the compound in the gastrointestinal fluids favours oral absorption. However, if the molecular weight is low (less than 200) the substance may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water (Renwick, 1994).

Moreover, the observation of systemic toxicity following exposure by any route is an indication for substance absorption; however, this will not provide any quantitative information.

In an acute oral toxicity study conducted with the test substance in rats marked signs of systemic toxicity were observed at 1000, 794 and 630 mg/kg bw (Key, 1982). Three males and four females died at 1000 mg/kg bw, one male and 3 females at 794 mg/kg bw and 3 males at 630 mg/kg bw. Signs of systemic toxicity were lacrimation, piloerection, hunched position, oscillated movements and shaggy coat following treatment in all dose groups. Other signs of systemic toxicity were lethargy starting at 630 mg/kg bw, eyes half closed, hyperthermia and difficult breathing at 794 and 1000 mg/kg bw. All surviving animals appeared normal on Day 4. All surviving animals showed acceptable body weight gain at the end of the observation period. Abnormalities noted at necropsy of animals that died during the study were mainly associated with the gastrointestinal tract. Abnormalities such as overloaded stomach, severe reddening of the forestomach, red patches on mucosal surface of the corpus and antrum of the stomach were observed. Furthermore, moderate until severe congestion in the liver and presence of bloody fluid in the thorax were noted. Additional observations were noted in one animal that died 4 days after treatment. Abnormalities noted in surviving animals were thickened areas covering partially the mucosal surface of the forestomach and adhesions between a) forestomach and liver, b) forestomach, liver and spleen, c) forestomach, liver, spleen and peritoneum. In this acute oral toxicity study a LD50 value of 835 mg/kg bw in male and female rats was calculated.

Additionally, a Combined Repeated Dose Toxicity Study with Reproduction/Developmental Toxicity Screening Test with dose levels of 15, 50 and 150 mg/kg bw/day was conducted (Key, 2018). No test item-related deaths or moribund animals occurred in any group throughout the study. In hematology, total leukocyte count, absolute lymphocyte count, monocyte count and large unstained cells counts were increased in both sexes at 150 mg/kg bw/day. Fibrinogen in males at 150 mg/kg bw/day and platelet count in males at 50 and 150 mg/kg bw/day were also increased. In clinical chemistry, alanine aminotransferase aspartate aminotransferase, gamma glutamyl transpeptidase and total bilirubin were increased in both sexes at 150 mg/kg bw/day. Increased liver and spleen weights in both sexes and increased weights of testes and epididymides were observed at 150 mg/kg bw/day. Test item related cholangiofibrosis, hydropic degeneration and necrosis of the liver n both sexes were observed at 150 mg/kg bw/day. No adverse effects on fertility were observed in parental animals. In the F1 pups, decreased body weight was observed on PND 13 at 150 mg/kg bw/day as a secondary response to parental toxicity. Therefore, the NOAEL for systemic and developmental toxicity was considered to be 50 mg/kg bw/day.

Based on available data from the acute oral and repeated dose toxicity study, oral toxicity was observed with the test substance and thus absorption of the test substance via the gastrointestinal tract has evidently occurred.

Dermal

The dermal uptake of liquids and substances in solution is generally expected to be higher than that of dry particles. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Thus, for this molecular weight level of the test substance dermal uptake can be seen to be moderate. The Log P value of the test substance is optimal for dermal absorption. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore, if the water solubility is between 100 and 10000 mg/L, dermal uptake is considered to be moderate to high.

The dermal permeability constant Kp of the substance was estimated to be 0.00462 cm/h using DermwinTM (v.2.01) taking into account an estimated log Pow of 2.33 and the molecular weight of 192.21 g/mol. Thus the absorption of the test substance is anticipated to be moderate.

Data from an acute dermal toxicity study revealed no effects of the test substance up to the limit dose of 2000 mg/kg bw (Key, 1983). Against the background of the demonstrated toxic potency after oral exposure, the dermal toxicity seems to be of low magnitude, presumably due to lower dermal uptake in contrast to oral absorption.

The dermal absorption was estimated at 40% based on a SAR model by:

Kroes R, Renwick AG, Feron V, Galli CL, Gibney M, Greim H, Guy RH, Lhuguenot JC, van de Sandt JJ. Application of the threshold of toxicological concern (TTC) to the safety evaluation of cosmetic ingredients. Food Chem. Toxicol. 2007, 45, 2533-2562

Shen, Kromidas, Schultz, Bhatia. An in silico skin absorption model for fragrance materials. Food Chem. Toxicol. 2014, 74, 164-176

The Jmax was estimated as 9.5 mg/cm²/h and semi-quantitatively translated into a dermal bioavailability as follows: Jmax <=0.1 - 10% dermal uptake; Jmax >0.1 <=10 - 40% dermal uptake; Jmax >10 - 80% dermal uptake.

Inhalation

Moderate log P values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. However, the test substance has a low vapour pressure of 0.07 hPa at 20 °C. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapour can be considered negligible.

Distribution

Distribution of a compound within the body depends on the physicochemical properties of the substance especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA, 2017).

Since the test substance is lipophilic (log Pow 2.33) the distribution into cells is likely and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues, if the substance is absorbed systemically. Substances with log P values of 3 or less would be unlikely to accumulate in adipose tissues with the repeated intermittent exposure patterns normally encountered in the workplace but may accumulate if exposures are continuous. Once exposure to the substance stops, the substance will be gradually eliminated at a rate dependent on the half-life of the substance.

Metabolism

No metabolism studies are available with the test substance itself. Prediction of compound metabolism based on physicochemical data is very difficult. Structure information gives some but no certain clues on reactions occurring in vivo. The potential metabolites following enzymatic metabolism were predicted using the QSAR OECD toolbox (v3.4, OECD, 2014). This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. 7 hepatic and 12 dermal metabolites were predicted for the test substance, respectively. Primarily, hydroxylation and degradation of the substance occurs in the liver and skin. In general, the hydroxyl groups make the substances more water-soluble and susceptible to metabolism by phase II-enzymes. Up to 38 metabolites were predicted to result from all kinds of microbiological metabolism for the test substance. Most of the metabolites were found to be a consequence of the degradation of the molecule. There was no evidence for differences in genotoxic potencies due to metabolic changes in in vitro genotoxicity tests. The studies performed on genotoxicity (Ames test, HPRT test and micronucleus test in mammalian cells in vitro) were all negative, with and without metabolic activation (Key, Ames, 2015; Key, HPRT, 2015; Key, MN, 2015).

Excretion

Only limited conclusions on excretion of a compound can be drawn based on physicochemical data. Due to metabolic changes, the finally excreted compound may have few or none of the physicochemical properties of the parent compound. In addition, conjugation of the substance may lead to very different molecular weights of the final product. The molecular weight (< 300 g/mol) and the water solubility of the molecule are properties favouring excretion via urine. Thus, the test substance is expected to be excreted predominantly via the urine.

 

References

ECHA (2017): Guidance on information requirements and chemical safety assessment – Chapter 7c: Endpoint specific guidance. European Chemicals Agency, Helsinki

Renwick AG (1994) Toxicokinetics - pharmacokinetics in toxicology. In Hayes,A.W. (ed.) Principles and Methods of Toxicology. Raven Press, New York, USA, pp.103.