Vinyl chloroacetate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: expert assessment

Adequacy of study:

weight of evidence

Study period:

2017

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: An assessment of the toxicokinetics behaviour of the substance assessment was performed based on available data on the substance and on its degradation products.

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

An assessment of the toxicokinetics behaviour of the substance assessment was performed based on available data on the physicochemical properties and toxicity of the substance following an oral or dermal exposure, along with data on the degradation products of the substance.

GLP compliance:

no

Test material

Radiolabelling:

other: not applicable

Results and discussion

Preliminary studies:

A hydrolysis study performed on vinyl chloroacetate, in accordance with the OECD Guideline 111, gave half-lives of 1.22 hours and 3.92 hours at pH 7 and pH 4, respectively. This test indicates that the substance is unstable and will undergo rapid hydrolysis. The hydrolysis rate is faster at neutral and high pH but still occurs at a rapid rate under acidic conditions. Therefore hydrolysis of vinyl chloroacetate is expected to occur rapidly following oral exposure, the pH ranging from pH 5–9 in the gastrointestinal tract. Since the hydrolysis tests were performed at 20°C, hydrolysis may be expected to occur at a faster rate following exposure on account of the higher temperature (~37°C) in the body.

Two degradation products were obtained in this study and identified as acetaldehyde (CAS 75-07-0 / EC 200-836-8) and chloroacetic acid (CAS 79-11-8 / EC 201-178-4). Considering the short half-life of vinyl chloroacetate, it can be expected that the degradation products will drive the in vivo toxicity of vinyl chloroacetate. The hazard profiles of acetaldehyde and chloroacetic acid are well documented by a number of reliable sources.

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Vinyl chloroacetate is expected to release chloroacetic acid and acetaldehyde following an oral exposure. There is no evidence of absorption following inhalation or dermal exposure.

Main ADME results 2

Type:

distribution

Results:

Following absorption, degradation products acetaldehyde and chloroacetic acid are well-distributed in the body.

Main ADME results 3

Type:

metabolism

Results:

Both degradation products are metabolised in the body.

Main ADME results 4

Type:

excretion

Results:

Degradation products are excreted mainly in urine and through respiration.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Oral Exposure:
- The acute oral toxicity study performed on rats resulted in deaths at 200 and 2,000 mg/kg and clinical signs of systemic toxicity at all doses. Therefore it can be concluded that absorption occurred.
- Vinyl chloroacetate is expected to undergo rapid hydrolysis in the stomach and small intestines to acetaldehyde and chloroacetic acid, with evidence that both degradation products will be rapidly absorbed in the gastrointestinal tract. The purpose of the study was not to identify the causes of the toxicity, but considering the acute oral toxicity of chloroacetic acid (LD50 = 90.4 mg/kg) it is reasonable to assume that the observed toxic effects may be related to this degradation product.

Inhalation Exposure:
- No studies were identified on the toxicity of vinyl chloroacetate following inhalation exposure.
- Considering the vapour pressure of vinyl chloroacetate (5.23 mmHg at 20 °C), exposure by inhalation cannot be excluded. Some vapours may be retained by the mucosal fluid which may eventually hydrolyse to acetaldehyde and chloroacetic acid. Inhalation studies in humans and animals have found that acetaldehyde is easily absorbed in the lung.

Dermal Exposure:
- Considering the molecular weight of vinyl chloroacetate (120.53 Da) and its relative lipophilic nature, the substance could be absorbed through the skin.
- Hydrolysis of the substance is not expected to be significant considering the lipophilic nature of the skin.
- An acute dermal toxicity study was performed on the substance and did not report signs of systemic toxicity at a concentration of 2,000 mg/kg bw. Considering the properties of the substance it could be expected that an absorption would lead to systemic effects. Therefore it can be concluded that no dermal absorption occurred or that the absorption was limited to an inconsequential amount of vinyl chloroacetate.

Details on distribution in tissues:

Distribution: following the results of the hydrolysis study, the assessment is based on the assumption that the substance will be rapidly hydrolysed following oral or inhalation exposure. Therefore the assessment of the distribution of the substance is based on the toxicokinetics properties of its degradation products, acetaldehyde and chloroacetic acid.

Acetaldehyde:
- Acetaldehyde is a small molecular weight (44.05 Da) and highly water soluble substance which will be widely distributed, mainly in the water compartments in the body.
- Available information from laboratory animals and humans indicates that acetaldehyde distributes rapidly following absorption. An inhalation study in male rats found that acetaldehyde was distributed in the blood, liver, kidney, spleen, heart, myocardium and skeletal muscle. Acetaldehyde concentrations were highest in the blood, while liver concentrations were low, relative to other organs, due to rapid metabolism.
- There is evidence to suggest that acetaldehyde can enter the foetal circulatory system through the placenta. Acetaldehyde was detected in foetuses 2 hours after intraperitoneal administration of 200 mg/kg of the substance to pregnant mice on gestation day 10.
- Acetaldehyde is a highly reactive electrophile, which reacts with nucleophilic groups of cellular macromolecules, such as proteins and DNA, to form adducts. Acetaldehyde, incubated with ribonucleosides and deoxyribonucleosides, forms adducts with cytosine or purine nucleosides. The acetaldehyde induced cross-linking of DNA has been implicated in an elevated rate of chromosomal aberrations occurring lymphocytes of alcoholics.

Chloroacetic acid:
- Following oral and subcutaneous exposure of [1-14C]-chloroacetic acid in rodents, the radiolabelled substance is rapidly and widely distributed to different tissues and organs with the highest concentrations appearing in the intestine, kidneys, liver, and spleen. The pattern of distribution shows an initial fast distribution into lipid-poor tissues, followed by slower, sustained uptake into lipid-rich tissues such as the brain. The distribution patterns do not appear to be dose-dependent, however repeated exposure to higher doses results in a significant increase in concentration in tissues compared to single exposure.
- High doses of chloroacetic acid have also led to the alkylation of thiol groups in liver and kidneys of rats. The alkylation of sulphydryl groups has been implicated in the inhibition of both pyruvate-dehydrogenase and α-ketoglutarate dehydrogenase enzymes in isolated rat heart mitochondria. Inhibition of these enzymes has a major impact on cellular energy production, resulting in lactate accumulation.

Details on excretion:

Excretion: the assessment is based on the assumption that the substance will be rapidly hydrolysed following absorption. Therefore assessment of the excretion of the substance is based on the toxicokinetics properties of its degradation products, acetaldehyde and chloroacetic acid.

Acetaldehyde:
- Based on the rate of metabolism of acetaldehyde by the liver, elimination of the metabolites, as water and carbon dioxide as well as sulfur-containing adducts, occurs mainly via urine and expired air.

Chloroacetic acid:
- Chloroacetic acid and its metabolites are rapidly eliminated, mainly via urine. Testing in rats showed that 90% of the administered dose was recovered in the urine within 24 hours after oral exposure; 82-88% within 3 days following intraperitoneal injection; and 50% by 17 hours after subcutaneous administration. After oral exposure in mice, 34-61% was excreted in urine after 72 hours. Other excretory routes are the expired air, as CO2, and faeces.
- Studies have shown that chloroacetic acid can interact with lipids such as cholesterol and be incorporated into phospholipids. The products of such conjugation reactions are more likely to be prone to retention rather than excretion, because the conjugates are a more lipophilic. However, toxicity effects related to these types of conjugates have yet to be established.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Metabolism: the assessment is based on the assumption that the substance will be rapidly hydrolysed following absorption. Therefore assessment of the metabolism of the substance is based on the toxicokinetics properties of its degradation products, acetaldehyde and chloroacetic acid.

Acetaldehyde:
- Acetaldehyde is an intermediate of ethanol metabolism in the liver following alcohol consumption, as a consequence many studies have been published in the context of ethanol metabolism.
- Data indicate an effective first-pass metabolism by the liver. Half-lives in the blood for acetaldehyde were around three minutes in rats (after repeated exposure by inhalation) and mice (single intraperitoneal injection). For humans, no reliable data on half-lives are available.
- Acetaldehyde is metabolised to acetic acid by aldehyde dehydrogenases, which exist in the cells of most tissues, including the liver and mucosal tissue of the respiratory tract. Acetic acid is subsequently degraded to carbon dioxide and water. Acetaldehyde dehydrogenases (ALDHs) show genetic polymorphism that gives rise to differences in vulnerability in humans: Approximately 40% of the Oriental population possess inactive mitochondrial ALDH2, which is associated with alcohol intolerance. There are two types of ALDHs in the human liver, cytosolic ALDH1 and mitochondrial ALDH2, however mitochondrial ALDH2 alone is responsible for acetaldehyde metabolism. A small proportion of acetaldehyde in the body is probably oxidised by cytochrome P450 2E1, and by different aldehyde oxidases.
- Studies of inhalation exposure to acetaldehyde in humans, intravenous injection in rabbits, and intraperitoneal exposure in rats show increases of sulfur-containing metabolites in urine, which are mainly associated with conjugation with thiol compounds, cysteine and glutathione.

Chloroacetic acid:
- Reliable literature studies exist for the metabolism of chloroacetic acid.
- Two metabolic pathways have been suggested for chloroacetic acid metabolism. The major pathway results in formation of S-carboxymethylcysteine and thiodiacetic acid. A minor pathway involves probable enzymatic hydrolysis of chloroacetic acid resulting in the formation of glycolic acid, which is mainly oxidised to carbon dioxide and, to a lesser extent, oxalic acid. Since glycolic acid was not observed in the hydrolysis study, this is in line with this route being a probable minor hydrolysis pathway.

Applicant's summary and conclusion

Conclusions:

An assessment of the toxicokinetics behaviour of the substance was performed based on available data on the physicochemical properties and toxicity of the substance following an oral or dermal exposure, along with data on the degradation products of the substance. It is not considered necessary to perform further testing.

Executive summary:

The absence of specific toxicokinetics data from animal testing means that it is not possible to make firm conclusions concerning the absorption, distribution, and excretion of vinyl chloroacetate. However, it is possible to use existing data on the physicochemical and toxicological properties of the substance, as well as data available for its degradation compounds, acetaldehyde and chloroacetic acid, to determine the likely toxicokinetics behaviour of vinyl chloroacetate.

According to the available information the absorption of vinyl chloroacetate is expected to occur mainly following oral exposure. Although absorption via inhalation and dermal routes cannot be excluded, absorption following oral exposure is expected to be the most significant. In the stomach and small intestine, vinyl chloroacetate undergoes hydrolysis to the degradation products, acetaldehyde and chloroacetic acid. These substances are rapidly absorbed and distributed throughout the body with the highest concentrations in the blood (acetaldehyde) and the liver and kidneys (chloroacetic acid). Metabolism of these compounds is rapid with the main metabolites being carbon dioxide, water, S-carboxymethylcysteine, thiodiacetic acid and various other adducts with sulfur. The primary elimination pathways are via urinary excretion and expiration of carbon dioxide and, to a smaller extent, via faeces. Based on some studies, it is expected that a small percentage of the degradation products may be retained in the body by conjugation with a variety of biomolecules, which may lead to longer term systemic effects.

Based on this assessment it is not appropriate to perform further animal testing on this substance.