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Description of key information

Based on the physicochemical properties and the results obtained in the toxicity tests, fractions of the reaction mass will be absorbed via the GI tract and become systemically available.

Uptake into the systemic circulation following dermal exposure is very limited due to high water solubility of the substance at room temperature. Also, based on the high water solubility and the results obtained in the respective toxicological investigation, it is unlikely that relevant amounts of the reaction mass will become systemically bioavailable via inhalation.

After becoming bioavailable, it is assumed that the substance and its metabolites will circulate within the blood stream and will finally be transported to the liver where Phase I and Phase II metabolism may occur. Ultimately the metabolism products will be excreted via the kidney in the urine or by exhalation as CO2.

Based on its BCF values neither the constituents of the reaction mass nor its potential metabolism products are considered to be bioaccumulative.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

1         Physico-Chemical Data on 2-Propyn-1-ol compound with methyloxirane

 

 

The organic reaction product composed of 2-Propyn-1-ol compound with methyloxirane appears as a clear colourless liquid at standard ambient temperature and pressure. Depending on the degree of polymerisation the molecular weight of the reaction product will be found in the range of 114.5 to 230.31 g/mol. At standard ambient pressure, the melting point is minus 22°C while the boiling point was determined to be at 101.8°C. The reaction product is very miscible with water soluble as indicated by the measured water solubility value of 1000 g/L at 25°C.The empirically measured logPow was found to be 0.0 at 24°C (shake flask method). A BCF value of 3.162 L/kg wet-weight was calculated using EPIWIN. The substance has a vapour pressure of 0.43 hPa at 20°C.

2         Toxicokinetic analysis of 2-Propyn-1-ol compound with methyloxirane

 

 

Absorption

 

Oral route:

Due to the very high water solubility and the low logPow of the reaction product, systemic uptake via passive diffusion is limited within the gastro intestinal (GI) tract. However, water soluble chemicals will readily dissolve into the GI fluids which in turn enhance the contact with the intestinal mucosa. Considering that the smaller a molecule, the more easily it may be taken up, reaction products with a molecular weight below 200 g/mol, which is the case for the majority of the UVCB, may pass through aqueous pores or may be carried through the epithelial barrier by the bulk passage of water.

With regards to toxicological data on the reaction product, an acute oral systemic toxicity study in rats determined the LD50 for male animals to be 464 mg/kg bw and for female animals to be higher than 464 mg/kg bw. For animals that died during the study, observed adverse effects included general congestion, bloody ulcerations in the glandular stomach and a yellow brown discoloration of the liver. Animals scarified after the end of the study did not show any pathological findings. Here, it remains unclear if these effects are caused by systemic toxicity of if they can be regarded as secondary effects caused by the local irritation of the glandular stomach. More detailed information relating to the bioavailability of the reaction product into systemic circulation following oral intake can be derived from a subacute combined repeated dose toxicity study with the reproduction and developmental toxicity screening test (OECD 422) and an oral 90-day repeated dose toxicity study (OECD 408). Here, results of the post mortem investigation revealed that the organ weights of kidney and liver were increased in both males and females at the high doses levels of 125 mg/kg bw/day (OECD 422) and 150 mg/kg bw/day (OECD 408) respectively. These effects provide evidence that the reaction product or its metabolites reaches the systemic circulation following oral administration. In the OECD 408 study, histopathological changes in the liver and kidneys were noted and the observed effects were considered to be adverse. In addition effects on the body weights of the animals and on hematology and clinical chemistry were observed in the OECD 408 study at 150 mg/kg bw/day. Overall, based on the physicochemical properties and the results obtained from the oral toxicity testing it can be assumed that the reaction product or its metabolites becomes systemically available following oral intake.

 

Dermal route:

Based on the high water solubility of the reaction product, dermal uptake is negligible. Its is commonly known that substances with a water solubility above 10 g/L and a logPow value of ≤ 0 are too hydrophilic to cross the lipid rich environment of the stratum corneum. These assumptions, based on the physicochemical properties, are further supported by results achieved from an acute dermal toxicity study with the 2-Propyn-1-ol compound with methyloxirane performed on rats (OECD 402). During this study, no systemic effects were observed and the LD50 was determined to be > 2000 mg/kg bw (limit dose). Also, no skin irritation potential and no immunological response were observed in a irritation test on rabbit skin (OECD 404) and Murine Local Lymph Node Assay (LLNA) (OECD 429) respectively.

Overall, the results from the dermal toxicity and sensitisation testing do not suggest that toxicological relevant amounts of the reaction product are absorbed and become systemically available and consequently support the assumptions based on the substance’s physicochemical properties.

 

Inhalation route:

Considering the vapour pressure and the resulting low volatility, it cannot be completely ruled out that fractions of the substance can be inhaled when handled at room temperature. However, vapours of very hydrophilic substances are retained in the mucus and are thus not available for systemic absorption. Furthermore, results obtained from thein vivoinhalation toxicity testing support the assumption that even if the substance becomes bioavailable following inhalation, no toxicity effects are to be expected. More specifically, no systemic toxicological effects related to the test substance were noted in an acute inhalation toxicity tests on rats (comparable to OECD 403). The respective LC50 was determined to be greater than 5.1 mg/L based on reweighing of the test material. This concentration was the maximum achievable vapour concentration for the test material.

 

Distribution

 

Once absorbed it is expected that the reaction products and its metabolites are distributed within the blood stream. Here the transport efficiency to the body tissues is limited by the rate at which the highly water soluble substances cross cell membranes. More specifically, access to the central nervous system or the testes is likely to be restricted by the blood-brain and blood-testes barriers (Rozman and Klaassen, 1996). The results observed in the subacute and subchronic toxicity studies provide evidence that a transport to the liver and kidney occurs.

Based on the low BCF value, the reaction product has a negligible potential to bioaccumulate in the human body.

 

 

Metabolism


Based on the chemical structure, the main components of the UVCB (sumformula: C6H10O2) most likely will undergo ether cleavage by addition of H2O in the strong acidic environment of the stomach or by Phase I enzymes once taken up into the body. This will lead to two metabolites, namely Prop-2-yn-1-ol (CAS # 107-19-7) and Propane-1,2-diol (CAS # 57-55-6). Propane-1,2-diol is converted by alcohol dehydrogenase to lactaldehyde by a NAD-dependent reaction. Lactaldehyde is then further metabolized to lactate which is a good substrate for gluconeogenesis.

Prop-2-yn-1-olmetabolism in rats and mice was examined by identifying urinary metabolites following oral administration of radiolabelled test substance. In male Sprague-Dawley rats, 56 % of the radioactivity administered was excreted in the urine within 96 hours. The highest concentration was observed in the first 24 -hour urine. The main metabolites were 2-propynoic acid, 3,3-bis[(2-(acetylamino)-2-carboxyethyl)thio]-1-propanol, 3-(carboxymethylthio)-2-propenoic acid, and 3-[[2-(acetylamino)-2- carboxyethyl]sulphinyl]-3-[[2-(acetylamino)-2-carboxyethyl]thio]-1-propanol accounting for 27, 20, 20, and 15 %, respectively, of the total radioactivity excreted in the urine during the first 24 hours post-administration. From the results, it was suggested that the metabolism of Propargyl alcohol in rats involves oxidation into 2-propynoic acid and multiple glutathione additions to the carbon-carbon triple bond yielding numerous metabolites. In mice, about 60 % of the radiolabel administered was excreted in the urine by 96 hours. The highest concentration was observed in the first 24-hour urine. The main metabolites were (E + Z)-3-[(2-amino-2-carboxyethyl)thio]-2-propenoic acid, 3-[[2-(acetylamino)-2-carboxyethyl]thio]-3-[[2-(amino)-2-carboxyethyl]thio]-1-propanol, 3,3-bis[(2-(amino)-2-carboxyethyl)thio]-1-propanol, and 3-[(2-formylamino-2-carboxyethyl)thio]-2-propenoic acid accounting for 41, 17, 15, and 13 %, respectively, of the total radioactivity excreted in the urine during the first 24 hours post-administration. The data suggested that metabolism of Propargyl alcohol in mice involves glucuronide conjugation to form 2-propyn-1-ol glucuronide as well as oxidation into 2-propynal which undergoes either multiple glutathione additions or oxidation into 2-propynoic acid (only ca. 2 %). Comparison of rat and mice data indicates quantitative and qualitative differences in formation of glucuronide conjugates and of 2-propynoic acid and metabolites derived from glutathione. In addition, extensive enterohepatic recycling of metabolites via the bile is also evident based on available data. In addition, metabolism via other Phase I enzymes is also possible together with Phase II conjugation reactions that may occur which covalently link an endogenous substrate to the reaction product itself or to its Phase I metabolites in order to ultimately facilitate excretion of the other components of the UVCB.

 

Excretion

 

Based on the expected biotransformation reactions, molecular size and water solubility, it is most likely that the final metabolites are excreted via the urine or via exhalation of CO2. Fractions of the chemical which are not absorbed within the GI tract will be readily excreted via the faeces.

4        References

 

ECHA (2008), Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

 

Marquardt H., Schäfer S. (2004). Toxicology. Academic Press,,, 2nd Edition 688-689.

 

Mutschler E., Schäfer-Korting M. (2001) Arzneimittelwirkungen. Lehrbuch der Pharmakologie und Toxikologie. Wissenschaftliche Verlagsgesellschaft, Stuttgart.

 

Rozman K.K., Klaassen C.D. (1996) Absorption, Distribution, and Excretion of Toxicants. In Klaassen C.D. (ed.) Cassarett and Doull's Toxicology: The Basic Science of Poisons. McGraw-Hill, New York.

 

Bonse G., Metzler M. (1978) Biotransformation organischer Fremdsubstanzen. Thieme Verlag, Stuttgart.