2-Propyn-1-ol, reaction product with 1-2.5 moles of oxirane

Endpoint summary

Description of key information

Based on the physicochemical properties and the results obtained in the toxicity tests, fractions of the reaction mass will most likely 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 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.
Based on its PC values the constituents of the reaction mass are considered to be bioaccumulative. 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Physico-Chemical Data on 2-Propyn-1-ol, polymer with ethylenoxid

 

The organic reaction product composed of 2-Propyn-1-ol, polymer with ethylenoxid appears as a clear yellowish liquid at standard ambient temperature and pressure.

 

Depending on the degree of polymerisation the molecular weight of the reaction product will vary be found in the range of 56.1 to 188.2 g/mol. With the major compound EO=1 (80%; m=100.1 g/mol) and the second major compound EO=2 (17%; m=144.2 g/mol)

Further due to the different ethoxylation products in the reaction mass the log pow varies from -0.7 to 2.6 (EO=1 -> log pow=1 EO=2 -> log pow=2.4). Therefore a mean log pow of 1.7 +-0.7 is used for kinetic assumption as a it reflects 97% of the mixture. 

The boiling point was calculated to be 177.2°C and the reaction product is totally miscible with water at any ratio at room temperature. The reaction product has a vapor pressure of 1.98 hPa at 20°C.

 

Toxicokinetic analysis of 2-Propyn-1-ol, polymer with ethylenoxid

 

Absorption

 

Oral route:

Following oral intake, and once in contact with the digestive fluids of the stomach, it is assumed that the unstable triple bond degrades and a double bond will form.

Due to the very high water solubility and the low logPow (range between -1 and 4) of the reaction product, systemic uptake via passive diffusion is possible within the gastro intestinal (GI) tract. Furthermore, 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 may pass through aqueous pores or may be carried through the epithelial barrier by the bulk passage of water.

 

Information from acute oral toxicity studies ranged from LD50 > 2000 mg/kg down to an LD50 for male animals of 464 mg/kg bw for a close homologue of the target substance. Effects observed are heart dilation, discoloration of the liver, apathy, respiratory distress, bloody ulcerations in the glandular stomach, redness of intestinge mucosa etc. 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, therefore clear absorption hints can not be derived from the acute toxicity studies.

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) with a close homologue substance (2-propyn-1-ol with methyloxiran CAS 38172-91-7) or from the new conducted OECD 408 studies with CAS 38172 -91 -7 or CAS 25749 -64 -8. Here, results of the post mortem investigation revealed that the organ kidney and liver were effected in both males and females at a high doses level. These effects provide evidence that the substances or its metabolites reaches the systemic circulation following oral administration.

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 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 source substance and with a close homologue (2-Propyn-1-ol compound with methyloxirane) performed on rats. During these studies, no systemic effects were observed and the LD50 was determined to be > 2000 mg/kg bw (limit dose). Also, no skin irritation potential are seen and also no immunological response were observed in a Murine Local Lymph Node Assay (LLNA) (OECD 429) with a homologue substance (2-Propyn-1-ol compound with methyloxirane).

Overall, the results from the dermal toxicity and sensitization 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, vapors of very hydrophilic substances are retained in the upper mucosa and thus do not reach in high amounts lower alveolar regions. Hence high water-soluble are less available for systemic absorption after inhalation. Nevertheless strong irritation of the mucosa (with dead’s) is observed in a inhalation risk test after 8h exposure to saturation concentrations (1.33.mg/L air). This underlines the assumption that the substance is retained in the mucosa but leads also there to irritating effects and consequently breathe difficulties which causes dead. Further effects despite strong mucosa irritation, bloody discharged nose and dyspnea are not reported, hence a systemic effect can not be observed. Nevertheless in another inhalation risk test of the substance shows an LD 50 > 2.01 mg/l air with one dead animal, died also on irritating effects (breath difficulties). For a close homologue (2-propyn-1-ol with methyloxiran CAS 38172-91-7) also irritating effects were observed but do not lead to a deads at saturation concentration (BASF 10I0224/877026).

In summary, no systemic toxicological effects related to the test substance were noted in an acute inhalation toxicity tests on rats.

 

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 a subacute toxicity study with a close homologue (2-propyn-1-ol with methyloxiran CAS 38172-91-7) provide evidence that a transport to the liver and kidney occurs (increased but not adverse organ weights). Due to the high watersolubility and the low log pow a accumulation is unlikely. 

 

Metabolism

Based on the chemical structure, the substance may be metabolized by Phase I enzymes. More specifically, based on the chemical structure a hydroxyl group is likely to be introduced by cytochrome P450 mediated oxidative de-alkylation. Furthermore, Phase II conjugation reactions 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.

 

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. Fractions of the chemical which are not absorbed within the GI tract will be readily excreted via the faeces.

 

Summary

 

Based on the physicochemical properties and the results obtained in the toxicity tests, fractions of the reaction mass will most likely 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 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.

Based on its PC values the constituents of the reaction mass are considered to be bioaccumulative.

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.