2-Butyne-1,4-diol, polymer with methyloxirane

Endpoint summary

Description of key information

Based on the physicochemical properties and the results obtained in the toxicity tests, the parent substance 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 and also, based on the high water solubility and the results obtained in the respective toxicological dermal toxicity test. It is unlikely that relevant amounts of the reaction mass will become systemically bioavailable via inhalation as the vapor pressure is very low and the high water solubility retains the substance in the upper mucosa.
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 substance is assumed to be not bioaccumulative in adipose tissues or other compartments. 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

There were no studies available in which the toxicokinetic properties (distribution, metabolism, elimination) of the 2-Butyne-1,4-diol, compd. with methyloxirane CAS 61596-96-1 were investigated. The expected toxicokinetic behaviour is derived from the physicochemical properties, the results from the available toxicological studies and the available literature following the information given in guidance document 7c:

 

Physico-Chemical Data on 2-Butyne-1,4-diol, compd. with methyloxirane

The organic reaction product composed of 2-Butyne-1,4-diol, compd. with methyloxirane is a liquid substance at standard ambient temperature and pressure.

 

Depending on the degree of polymerisation the molecular weight of the reaction product will vary but mean value of EO degree is 1.2 leading to a molecular mass of 155g/mol.

The log pow was determined to be -0.78 and the boiling point was measured as >=99.3°C. The substance is totally miscible with water at any ratio at room temperature and has a vapor pressure of 1.1 hPa (20°C)

 

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

 

Absorption

 

Oral route:

Due to the very high water solubility and the low logPow (-0.78) of the substance, 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 study shows moderate toxicity (LD50 = 275 mg/kg) concluding that oral absorption may be happen. Nevertheless the exakt amount of absorption stays unclear but is expected to be high and anticipated to be 100%

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). Here, results of the post mortem investigation revealed that the organ weights of kidney and liver were increased in both males and females at a high doses level of 125 mg/kg bw/day. These effects provide evidence that the reaction product or its metabolites reaches the systemic circulation following oral administration. However it has to be mentioned that no histopathological changes in the liver and kidneys were noted and the observed effects were not considered to be adverse. Furthermore, no adverse effects on fertility and development of the offspring were noted and the respective NOAELs for male and females were determined to be 125 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 substance or its metabolites becomes systemically available following oral intake and that the bioavailability must be high (100%).

 

 

Dermal route:

Based on the high water solubility of the substance, 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 substance and close homologues (BASF, 1980, 2012 and 2012). During these studies, no systemic effects were observed and high LD50 were determined. Also, no skin irritation potential is observed and the substance is no surfactant. 

Overall, the results from the dermal toxicity and phys-chem. data do not suggest that high amounts of the substance are absorbed and become systemically available, but nevertheless as concrete information on absorption is missing dermal absorption of 50% is used for risk assessment, but may represent an worst case concerning this route.

 

 

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 in an inhalation risk test of a close homologue substance (2-propyn-1-ol with methyloxiran CAS 38172-91-7) with an LD 50 > 2.01 mg/l animals showed irritation of the mucosa (BASF 10I0224/877026). This underlines the retention of the substance in upper airway which may lead to unwanted effects (bloody nose) and may increase the systemic availability. But as no death occurred this systemic may be limited compared to the oral uptake.

In summary, no systemic toxicological effects related to the test substance were noted in an acute inhalation toxicity tests on rats. Uptake may be possible via upper respiratory system and enhanced by irritation but limited due to the high water solubility. Oral ingestion after zilia transport from the upper airway to the GI tract is the most likely exposure after inhalation.

As worst case assumption for inhalative absorption 100% absorption is used for risk calculation.

 

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 to an endogenous substrate (glucuronide or sulfate) the substance itself or to its Phase I metabolites. Afterwards due to high water solubility fast excretion is expected.

 

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.

 

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.