Hex-3-yne-2,5-diol

Endpoint summary

Description of key information

Based on the results of the experimental investigations as well as on the physico-chemical properties the test item is considered to be bioavailable via oral and inhalation route and also via dermal route to a certain extend. Once systemic available the substance might be widely distributed through the organism. Oxidation of the test substance to hex-3-yne-2,5-dion and a subsequent reduction of the triple bond by NAD(P)H-linked reductase is assumed. Metabolic activation could not be excluded. Due to the low molecular weight, the high water solubility (>500 g/L) and the presumed metabolism hex-3-yne-2,5-diol and/or its metabolites are expected to be excreted via urine. Based on the low log Pow value no bioaccumulation of the test substance is expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The test item is a solid at room temperature with a melting point of 42 °C and a boiling point of 231 °C. It has a molecular weight of 114.16 g/mol, a density of 1.018 g/cm³(at 25 °C) and a log Pow value of -0.24 (25 °C). The substance has a vapour pressure of 0.1 Pa (20 °C) and is soluble in water. The pH value is 5 - 7 (500 g/L, 20 °C).

 

The main exposure route at room temperature is dermal as the vapour pressure at 20 °C is considered to be negligible and exposure via inhalation is considered to be unlikely.

 

In an acute oral toxicity study with hex-3-yne-2,5-diol in rats (BASF, 1973) the LD₅₀was determined to be 140 mg/kg bw for male and female rats. Besides clinical signs like apathy and dyspnea, acute heart dilatation and congestive hyperemia were observed. Bloody ulceration in the stomach, discoloration of the liver and the kidney and slight lung edema were noted. In an acute inhalation toxicity study rats were exposed to a saturated atmosphere of the test item for up to 8 hours (BASF, 1971). No animal died after a 1-hour exposure period. 3 of 6 animals died after 3-hour exposure and 6 of 6 animals died after 8-hour exposure. Pulmonary congestion and congestion in the liver, degeneration of the liver and heart dilatation were observed. In an acute dermal toxicity study with the test item in rats (BASF SE, 2002) no mortality occurred and the LD₅₀was determined to be > 2000 mg/kg bw. Neither any clinical signs of systemic toxicity nor any macroscopic pathologic abnormalities were observed. Moderate to severe dermal irritation was noted at the site of test item application.

In the acute dermal irritation/corrosion studies (BASF, 1971, 1973) rabbit skin was exposed to the unchanged test substance for 20 hours. Slight to moderate erythema and edema were observed, not fully reversible within 8 days. Hex-3-yne-2,5-diol caused serious eye damage in the available eye irritation studies (BASF 1971, 1973). Administration of 5.0, 10.0 and 25 % of the test item for three consecutive days on the ear of mice revealed a statistically significant and biologically relevant increase in lymph node weight and lymph node cell count was observed in all dose groups in comparison to the vehicle control. Therefore, hex-3-yne-2,5-diol is considered to be a skin sensitiser.

A 14 day dose range finding study (BASF SE, 2012) using oral administration of hex-3-yne-2,5-diolwas performed in male and female Wistar rats in order to obtain first information on the toxic potential of the test item after long-term administration to allow a dose-setting for a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test. The test substance was administered orally (by gavage) once a day for a total of 14 days at 0 (vehicle control), 10, 25, 60, and 120 mg/kg bw/day. No mortality and no test item-related clinical signs were observed through this study. Animals of both sexes had lower red blood cell counts, haemoglobin, haematocrit and mean corpuscular haemoglobin concentration at 120 mg/kg bw/day, while reticulocytes, red blood cell distribution width and mean corpuscular volume were increased compared to controls. Collectively, the data suggest regenerative macrocytic hypochromic anaemia. At 120 mg/kg bw/day, lower alkaline phosphatase (ALP; males) and inorganic phosphate levels (males, also at 60 mg/kg bw/day) were seen, while total bilirubin (both sexes), total protein, albumin and cholesterol (both for females only and also at 60 mg/kg bw/day) were increased. The increase in bilirubin may be support the evidence collectively suggesting hemolytic anaemia. Absolute and relative liver weights were markedly higher for both sexes at 60 and 120 mg/kg bw/day, and absolute and relative spleen weights were also increased at 120 mg/kg bw/day (males and females). Enlarged spleen was noted for all males and females at 120 mg/kg bw/day. Additionally, thickened limiting ridge of the stomach was noted for one female and all males at this dose level. Based on these results the following three doses were selected for the aforementioned combined repeated dose toxicity study with the reproduction/developmental toxicity screening study: 5, 20 and 60 mg/kg bw/day.

In the main study one female was killed in extremis and one female was found dead at 60 mg/kg bw/day. Both of these animals were noted with necrosis of the glandular stomach at the microscopic examination, which was possibly related to treatment. No clinical signs of toxicity were noted during the observation period. No test-item related effects on body weight and food consumption were noted.

Males at 60 mg/kg bw/day had significantly lower red blood cells, haemoglobin, and mean corpuscular haemoglobin concentration, along with increased reticulocytes and mean corpuscular volume. Females at this dose level had significantly increased neutrophils and decreased lymphocytes (also seen for females at 20 mg/kg bw/day, but was not statistically significant). These data collectively suggest a mild regenerative macrocytic hypochromic aenemia. Observed changes in clinical chemistry in male animals of the high dose group (significantly lower alkaline phosphatase and significantly higher inorganic phosphate levels than controls) were not considered to be biologically relevant. Absolute and relative liver and spleen weights were higher for animals for both sexes at 60 mg/kg bw/day (absolute liver weights were not significantly higher for females at this level). At 20 mg/kg bw/day, absolute liver weights were higher for animals of both sexes, though the difference was not significantly different from controls. Liver to body weight ratios were significantly higher for males at this dose level, however. Macroscopic findings noted for animals at 60 mg/kg bw/day included black discoloration of the spleen, dark red foci on the stomach glandular mucosa, enlarged spleen and/or liver. Treatment-related microscopic findings were present in the stomach, spleen, bone narrow, liver and kidney. Neither reproduction nor developmental toxicity were observed up to the highest dose level tested (60 mg/kg bw/day). Based on these results, the No Observed Adverse Effect Levels (NOAEL) for general systemic effects was determined to be 5 mg/kg bw bw/day. The NOAEL for reproductive and developmental parameters were determined to be 60 mg/kg bw/day.

 

Absorption

After oral administration the substance is assumed to dissolve in the gastrointestinal fluids and absorption via aqueous pores or carriage across membranes with the bulk passage of water might occur as indicated by the high water solubility. In addition, absorption of the substance via passive diffusion might be favoured due to the log Pow value of -0.24. The LD₅₀evaluated in an oral acute toxicity study and the pathological and histopathological findings after repeated oral administration indicate that the compound becomes bioavailable after oral administration.

The test item is solidified or highly viscous at room temperature and the vapour pressure of the test item at 20 °C is low. Therefore, inhalation of dust or vapour is unlikely. However, if the test item becomes available for inhalation, the test item might cross the respiratory tract epithelium by passive diffusion or active transport via aqueous pores as indicated by the small molecular weight and the physic-chemical properties of the substance. This assumption is supported by the results of the acute inhalation toxicity studies in which mortality and signs of systemic toxicity were observed.

Dermal absorption of hex-3-yne-2,5-diol is estimated to be low as uptake into the stratum corneum is limited by a high water solubility and a log Pow value below 0. No signs of systemic toxicity were observed in the available acute dermal toxicity studies. However, since the available LLNA revealed a skin sensitising effect, penetration through the skin has to occur to a certain extend.

 

Taken together, experimental data indicate bioavailability of the test substance via oral and inhalation route and to a certain extend also via dermal route.

Distribution

A wide distribution of the test substance in the organism is expected due to its low molecular weight and high water solubility. This assumption is supported by the adverse effects observed in the stomach, spleen, liver, kidney and bone marrow in the available combined repeated dose toxicity study with the reproduction/developmental toxicity screening test. Based on the low log Pow value no bioaccumulation of the test substance is expected.

 

Metabolism

The test substance might be oxidised to hex-3-yne-2,5-dion. A reduction of the triple bond by NAD(P)H-linked reductase is further considered resulting in corresponding alkene- and alkane-derivatives as already shown by Kitamura S. et al. (2002). In order to facilitate excretion conjugation of the parent compound and/or its metabolites with endogenous substrates is expected.

The test item did not induce gene mutations neither in the Ames test nor in the HPRT test in mammalian cells in the absence and in the presence of a metabolic activation system, respectively.However, there are indications of genotoxicity of the test item and/or its metabolites from the present cytogenetic test (BASF SE, 2012). In the presence of a metabolic activation system hex-3-yne-2,5-diol or rather its metabolites were shown to be clastogenic in vitro. Based on these data metabolic activation could not be excluded.

 

Excretion

Due to the low molecular weight, the high water solubility (>500 g/L) and the presumed metabolism hex-3-yne-2,5-diol and/or its metabolites are expected to be excreted via urine.

 

Conclusion

Based on the results of the experimental investigations as well as on the physico-chemical properties the test item is considered to be bioavailable via oral and inhalation route and also via dermal route to a certain extend. Once systemic available the substance might be widely distributed through the organism. Oxidation of the test substance to hex-3-yne-2,5-dion and a subsequent reduction of the triple bond by NAD(P)H-linked reductase is assumed. Metabolic activation could not be excluded. Due to the low molecular weight, the high water solubility (>500 g/L) and the presumed metabolism hex-3-yne-2,5-diol and/or its metabolites are expected to be excreted via urine. Based on the low log Pow value no bioaccumulation of the test substance is expected.