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Description of key information

Based on consideration of physicochemical properties, the substance would be expected to be absorbed by the mammalian system. Absorption rates are set at 100% for oral, 100% for dermal and 100% for inhalation.

Despite the lack of systemic toxicity reported by any of the acute and repeated dose toxicity studies, the physicochemical properties of the substance suggest that there will be wide distribution of the substance to such organs as the liver, kidney and spleen. Metabolism of the substance in perfused rat livers has been investigated (Desrochers et al., 1992).  The substance is taken up by the isolated liver of fed or starved rats and is converted to the physiological ketone bodies R-3-hydroxybutyrate and acetoacetate. Ultimately excretion is expected to be urinary, but might also be faecal following oral dosing. Based on the available data, the substance is not expected to bioaccumulate.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information

The toxicokinetic behavior after exposure to (R)-(-)-butane-1,3-diol is assessed.

To date, little to no relevant analytical toxicokinetic testing data has been generated for (R)-(-)-butane-1,3-diol. However, information on the metabolism of (R)-(-)-butane-1,3-diol in perfused rat livers and information on the physicochemical properties can be used as a basis for the assessment of toxicokinetics.

Absorption

Passive absorption of a substance into a test species is governed by the physical-chemical properties of the substance, particularly its molecular size, log P, and water solubility (ECHA, 2014). The molecular size of the substance is 90.121 g/mol suggesting favourable oral absorption. The predicted moderate log P of -0.9 and the very hydrophilic nature of the substance (i.e., predicted water solubility of 999,800 mg/L) suggests favourable conditions for oral absorption by passive diffusion. The moderate predicted vapour pressure of greater than 8 to less than 10 Pa at 20 °C, log P and water solubility suggests that exposure via inhalation cannot be completely excluded. However, as the predicted water solubility is above 10,000 mg/L and the log P value is below 0, the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum and dermal uptake for these substances will be low.

Oral

Passive absorption of a substance into a test species is governed by the physical-chemical properties of the substance, particularly its molecular size, log P, and water solubility (ECHA, 2014). The molecular size of the substance is 90.121 g/mol suggesting favourable oral absorption. The predicted moderate log P of -0.9 and the very hydrophilic nature of the substance (i.e., predicted water solubility of 999,800 mg/L) suggests favourable conditions for oral absorption by passive diffusion. The substance does not contain ionisable functional groups meaning the substance does not have any dissociation constant values. Also, a review of the chemical structure of the substance shows that the substance is a glycol, possessing only alcohol functional groups. Since alcohols are generally resistant to hydrolysis, the substance is not expected to hydrolyse in the gastrointestinal tract. To further assess the absorption potential via the oral route, a Frye, et al. (1981) reported possible central nervous system depressant effects following oral administration of (R/S)-1,3-butylene glycol in rats needs to be considered as limited toxicological effects were observed in acute and repeated dose toxicity studies. However, given the physical-chemical properties of the substance, a default value for oral absorption of the substance is set as 100%.

Dermal

The key physical-chemical property that affects dermal absorption potential is log P. The molecular size of 90.121 g/mol favours dermal uptake. However, as the predicted water solubility is above 10,000 mg/L and the log P value is below 0 the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum and dermal uptake for these substances will be low. Given that the integrity of the stratum corneum is an important factor affecting dermal absorption, skin irritation potential needs to be taken into account. The in vitro and in vivo skin irritation study results showed the substance is considered to be not irritating to skin; therefore, an increase in dermal absorption potential due to impaired skin is not anticipated. In general, while the physical-chemical properties suggest dermal absorption will be low there are no data to support this, and there are no data demonstrating that dermal absorption will be lower than oral absorption. Thus, the default value for dermal absorption of the substance is set as 100%.

Inhalation

In general, water-soluble mists or vapours would readily diffuse/dissolve into the mucus lining of the respiratory tract. The moderate predicted vapour pressure of greater than 8 to less than 10 Pa at 20 °C suggests that exposure to vapours via inhalation cannot be completely excluded. While, the log P value of -0.9 would favour absorption directly across the respiratory tract epithelium by passive diffusion, the very hydrophilic nature of the substance would suggest retention within the mucus. Material retained by the mucus would either be cleared via coughing or swallowed and enter the gastrointestinal tract. Consequently, absorption via inhalation is considered to be comparable to the oral route and a default value for inhalation absorption is set as 100%.

Distribution

None of the acute and repeated dose toxicity studies showed any significant systemic toxicity which is consistent with the low hazard associated with the racemic form of the substance. Despite the lack of systemic toxicity, the very hydrophilic nature of the substance combined with a low molecular weight and a log P less than 0 suggest that there will be wide distribution of the substance to such organs as the liver, kidney and spleen. 

Metabolism

The metabolism of the substance in perfused rat lives has been investigated (Desrochers et al., 1992).  The substance is taken up by the isolated liver of fed or starved rats and is converted to the physiological ketone bodies R-3-hydroxybutyrate and acetoacetate.

Excretion

Following metabolism to the physiological ketone bodies R-3-hydroxybutyrate and acetoacetate, ultimate excretion is expected to be urinary, but might also be faecal following oral dosing. Based on the available data, the substance is not expected to bioaccumulate.

References

Desrochers S, David F, Garneau M, Jetté M, Brunengraber H (1992). Metabolism of R- and S-1,3-butanediol in perfused livers from meal-fed and starved rats. Biochem J 285:647-653. (See IUCLID section 7.1.1)

 

ECHA (2014). Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. Volume 2.0, November 2014. Available at:https://echa.europa.eu/documents/10162/13632/information_requirements_r7c_en.pdf/e2e23a98-adb2-4573-b450-cc0dfa7988e5

 

Frye, G. D., et al. Effects of acute and chronic 1,3-butanediol treatment on central nervous system function: a comparison with ethanol. Journal of Pharmacology and Experimental Therapeutics 216.2 (1981): 306-314. (See IUCLID section 7.9.1)