Alcohols, C11-15-secondary, ethoxylated

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Description of key information

No toxicokinetic study has been conducted. data from physicochemical properties and in vivo toxicity tests have been used to predict the toxicokinetics of Softanol 30.

There is limited evidence that the test substance is absorbed via the gastrointestinal tract and some absorption via the skin or lungs cannot be ruled out if exposure occurs. There is also evidence of some systemic distribution to the liver. There is no evidence of metabolism or metabolic fate. Excretion via the kidney is considered to be the major route of excretion based on the molecular weight of Softanol 30 (without taking into account phase 2 metabolism) and supporting evidence from other alcohol ethoxylates whereas biliary excretion is considered possible based on a slight increase in liver weight. The liver and kidneys may be sites of metabolism. There was no information on bioaccumulation.

Additional information

No specific study was performed on the absorption/distribution/metabolism/excretion (ADME) of this substance (Softanol 30) but data are currently available from the physico-chemical and in vivo toxicology studies. Softanol 30 is not a single chemical structure but a series of closely related C11-15 secondary alcohol ethoxylates differing by chain length. The substance is a UVCB with high purity (100%). The physicochemical properties are very similar between the different chain lengths because of the closeness of the homologues. The similarity between the properties of the homologues in the mixture enables a prediction of toxicokinetics to be made which applies to the entire UVCB. Studies specifically conducted on other alcohol ethoxylates to determine toxicokinetics have been reported (HERA, 2009) and provide a useful addition to available evidence.

Absorption

Oral route The physico-chemical characteristics of Softanol 30 suggest that the substance will be well absorbed via the gastro-intestinal tract. Its molecular weight is small at 334 (MW< 500), its Log P value is high (Log P = approximately 6.0) and its solubility in water is moderate at 1.1 mg/L. The high logP value may suggest low oral absorption by the Lipinski rule (Lipinski et al, 2001). There were no deaths but there were non-specific clinical signs of toxicity in the acute oral study. In the repeated dose studies in rats test treated with Softanol 30 there were transient effects on body weight, increased liver weights and disturbances in clinical biochemistry, but no target organ toxicity. In the developmental toxicity study low body weight, food consumption and low fetal body weights were the only effects of the test material. There was no evidence of direct systemic toxicity. With little evidence of direct systemic toxicity but non-specific signs of general toxicity it is difficult to confirm significant absorption by the gastrointestinal tract. It is likely that some absorption does occur as evidenced by the increased liver weight and disturbances in clinical biochemistry parameters. A study conducted by Unilever (1978) and reviewed by HERA (2009) showed that orally intubated 14C12AEx alcohol ethoxylates was extensively absorbed and excreted via the urine in rats. There was little difference between the oral, intraperitoneal and subcutaneous routes. Dermal route Softanol is a liquid with a MW of 334 and a Log P value of >6.0. Its solubility in water is 1.1 mg/L at 20°C. A substance in a liquid state with MW of circa 300 and a high Log P value possibly suggests low dermal absorption. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Between 1-100 mg/L absorption is anticipated to be low to moderate. Softanol 30 physico-chemical properties indicate that it might not be well absorbed through the skin, and there was no evidence of a systemic effect in the acute dermal toxicity study thus providing circumstantial evidence of low absorption. Softanol 30 is classified as a skin sensitiser based on in vivo data, suggesting sufficient dermal absorption to elicit a response. This is supported by evidence of local erythema and scales on the back of rats in an acute dermal toxicity study. In vivo studies reviewed by HERA (2009) showed that a variety of dermally applied 14C alcohol ethoxylates were well-absorbed through the skin. The detail of those studies is not available but the reviewers consistently support significant dermal absorption. The HERA (2009) review also discusses human dermal absorption data for C12AE6 which shows that human skin is more resistant to dermal absorption than rat skin. In light of the above and in view of the fact that there are no specific data on C11-15 secondary alcohol ethoxylates, it is considered not possible to provide a quantitative estimate of human dermal absorption. Inhalation route With a vapour pressure of 0.013 Pa at 25°C and boiling temperature is >280°C, Softanol 30 is not a highly volatile substance and therefore not likely to be available for inhalation as a vapour, however no inhalation study is available to investigate absorption via the inhalation route.

Distribution

The findings from the oral acute and repeated dose studies provide limited evidence that the test substance is distributed systemically when absorbed by the gastrointestinal tract. In the acute oral toxicity study there were no deaths at 2000 mg/kg. In the repeated dose study there was evidence of systemic distribution to the liver (higher liver weights and lower total bilirubin). There was no evidence of systemic distribution after dermal application. There is no evidence of distribution to the fetus since there was no adverse effect on survival but exposure cannot be ruled out.

Metabolism

No data are available on metabolism in the existing toxicity studies. There was limited evidence of an effect on tissues with high metabolism capability (increased liver weight) which could have provided evidence for metabolism.

Excretion

Molecular weight of Softanol 30 is relatively low (334 average) and absorbed small organic compounds are more likely to be excreted in the urine. Data from the HERA review (2009) support the urine as the major excretory route for alcohol ethoxylates, irrespective of the route of exposure. Biliary excretion is more likely for high molecular weight compounds either because of biotransformation by phase 2 conjugation or because the parent is innately large (>500 MW).

Conclusion

There is limited evidence that the test substance is absorbed via the gastrointestinal tract and some absorption via the skin or lungs cannot be ruled out if exposure occurs. There is also evidence of some systemic distribution to the liver. There is no evidence of metabolism or metabolic fate. Excretion via the kidney is considered to be the major route of excretion based on the molecular weight of Softanol 30 (without taking into account phase 2 metabolism) and supporting evidence from other alcohol ethoxylates whereas biliary excretion is considered possible based on a slight increase in liver weight. The liver and kidneys may be sites of metabolism. There was no information on bioaccumulation.

References HERA (2009) Human and Environmental Risk Assessment on ingredients of European household cleaning products: Alcohol Ethoxylates v2 Lipinski, CA, Lombardo, F, Dominy, BW and Feeney, PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews, 46, 3-26