Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics
Adequacy of study:
other information

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion

Executive summary:

There is no reliable and relevant information source in which the toxicokinetic properties (absorption, distribution, metabolism, elimination) of the substance were investigated. The expected toxicokinetic behaviour is derived from the physicochemical properties and the results from the available toxicological data following the guide given in the REACH guidance document R.7c.

The substance is composed of constituents having a molecular weight around 210. It is a liquid with an estimated water solubility of 15 mg/L. Vapour pressure was determined to be about 247 Pa at 25 °C and it has lipophilic properties (log Kow = 4.6-4.8). The surface tension is 62.3 mN/m at 22 °C. Detailed information can be found in section 4.

Absorption:

In acute oral toxicity studies, no systemic toxic effects were observed. Only local slight irritant effects were identified in an acute dermal toxicity study. However, in a reproduction /developmental toxicity screening test and in a 4-week repeated dose toxicity study by oral route, the main effects elicited by the substance were increased salivation, thyroid and liver hypertrophy as well as hyaline droplet nephropathy in males only. These latter observations indicate bioavailability of the substance via oral route.

Although no signs of toxicity were observed in an acute dermal toxicity study and in skin sensitization studies, the substance has a molecular weight < 500 and is a lipophilic substance (log Kow = 4.6 -4.8) therefore dermal absorption is expected. Due to its low water solubility, dermal absorption may be low to moderate, but potentially enhanced by the slightly irritant properties of the substance, as damage to the skin surface may enhance penetration.

Thus, indications of oral and dermal uptake of the substance are given, confirming the bioavailability of the substance by oral and dermal routes.

Distribution:

The physico-chemical information (low molecular weight, lipophilicity and low water solubility) indicates that the substance could be distributed to many tissues and, due to its lipophilicity, may have a particular affinity for fatty tissues.

Metabolism:

No data are available but, in two in vitro genotoxicity studies (chromosome aberration in human lymphocytes cultures and in L5178Y tk+/-Mouse Lymphoma Assay), lower cytotoxicity was observed in conditions of exposure with metabolic activation, showing that the substance was metabolised in less cytotoxic metabolites. This indicates that the substance may be metabolised by hepatic microsomal fractions. This hypothesis is confirmed in an in vivo repeated dose toxicity study where an adaptative response to oral exposure, resulting in increased liver weight and hepatocellular hypertrophy, was observed in both sexes. Thus the substance is probably metabolised in the liver.

Excretion:

There are several facts indicating that the substance would be mainly excreted in urine. First, it is a small molecule with a molecular weight lower than 300 which means that not more than 5-10% may be excreted in bile. In addition, in a 4-week repeated oral toxicity study, microscopic kidney changes identified as increased severity of hyaline droplets in the proximal tubules of the kidneys were evident together with an increase in absolute and relative kidney weights in males of the high dose group. This shows that urinary excretion is probably the main route of excretion for the substance and/or its metabolites.

Accumulative potential:

Based on the physico-chemical information (log Kow and low water solubility), it is concluded that the potential for bioaccumulation is low.