Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

In summary, the absorption for the oral route is likely to be close to 100%, and for the dermal and inhalation routes is assumed to be 100%. Bioaccumulation of the substance is not expected.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

In accordance with the section 8.1.1 of Annex VIII of Regulation (EC) No 1907/2006 (REACH), the toxicokinetic profile of the substance (i.e. absorption, distribution, metabolism and elimination) was derived from the relevant available information collated in the dossier. The physicochemical properties of the substance, the results obtained from acute, repeated-dose, and reproductive toxicity studies, as well as information gained from genotoxicity assays were used to predict its toxicokinetic behaviour.

Absorption:

Oral absorption:

The low molecular weight (i.e., 176 g/mol, being less than 500 g/mol), moderate log Kow value (i.e., 2.94±0.01, being between -1 and 4), and moderate water solubility (i.e., 609 mg/L) of the substance favour its absorption from the gastrointestinal tract. The systemic effects (i.e., mortality, reduced body weight, changes in haematological and serum biochemistry parameters, changes in organ weights) that have been observed in oral gavage toxicity studies in rodents (acute, repeated dose, and reproductive toxicity screening studies) support that the substance is absorbed from the gastrointestinal tract. In the absence of specific toxicokinetic data, however, the exact extent of such absorption cannot be quantified based on the information from these studies. Taking into consideration the physicochemical properties of the substance, absorption is expected to be moderate to high.  

In light of these data, and the lack of specific information on any the registered substance or its supporting substances, the registered substance was assumed to be 100% bioavailable by oral route for the purposes of human health risk assessment.

Dermal absorption:

Factors that influence the ability of a compound to penetrate through the stratum corneum and partition into the epidermis includes its molecular weight (i.e., poor absorption if molecular weight is greater than 500 g/mol), water solubility (i.e., moderate to high dermal uptake between 100 to 10,000 mg/L) and log Pow (i.e., absorption favoured between ‑1 and 4; values of 2 to 3 are optimal). As such, the physical-chemical properties of the substance (i.e., MW = 176 g/mol; water solubility = 609 mg/L; Log Pow = 2.94) favour its absorption through the skin. However, no evidence of systemic toxicity was observed in a single-dose dermal toxicity study where the substance was applied to the skin of rats at a dose of 2000 mg/kg body weight in a corn oil vehicle. The lack of effects observed following dermal application of the substance at a dose that was shown to mediate systemic toxicity following oral administration suggests dermal uptake is unlikely to be 100% of the dose. Taking all of the information into consideration, no specific conclusions can be reached as to the percent absorption from the acute toxicology study. As with the dermal toxicity study, there were no signs of systemic effects in rabbits following application of the substance to the skin for 4 hours in a dermal irritation study.

In light of these data, and the lack of specific information on any the registered substance or its supporting substances, a dermal absorption of 100% was conservatively assumed for the purposes of human health risk assessment.

Inhalation absorption:

Toxicokinetic and toxicological data were not identified for the inhalational route of exposure and the substance is not marketed or used in its solid or granular form. The low vapour pressure (9.8 x 10-2 Pa, which is lower than 0.5 kPa) and high boiling point (279°C, which is greater than 150°C) would indicate low volatility of the solid substance; as such, inhalational exposure is unlikely to occur. For safety reasons, however, 100% absorption via the inhalation route was conservatively assumed for the purposes of human health risk assessment.

Distribution:

Specific studies on the distribution of the substance have not been conducted. Based on the results of the 28-day oral toxicity study in rats, certain conclusions can be reached regarding tissue distribution. The increased liver weights and hypertrophy of the centrilobular hepatocytes observed in rats administered doses of 1000 mg/kg body weight/day indicate the substance is likely to have distributed to the liver following oral exposure. The substance also appeared to be distributed to the kidneys based on the observation of some non-adverse effects and taking into consideration the likely urinary excretion of the substance.

Hypoactivity, sedation, and coma were reported in animals receiving a single dose of 2000 mg/kg body weight, and hypoactivity and slight reduction in motor activity were reported in animals receiving 1000 mg/kg body weight/day for 4 weeks. No clear conclusion could be made regarding the tissue distribution of the substance based on these findings, given that these effects are possibly secondary to systemic toxicity associated with large doses of the test substance.  

Although there were some slight indications that the substance may have affected the viability of offspring of animals exposed to the substance in the reproductive toxicity screening study, it cannot be conclusively determined whether the compound is able to pass through the placental barrier or into the breast milk, or whether the odour of the substance itself may have affected the palatability of the milk or altered the interactions between dams and pups

Metabolism:

Studies of the metabolism of the substance have not been conducted, so no conclusions can be drawn at this time. Adaptive response in the liver observed in the 28-day repeated dose toxicity study may indicate liver metabolism of the substance.

Excretion:

The registered substance, having a molecular weight lower than 300 g/mol, is expected to be mainly excreted in urine and no more than 5-10% may be excreted in bile. Any substance that is not absorbed from the gastro-intestinal tract, following oral ingestion, will be excreted in the faeces.