Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
other: Paper-based toxicokinetic assessment
Adequacy of study:
key study
Study period:
2020
Reliability:
1 (reliable without restriction)

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion

Executive summary:

TOXICOKINETIC ASSESSMENT: YX8000D

INTRODUCTION

In accordance with the Section 8.8.1 of Annex VIII in Regulation (EC) No 1272/2008, the toxicokinetic profile of YX8000D was derived from all available substance-specific information as collated in the registration dossier. The assessment is based on the Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017).

PHYSICOCHEMICAL PROPERTIES

YX8000D is a mono-constituent substance with a molecular weight of 352.51 g/mol. It is hydrolytically stable under the physiological condition. It is a colourless liquid with no boiling point below 400°C and a low vapour pressure of 0.000211 Pa at 25°C (calculated value). The registered substance has a relatively low water solubility of 63.1 mg/L at 20°C with a moderate log Pow value of 4.0. Due to its moderate molecular weight and log Pow value, the substance is expected to be absorbed via the oral and dermal routes. Its low vapour pressure and anticipated high boiling point suggest that the substance is poorly available as a vapour for inhalation exposure.

ABSORPTION

Signs of oral absorption are seen in the results of the 14-day range-finding study and combined repeated dose and reproduction/developmental toxicity test in rats (Saitoh, 2019), both of which were conducted in the rat via gavage.

Although the registered substance is not classified for skin or eye irritation, there are signs of irritation on skin and eyes of rabbits (Remmele and Leibold, 2005a,b). A sign of local irritation was also observed in the gastro-intestinal tract of rats in the OECD 422 study following oral gavage administration (Saitoh, 2019). It may be possible that the irritant property of the registered substance would have damaged to the skin surface, and consequently enhanced a penetration of substance in the skin to some extent. Signs of dermal absorption of the registered substance are evidenced by the positive skin sensitisation response in the local lymph node assay (LLNA) in mice (Gamer and Leibold, 2005).

There are no in vivo mammalian studies available via the inhalation route for the registered substance. However, due to its physico-chemical properties, inhalation is not considered to be the most significant route of exposure.

DISTRIBUTION

The moderate molecular weight and relatively low water solubility of the registered substance are considered unlikely to allow it to disperse into the water compartment of blood for systemic distribution. Due to its moderate log Pow value, YX8000D is likely to be accumulated in body fat.

The positive skin sensitisation result in the LLNA (Gamer and Leibold, 2005) suggests that the registered substance binds to carrier proteins in the blood once molecules enter the circulatory system.

METABOLISM

The result of the OECD 422 study showed the evidence of non-adverse adaptive responses in the liver in rats (Saitoh, 2019). The associated changes in clinical chemistry parameters suggest the enhanced hepatic metabolism. Increased thyroid weights and follicular cell hypertrophy of the thyroid, as well as decreased serum thyroxine (T4) levels may have been a consequence of induced hepatic enzyme following oral administration of the registered substance.  

YX8000D produced positive results for gene mutations in both the presence and absence of metabolic activation in the bacterial mutation test (Engelhardt and Leibold, 2004) and in vitro mouse lymphoma assay using the thymidine kinase (Kajiwara, 2019). The substance was found not to cause chromosome damage or loss in the mouse micronucleus test (Schwind and Hellwig, 2005). Overall, the results of the genotoxicity studies suggest that metabolism did not influence genotoxicity of YX8000D.

EXCRETION

There is no evidence to indicate the route of excretion. Given its moderate molecular weight and log Pow value, the registered substance may preferentially go through biliary excretion than urinary excretion. Any test material that is not absorbed will be excreted in the faeces.

REFERENCES

ECHA (2017) Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7c: Endpoint specific guidance, Version 3.0, June 2017.

Engelhardt, G. and Leibold, E. (2004) Salmonella Typhimurium / Escherichia Coli reverse mutation assay (standard plate test) with Hydrierter Bisphenol - A – bisglycidylether. Report No. 40M0057/044046. Unpublished report.

Gamer, A.O. and Leibold, E. (2005) Hydrierter Bisphenol-A-bisglycidylether - Murine Local Lymph Node Assay (LLNA). Report No. 45H0057/042047. Unpublished report.

Kajiwara, A. (2019) In vitro gene mutation study of YX8000D in mouse lymphoma cells. Report No. B180555. Unpublished report.

Remmele, M. and Leibold, E. (2005a) Hydrierter Bisphenol-A-bisglycidylether - Acute dermal irritation / corrosion in rabbits. Report No. 18H0057/042086. Unpublished report.

Remmele, M. and Leibold, E. (2005b) Hydrierter Bisphenol-A-bisglycidylether - Acute eye irritation in rabbits. Report No. 11H0057/042097. Unpublished report.

Saitoh, T. (2019) Combined repeated dose and reproduction/developmental toxicity test of YX8000D by oral administration in rats. Report No. P180450. Unpublished report.

Schwind, K.R. and Hellwig, J. (2005) Cytogenetic study in vivo with Hydrierter Bisphenol-A-bisglycidylether in the mouse micronucleus test after two oral administrations. Report No. 26M0057/044170. Unpublished report.