Pyrimido[5,4-g]pteridine-2,4,6,8-tetramine, 4-methylbenzenesulfonate (1:1)

Endpoint summary

Description of key information

The irritation potential of this mixture is derived from toxicological information about the endproduct, the main by product and one toxicological relevant impurity. Two GLP conform studies in rats according OECD guideline 404 and 405 were performed with the end product Slight and transient reactionson skin and eyes were observed. All symptoms resolved within 72h. The by product was tested in a GLP conform study according OECD guideline 405 and in a non-GLP conform study. Application of 0.5g of the by product to skin or eyes of rabbits resulted in severe irritation. The by product is labelled as irritanting to skin, respiratory system and eyes (R 36/37/38). Due to the strong irritating potential of the by product which accounts for 30% of the mixture, leasons of skin and eyes cannot be excluded. On the other hand, the mixture is present as a salt and has a pH of 5 which indicates that corrosive effects will be less pronounced as compared to the pure by product.

Additional information

Reasons for read across

The substance was not tested for irritation to skin or eyes. The test item is a mixture which consist mainly of the end product (app. 50 %) and a by product (app. 30 %) as well as of different impurities and isomers of the end product. Therefore, information about acute toxicity are derived from studies with the end product and the by product. Moreover, one toxicological relevant impurity exceeds 1 % and is also taken into account for this summary.

 

Performance and observations

A GLP conform study was performed to assess the acute dermal irritation potential of the end product in White New Zealand rabbits according to the OECD guideline 404. Three rabbits were exposed to 0.5 grams of the test substance (purity: 94.8 weight-%) applied onto clipped skin for 4 hours using a semi-occlusive dressing. Observations were made 1, 24, 48 and 72 hours after exposure.

Exposure to the test substance resulted in very slight erythema and no or very slight oedema in the treated skin-areas of the rabbits, which had resolved within 24, 48 or 72 hours.

Yellow staining of the treated skin by the test substance was observed between days 1 and 3 on all animals which did not hamper the scoring of the skin reactions.

To assess the acute eye irritation or corrosion potential a GLP conform eye irritation test in White New Zealand rabbits was performed according to the method described in OECD guideline 405. Single samples of approximately 45 mg of the test substance (a volume of approximately 0.1 ml, purity: 94.8 weight-%) were instilled into one eye of each of three rabbits. Observations were made 1, 24, 48 and 72 hours after instillation.

Instillation of the test substance resulted in effects on the iris and conjunctivae. Iridial irritation (grade 1) was observed among all animals on day 1 and had resolved within 24 hours. Irritation of the conjunctivae was seen as redness, chemosis and discharge, which had completely resolved within 72 hours in all animals. No corneal opacity was observed, and treatment of the eyes with 2% fluorescein, 24 hours after test substance instillation revealed no corneal epithelial damage in any of the animals. Remnants of the test substance were present in the eyes of all animals on day 1. Yellow staining of the fur on the head and paws, caused by the test substance, was noted during the observation period.

 

A GLP conform study was performed to assess the acute dermal irritation potential of the by product in White New Zealand rabbits according to OECD guideline 404. One and three rabbits were exposed to 0.5 grams of the test substance applied onto clipped skin for 4 hours and three minutes, respectively using a semi-occlusive dressing. Examinations were made 0.5, 1, 24, 48 and 72 hours and 7d after exposure.

Exposure to the by product for 4h resulted in corrosion of the skin and formation of scars. Dermal application for 3min leads to formation of erythema which resolved up to day 3 of post observation period. 

In another, non-GLP study, ninewhite rabbits, received a single intraocular application of 0.1 millilitre of the test article. The contralateral eye, remaining untreated, served as a control. The eyes of six animals remained unwashed for 24 hours; the eyes of the remaining three animals were washed out 30 seconds after instillation of the test article. Observations of corneal opacity, iritis, conjunctivitis, and other effects were recorded 24, 48, and 72 hours after treatment and at 4, 7, 14 and 21 days if irritation persisted. The test article was used as received.

The by product caused severe ocular irritation under the condition of this test. The washing procedure reduced the severity of irritation.

 

Detailed information about the irritation potential of the impurity is not available. According safety data sheets from different chemical and pharmaceutical companies, the substance might cause respiratory tract irritation, skin irritation and mechanical irritation to eyes. The toxicological properties of this substance have not been fully investigated.

 

Discussion

Application of the end product to skin or eyes resulted in slight erythema on skin and transient irritation of conjunctiva. All symptoms resolved within 72h.

Exposure of the by product to skin and eyes leads to corrosion and, thereafter, formation of scabs on skin. Thus, this by product is considered as irritating to skin and eyes.

Due to the strong irritating potential of the by product which accounts for 30% of the mixture, leasons of skin and eyes cannot be excluded. On the other hand, the mixture is present as a salt and has a pH of 5 which indicates that corrosive effects will be less pronounced as compared to the pure by product.