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

Endpoint summary

Description of key information

Acute oral or dermal effects of this mixture are 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 423 and 402 were performed with the end product. No mortalities occured, clinical signs resolved within post observation period. Single oral application (OECD guideline 401) of the by product to rats at 1250, 1600 and 2000 mg/kg bw resulted in mortalities and severe clinical signs. Single dermal application of the by product onto rabbit skin did not induce any adverse effects.  The mixture is present as a salt and has a pH of 5 which indicates that corrosive effects after oral exposure will be less pronounced in comparison to the pure by product.

Additional information

Reasons for read across

The substance was not tested for acute oral or dermal toxicity. 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

To evaluate oral and dermal acute toxicity of the main product, acute oral and dermal toxicity studies were performed.

A GLP conform study was performed to assess the acute oral toxicity in the rat according to OECD guideline 423.

The test substance was administered by oral gavage to three Wistar rats of each sex at 2000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (day 15).

No mortality occurred. Hunched posture, uncoordinated movements and/or lethargy were shown by the females on days 1 and/or 2, while piloerection was shown by one male on day 1. Additionally, one male and one female animal showed green faeces between days 3 and 7. No abnormalities were found at macroscopic post mortem examination of the animals. The oral LD50 value of the test substance in Wistar rats was established to exceed 2000 mg/kg body weight.

A GLP conform study was performed to assess the acute dermal toxicity in the rat according to OECD guideline 402.

The test substance was administered to five Wistar rats of each sex by dermal application at 2000 mg/kg body weight for 24 hours. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (day 15).

No mortality occurred. Two males showed ptosis, hunched posture and/or piloerection on days 1 and/or 2. Other clinical signs noted during treatment among all animals consisted of chromodacryorrhoea, scales and/or scabs. The animals had recovered from the symptoms between days 7 and 15. No abnormalities were found at macroscopic post mortem examination of the animals. The dermal LD50 value of the test substance in Wistar rats was established to exceed 2000 mg/kg body weight.

 

Acute oral toxicity of the by product was evaluated in a GLP conform study according OECD guideline 401. The test substance was administered by oral gavage to five Wistar rats of each sex at 1250, 1600 and 2000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (day 28).

Two male animals died at 2000 mg/kg bw. Two, three and four female animals died at 1250, 1600 and 2000 mg/kg bw, respectively. Mortalities occurred up to day 13. Respiration, locomotion and reflexes were impaired. Ventral position, blepharoplegia, lacrimation, miosis and diarrhoea were observed. Moreover, animals showed tactile hyperaesthesia, bloody crusted snouts and eyelids and swelled abdomen. Macroscopic examination of dead animals revealed discolorations at liver, pancreas, gastrointestinal tract and connective tissue as well as gastrointestinal bleeding and ablation of gastrointestinal mucosa. Moreover, clear red-yellowish secrete was found in abdomen. Examination of sacrificed animals revealed pathological findings at spleen, lung, adrenal glands and gastrointestinal tract. Partially, the stomach was adhered to surrounding tissue. Body weight gain was decreased up to the end of the post observation period. Based upon the findings of this study, LD50 is considered to be 1410 mg/kg bw.

In another, non-GLP study, six (3 male, 3 female)white rabbits received a single dermal application of the test article at a dose level of 2000 mg/kg bw. The skin of three animals (2 male, 1female) was abraded; the remaining animal’s skin remained intact. The test sites were occluded for 24 hours, at which time the occlusive wrap and any remaining test article were removed. Animals were observed tor pharmacologic activity and drug toxicity 1, 3, 6, and 24 hours after treatment, and daily thereafter tor a total o1 14 days. Non-survivors and anima1s surviving the 14 day observation period were subjected to gross necropsy, with all findings noted.

No unscheduled mortalities occurred. Any clinical symptoms or abnormalities were not observed.

 

Information about acute toxicity of the impurity is not available.

 

Discussion

Oral application of the end product did not induce any mortalities or signs of toxicity. One male and one female animal showed green faeces between days 3 and 7. No explanation can be given for this finding. It might be related to staining properties of the test substance.

After dermal application, yellow staining of the treated skin was observed. The test item is a dye and coloration of skin is therefore not considered as an adverse effect.

 

Oral administration of the by product to Wistar rats leads to mortalities and severe clinical signs. Thus, this substance is considered to be as toxic if swallowed. However, dermal application did not induce any adverse effects.

 

Due to the acute oral toxicity of the by product which accounts for 30% of the test item, toxic effects after oral exposure to the mixture cannot be excluded. On the other hand, the mixture is present as a salt and has a pH of 5 which indicates that the corrosive effects will be less pronounced in comparison to the by product.