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

Endpoint summary

Description of key information

Repeated dose toxicity of this mixture is derived from toxicological information about the endproduct, the main by product and one toxicological relevant impurity. A GLP-conform28d study according OECD guideline 407 was performed with the end product. The test substance was administered by oral gavage at concentrations of 0-1000 mg/kg bw  for 28 consecutive days to wistar rats. No mortalities, signs of toxicity or any abnormalities occured.  A GLP-conform28d study according OECD guideline 407 was performed with the by product. The test substance was administered by oral gavage at concentrations of 0-500 mg/kg bw  for 28 consecutive days to wistar rats. Increased salivation and decreased urine pH-value were observed at the high dose group. No mortalities or signs of toxicity occured. 

Additional information

Reasons for read across

The substance was not tested for repeated dose 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 repeated dose 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

The subacute oral toxicity of the end product (purity 94.8 %) in the rat was investigated in a GLP conform study according to OECD guideline 407 by gavage application for 28 consecutive days, followed by a 14 day recovery period. Based on the results of a 5-day range finding study, the dose levels for the 28-day toxicity study were selected to be 0, 50, 150 and 1000 mg/kg/day. One control group and three treated groups were tested, each consisting of 5 males and 5 females. The following parameters were evaluated: clinical signs daily; functional observation tests; body weight and food consumption weekly; ophthalmoscopy at week 4; clinical pathology and macroscopy at termination; organ weights and histopathology on a selection of tissues.

No mortality occurred during the study period. There were no clinical signs of toxicity or behavioural changes during the study period that were considered to be related to treatment. Body weight gain and food consumption were unaffected by the substance. Haematology and clinical biochemistry did not reveal any abnormalities. Gross pathology and histopathology were without findings.

 

In a GLP-conform 28d study according OECD guideline 407 repeated dose toxicity of the by product was tested in rats. The substance was administered to Wistar rats (5 per sex and dose) for 28 consecutive days by oral gavage at concentrations of 0, 4, 20, 100 and 500 mg/kg bw, following 14 days post observation period. All groups were tested and checked for body weight and food consumption (twice weekly), for mortality / viability and clinical signs (daily) and for behaviour. Haematology, clinical biochemistry and urinanlysis were performed at the end of the study. Examination of organ weight as well as pathology and histopathology of selected tissues followed after sacrifice.

Increased salivation was observed at male animals of the 500 mg/kg bw group between days 26 and 28. In the same group, a decreased pH-value was detected at animals of both sexes. Moreover, a strong increased kidney in one female rat and dark discoloured livers in two male animals were observed at the 500 mg/kg group. All other tests and examinations were without any findings in all treatment groups. No unscheduled deaths occurred.

 

Discussion

Oral gavage application of the end product for 28 consecutive days to rats did not induce any mortalities or signs of toxicity. All other examinations were also without findings.

 

Oral administration of the by product to Wistar rats for 28 consecutive days caused increased salivation at animals of the 500 mg group. This effect is considered as sign of intolerance to the substance. Decreased urine pH-values were detected in the same group which is attributed to the low pH of the test item and not an adverse effect. With regard to the results of the acute oral toxicity study where single administration of 1250 mg to rats caused mortality, a rampant dose-response curve is expected for this test substance.

 

Detailed information about repeated dose toxicity of the impurity is not available. According safety data sheets from different chemical and pharmacological companies, the substance might cause digestive tract disturbances. The toxicological properties of this substance have not been fully investigated.

 

Neither the end product nor the by product caused mortalities, adverse effects or signs of toxicity in repeated dose toxicity studies. Therefore, toxicity after subacute oral exposure is not expected.