2,6-diamino-1H-pyrimidin-4-one

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

The following was taken from the Scientific Opinion issued by EFSA ( EFSA Journal 2009; 7(12):1397):

2,4 -diamino-6-hydroxypyrimidine was tested in a 90-day oral toxicity study in Wistar rats at dose levels of 200, 800 and 1600 mg/kg bw/day. There were no pre-terminal deaths in any of the study groups. Mild to severe and dose related salivation was observed in all the substance treated groups. There was no treatment related changes in body weight gain and mean food intake. Ophthalmological examination of all animals did not reveal any eye abnormalities at the end of treatment and recovery periods. Haematological examination revealed that mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH) were significantly increased in the two high-dose groups and in the high-dose recovery group of both sexes. Several other differences in haematological parameters were recorded between the treated and control groups but the findings were inconsistent and/or within the physiological range. Clinical chemistry examination revealed significant increase in plasma cholesterol in the high dose groups of both sexes. Several differences in other clinical chemistry parameters were recorded between the treatment and the control groups but the findings were inconsistent, within physiological range or did not show any dose dependency.

Macroscopic examination revealed no lesions of pathological significance. The absolute weights of

liver, kidney and spleen were significantly increased in the mid- and high-dose males and the highdose

females. The significantly increased relative weights of kidney, liver and spleen were recorded

only in the high-dose males. The lack of any histopathological changes in the kidneys, liver and spleen

indicate that the increases in the absolute weights recorded in the mid- and the high-dose male groups

and in the high-dose female group as well as the increases in the relative weights of these organs in the

high-dose male group could be due to an adaptive response to the test substance.

The decreases in absolute weights of the ovaries in the low- and mid-dose groups, in the absolute heart

weight in the low-dose group or in the relative weights of the ovaries and the heart in all treated

groups, and of the thymus in the high-dose group were recorded in females only, were not

accompanied by histopathological changes, and the dose response was not apparent and therefore

could be considered incidental findings.

No treatment related changes were observed in home cage and handling observations of

neurobehavioral observations. In open field observation significantly reduced rearing count was

observed in male rats from the high-dose group (week 5) and in the high-dose recovery group (week 1

and 3) and in females from the low dose group (week 1), from the mid-dose group (week1 and 3) and

the high-dose group (week 10, 14, 16) as compared to the controls.

In the Functional Observation Battery, significant reduction was observed in motor activity of the

high-dose groups and hind limb foot splay of the mid-dose male group.

Changes observed in the approach response, touch response, click response and tail-pinch response of

high dose treated rats could be considered as treatment related.

The test substance seems to have neurotoxic potential based on the clinical observation and results of

the neurobehavioral tests where changes were observed in the approach response, touch response,

click response, tail pinch response, as well as more severe salivation and a reduced motor activity in

the high-dose group. Although, the salivation is transient and could be due to administration by

gavage it cannot be excluded that the dose related salivation observed in all treatment groups is related

to neurotoxicity, giving a LOAEL value of 200 mg/kg/bw for this 90-day study. By application of an

uncertainty factor of 3, a NOAEL of 70 mg/kg bw can be derived."

Salivation is often related to bad taste or local irritation. As all tested dose levels are high, salivation is not likely to be indicative of neurobehavioural effects.

Justification for classification or non-classification

In the subchronic oral toxicity study, no serious effects were observed at 200 mg/kg bw. This dose level is higher than the cut-off value of 100 mg/kg bw for STOT-RE (UN GHS). Therefore, the substance does not need to be classified for oral repeated dose toxicity according to GHS critiera.