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Description of key information

In a subchronic oral toxicity study in rats, the local NOAEL was 25 mg/kg bw/day (based on caecitis accompanied by colitis or proctitis in the large intestine in males and females) and the systemic NOAEL was 250 mg/kg bw/day (an increase in hyaline droplet accumulation in the proximal tubular epithelium of the kidney in females) for ZPS.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

In a subchronic (13 weeks) GLP compliant study performed according to a protocol similar to OECD guideline 408, Crl:CD (SD)BR rats (n=10/sex/dose) were exposed via dietary administration to dose levels of 0, 25, 250 and 2500 mg/kg bw/day of the substance (Hazleton UK, 1990). Male and female animals treated at 2500 mg/kg bw/day gained less weight than the control animals: male animals consumed slightly more food than the control animals. At week 1 the concentration of the test article (as supplied) in the high dose diet was about 7 to 8%, the concentration increased so that by week 13 it was about 11 to 14%. At such high test article concentrations it is possible that the nutritional quality of the diet is impaired resulting in an effect on the body weight of the animals. The effect on body weight at 2500 mg/kg bw/day may therefore be a result of nutritional imbalance rather than toxicity due to ZPS administration. In males treated at 2500 mg/kg bw/day there was an increase in mean cell haemoglobin concentration and slight decreases in red blood cell count and haemoglobin concentration. This may be reflection of poor nutrition in these animals. Plasma urea levels were elevated in male animals treated at 2500 mg/kg bw/day. In the absence of any histopathological findings in the kidneys other than hyaline droplets, this change may also reflect the poor nutrition of these animals. There were changes in prothrombin and activated partial thromboplastin times in animals, males in particular. The significance of these changes is uncertain and it is possible that the green discoloration of the plasma may be affecting the analyses. Meaningful interpretation of some of the clinical chemistry parameters was prevented by test article in the plasma interfering with some of the analyses at a dose level of 2500 mg/kg bw/day. It is possible that the analyses may have been affected at 25 and 250 mg/kg bw/day, however, since mean values were similar to control values it is considered unlikely that there was interference at these dose levels.

Histopathologically, the main effect of treatment was caecitis accompanied by colitis or proctitis in the large intestine of animals treated at 250 and 2500 mg/kg bw/day and squamous hyperplasia of the limiting ridge of the forestomach in animals treated at 2500 mg/kg bw/day (effects in the forestomach are not relevant for humans). The significance of these changes in animals fed at 2500 mg/kg bw/day of the substance in the diet is uncertain. The changes may represent a low-grade mucosal irritation or be secondary to nutritional imbalance, accumulation of test substance in diet or to a disturbance of the normal luminal flora. In females treated at 2500 mg/kg bw/day there was an increase in hyaline droplet accumulation in the kidney proximal tubular epithelium. This probably reflects changes associated with excretion of the test article.

In conclusion, 25 mg/kg bw/day is considered the local NOAEL (based on caecitis accompanied by colitis or proctitis in the large intestine of animals treated at 250 mg/kg bw/day, the significance of these changes in animals fed at 2500 mg/kg bw/day of the substance in the diet is uncertain) and 250 mg/kg bw/day is considered the systemic NOAEL (based on an increase in hyaline droplet accumulation in the proximal tubular epithelium of the kidney in females).

Adult female Sprague-Dawley rats were dosed daily by gavage for 14 days (range finding study) at levels of 200, 500, 750, 1500, 2500 mg/kg bw/day (n=5 females/dose) and then killed by CO2 asphyxiation and necropsied (The Procter & Gamble Company, 1986). No overt toxicity was observed and neither body weight nor food consumption were significantly reduced over control values. Blue discolouration of viscera was observed with doses as low as 200 mg/kg bw/day and the number of organs discoloured as well as the intensity of blue colour increased with increasing dose levels. Results of this dose range finding study suggest that levels as high as 2500 mg/kg bw/day could be used in a teratologic evaluation of this substance and that blue discolouration of maternal tissue is expected with dose levels as low as 200 mg/kg bw/day.

Justification for classification or non-classification

Based on the results of the oral repeated dose toxicity study ZPS does not need to be classified according to Directive 67/548/EEC and according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.