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Both sub-chronic and chronic data are available. NOAELs were generally in the range of 167-200 mg/kg/day in rats.
For repeated dose toxicity, confidence is gained by the evaluation of several generations in the two-year studies. These studies provide a profile of limited repeated dose toxicity for TNPP.
A 90-day exposure to a dose of 5000 mg/kg/day (5%) of TNPP in rat resulted in the observation of toxic symptoms and of pathological changes in the kidney, but no adverse effect was observed at lower doses. Over a longer period (2-year), ingestion of TNPP at a dose level of 10 000 ppm (corresponding to 500 mg/kg/d in rats) led to a slight retardation of growth in male rats, an increase of the liver weight in F0 female rats and a thyroid change (doubtful relationship to dosage) in dogs. One male dog exposed to 10 000 ppm also exhibited a renal chronic inflammation in pelvis. In these 2-year studies, 3300 ppm of TNPP in the diet (corresponding to 167 mg/kg/d in rats), was derived as a NOAEL, both for rat and dog. In the modified and enhanced OECD TG 421 study with rats, the NOAEL for systemic toxicity was established at 200 mg/kg/day, based on an excessive rooting behaviour in males and females and on a treatment-dependent corticomedullary junction mineralisation of the kidney in males observed at the highest dose level (1000 mg/kg/day). However, microscopic examination was only performed on 5 males and 5 females of the control and the highest dose group, thus, the NOAEL could not be used for the risk assessment.
Based on this lack of information in the study of Tylet al.and on the respective duration of the studies, the NOAEL used for risk assessment for repeated dose toxicity is 3300 ppm (corresponding in rats to 167 mg/kg), derived from the 2-year study in rat (Food and drug research laboratories) and based on the following limited effects: a slight retardation of growth in males and an elevation of the absolute liver weight in F0 females. This NOAEL is rather conservative.
Factors such as hydration, diet, or intratubular pH may alter the mineral balance within kidneys (Montgomeryet al, 1990 ; Kahnet al., 2002). Additionally, compounds with vitamin D activity could promote mineralisation. Compounds such as oestrogen or having estrogenic activity can influence mineralisation as well, however, the high-dose, F0 and F1 females did not show any evidence of increased severity of mineralisation. There are sex-related differences in the renal metabolism and handling of some xenobiotics in the rat kidney which could have also influenced this change. In particular female kidneys present some kind of down regulation to oestrogen-like compounds as they are exposed to a high level of oestrogens in physiological conditions, whereas male kidney which are not exposed to such a high level of oestrogen are more reactive to an oestrogen-like stimulation.
It could be suggested that abnormal rooting behaviour, reported in rats at 1000 mg/kg/day in the study of Tylet al. (2002) could be linked with a neurotoxic activity of the test compound. However, “rooting in bedding” typically postdosing (but also predosing) in a dose-related incidence was observed in every gavage study performed in rats in the laboratory which conducted the study and in many others too. The consensus is that it is an expression of taste aversion, likely the animal’s attempt to get rid of the bad taste in its mouth from the oral gavage dosing. The higher the dose, the more test material, the greater the incidence of rooting; in this study all rooting was observed postdosing. This behavior is therefore considered indicative of a conditioned adaptive behavior. Furthermore, abnormal behaviour was not observed in the other available studies. An unpublished study carried out by the Dutch National Institute of Public Health and Environment, on delayed neurotoxicity in chickens did not show any evidence of delayed neurotoxicity in chickens for TNPP (Van Velsenet al.,1980).
The results from the repeat dose toxicity studies of TNPP do not meet any triggers for classification.
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