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BASF (1997( reported a screening test using male and female Wistar rats (administration gy gavage for 3 weeks). Doses used were 500 and 1500 mg/kg. In both sexes of the high dose group, food consumption and body weight were affected and the animals exhibited clinical signs of toxicity (e.g. diarrhea). In the mid dose group still a slight impairment of body weight was seen in males. Changes in clinical pathology testing were seen in the high dose animals only. Most of these findings are indicative of functional impairment of kidney. The occurrence of renal tubular and transitional epithelial cells as well as granular casts in the urine specimens are clear signs of tubular damage or injury. Furthermore, the slightly increased urea concentrations in the sera of the high dose animals and hematuria in the high dose males are also indicative of kidney damage. The lowered urine pH is probably a consequence of the pH effect of increased concentrations of the acidic test compound in the urine specimens and the crystals of "unknown origin" seen in isolated animals of both sexes in the highest dose group presumably consist of crystalline CaNaNTA. Kidney weights were increased in high dose males (relative weights) and females (absolute and relative weights) and in mid dose females (relative weights). This increase in weight correlates to a vacuolization of the proximal tubule, degeneration of the pars recta, and to an increased severity of basophilic (regenerative) tubules.

BASF (2003) studied the mode of action in the kidney of male Wistar rats (administration in the diet for 4 weeks). The unchanged test substance (Trilon A; CAS No. 5064-31 3) was given in a daily dose of 150 ppm. Induction of oxidative stress in kidneys was determined by measuring lipid peroxidation and 8-HO-dG. Lipid peroxidation was not affected. There was, however, a statistically significant decrease in 8-HO-dG levels in kidney DNA from treated rats (35% lower than control). Although absolute levels of 8-HO-dG were rather high in this study, the effect is nevertheless considered to be biologically relevant because the data are rather consistent and were confirmed by the analysis of a second set of digested DNA-samples.

A 90-day feeding study with Trilon A (CAS No. 5064-31-3) resulted in a NOAEL of < 150 mg/kg for male and female rats and a LOAEL < 560 mg/kg for male and female rats. The animals were offered concentrations of about 150, 560, 750 and 1500 mg/kg/d. In the high dose level, the following pathological effects were found: Abnormally large kidney with very rough uneven surface in 4/5 male sand 2/5 females, decrease in body weight gain, increase in liver and kidney weight, red blood cell count was significantly below normal (but only in males), hemoglobin was distinctly lower than normal (Nixon, 1971).

The dermal NOAEL was found to be 50 mg/kg bw, applying 2 ml/kg of a 2.5% aqueous solution of Na3NTA for 20 or 65 treatments to rabbits in concentrations of 50 and 200 mg/kg/d. No adverse effects were observed; hematologic values were within the normal limits. No treatment-associated changes were registered in any of the 15 internal organs examined (Nixon, 1971).

A NOAEL of 9 mg/kg was found in two studies done with male Wistar rats (BASF, 1998/1998). Na3NTA and Fe-NTA were given intraperitoneally resp. orally (gavage) for 4 weeks. Doses for the intraperitoneal route were 9 and 926 mg/kg (Na3NTA), 25 mg/bw (Fe-NTA); orally doses were 50, 200 and 1000 mg/kg. The comprehensive examinations demonstrate that Na3NTA and FeNTA differ in extent, pattern and mechanism of inducing kidney toxicity. The results indicate that the Na3NTA-related effects are not mediated by an internal formation of FeNTA.

Justification for classification or non-classification

Since the classification proposal for NTA is R40 (GHS: Carc. Cat. 2), classification for repeated dose toxicity is not necessary.