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EC number: 277-749-7 | CAS number: 74181-84-3
In this study, the possible effects of EDTA-CuNa2 on reproductive performance and development, and its sub-chronic toxicity were examined in groups of 12 male and 12 female Wistar rats. EDTA-CuNa2was administered daily by gavage during a premating period of 10 weeks and during mating, gestation and lactation until postnatal day 4. The dose levels were 0 (tap water only), 150, 500 and 1500 mg/kg bw/day. Due to mortality, the high-dose level was reduced to 1050 mg/kg bw/day from day 9 of the study.
The content and homogeneity of the test substance in the carrier were confirmed by analysis.
All male and female rats of the high-dose group were found dead or killed in moribund condition before the start of the mating period. Three males of the mid-dose group were killed in moribund condition during or at the end of the mating period.
Clinical signs observed in rats of the high-dose group and, to a lesser extent, in the mid-dose group included thin appearance, hunched posture, piloerection, blepharospasm, swollen abdomen, soft faeces and green watery discharge around perineum.
Neurobehavioural observations and motor activity assessment did not indicate specific neurotoxic effects of the test substance. Ophthalmoscopic examination did not reveal any treatment-related changes.
Body weights were decreased in males of the high-dose group, and, from the end of the premating period, in males of the mid-dose group. During lactation, female body weights were increased in the remaining treatment groups. Feed intake was reduced in males of the high-dose group.
Haematology and clinical chemistry findings are indicated in section 7.5.1.
The surviving rats (control, low- and mid-dose group) were killed on day 90 (males) or on day 4 of lactation (females).
- Terminal body weights were decreased in males and increased in females of the mid-dose group.
- The absolute and the relative weights of the heart were decreased in the mid-dose group in both sexes.
- The relative weight of the kidneys was increased in males of the mid-dose group. In females of this group, the absolute kidney weight was increased.
- The absolute and the relative weights of the spleen were increased in the mid-dose females.
- The absolute and the relative weights of the ovaries were decreased in females of the mid-dose group.
- The absolute weight of the testis was decreased in mid-dose males.
The main gross finding in animals of the mid-dose group (and in intercurrently killed animals of the high-dose group) were enlarged intestines with green/watery contents, a pale and/or green appearance of the liver and kidneys, small epididymides and seminal vesicles, enlarged dark spleen, small thymus and a variety of changes in the stomach.
Microscopic examination revealed histopathological changes in the kidneys, the liver and the spleen.
- The histopathological changes in the kidneys were characterised by tubular necrosis and degeneration, tubular epithelial cell karyomegaly and accumulation of brown pigment. These changes were mainly present in the mid-dose animals. However, tubular epithelial brown pigment was also noted in the kidneys of 6/10 low-dose males.
- The changes in the liver were accumulation of periportal macrophages, especially in the mid-dose males, hepatocellular karyomegaly, brown pigment accumulation, bile duct hyperplasia and (multi)focal infiltration of mononuclear inflammatory cells. These changes were mainly present in the mid-dose animals. However, mononuclear cell infiltrate was also noted in the liver of 6/10 low-dose males and 3/10 low-dose females.
- The changes in the spleen were accumulation of brown pigment and accumulation of macrophages in the white pulp in animals of the mid-dose group.
The decedent high-dose animals were subjected to microscopical examination only on the basis of macroscopic observations. The microscopic observations in this group confirmed the above histopathological changes.
There were no effects of the test substance on male fertility parameters (epididymal sperm motility, sperm count and sperm morphology, and testicular sperm count and daily sperm production). No treatment-related effects were seen in any of the reproductive or developmental indices.
Based on the effects in liver and kidneys in the low-dose group, the no-observed-effect level (NOEL) for parental toxicity was lower than 150 mg/kg bw/day. Because fertility parameters,reproductive performance and development were not affected by the test substance, the NOEL for reproduction and developmental effects was placed at ≥ 500 mg/kg bw/day.
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