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EC number: 222-321-7 | CAS number: 3425-61-4
Number of animals
Statistically significant: *: p<0.05.
The significance concerned the organ weight values and not the percentages.
- not observed in this group.
Hyperplasia; squamous cells
-: not observed in this group.
Hyalin droplets in tubular epithelium
Incidence and severity of hyaline droplets in kidney of controls and high-dose group males rats with hematoxylin/eosin and alpha 2 µ globulin stainings
Alpha 2 µ globulin antibody
The objective of this study was to evaluate the potential toxic effects of the test item following daily oral administration (gavage) to male and female rats from before mating, through mating and, for females, through gestation until day 5 post-partum(p.p.), based on the OECD guideline No. 421, 27 July 1995. This study provides information on male and female reproductive performance, such as gonadal function, mating behavior, conception, development of the conceptus and parturition. The study was conducted in compliance with the principles of Good Laboratory Practice Regulations.
Three groups of ten male and ten female Sprague-Dawley rats received the test item daily by oral (gavage) from before mating, through mating and, for the females, through gestation until day 5p.p.. The test item was administered as an emulsion in the vehicle, drinking water treated by reverse osmosis, at dose-levels of 10, 30 or 100 mg/kg/day. Another group of ten males and ten females received the vehicle alone under the same experimental conditions and acted as a control group. A constant dosage-volume of 5 mL/kg/day was used. The animals were checked at least twice daily during the dosing period for mortality and morbidity and once daily for clinical signs. Body weight and food consumption were recorded at least once a week for males until sacrifice and at least once a week for females until mated. Body weight and food consumption of females were recorded on days 0, 7, 14 and 20p.c.and days 1 and 5p.p.. The animals were paired for mating after 2 weeks of treatment and the dams were allowed to litter and rear their progeny until day 5p.p.. The total litter sizes and numbers of pups of each sex were recorded after birth. The pups were observed daily for clinical signs, abnormal behaviour and external abnormalities, and weighed on days 1 and 5p.p.. The males were sacrificed after 5 weeks of treatment and the dams on day 6p.p.. Final body weights and selected organs weights (epididymides, liver, testes, thyroid with parathyroids, adrenals, brain, heart, kidneys, spleen, thymus) were recorded and a macroscopicpost-mortemexamination of the principal thoracic and abdominal organs was performed, with particular attention paid to the reproductive organs. A microscopic examination was performed on selected organs from the control and high-dose groups (epididymides, liver, testes, ovaries, kidneys, stomach with forestomach) and the low- and mid-dose groups (forestomach of both sexes and kidneys of males), and on all macroscopic lesions. The pups were sacrificed on day 5p.p.and submitted for a macroscopicpost-mortemexamination of the principal thoracic and abdominal organs.
There were no test item-related unscheduled deaths.Ptyalism was observed in males and females at 100 mg/kg/day throughout the whole study.There were no toxicologically relevant effects on male and female mean body weight, mean body weight gain or mean food consumption and on mean mating, fertility and delivery data.At pathology in males and females given 100 mg/kg/day, marked squamous cell hyperplasia with hyperkeratosis, occasionally associated with erosion/ulcer and inflammation was observed in the forestomach. These changes were considered to be adverse and correlated with gross observations (thickening and/or white or brown discoloration). In kidneys of males, increased incidence and severity of hyaline droplets was seen in proximal tubular cells. Immunohistological staining with an alpha-2µ-globulin antibody was performed in the kidneys from control and high-dose males. The positive staining confirmed that the eosinophilic hyaline droplets corresponded to alpha-2µ-globulin.As this alpha-2µ-globulin is specific to the rat, these higher incidence and severity seen in test item-treated males at 100 mg/kg/day were considered to be not relevant to human. The kidney changes probably correlated with the punctiform white discoloration seen at necropsy. There were no histological correlates to the slightly higher mean liver weight in females at 100 mg/kg/day (up to +12% from controls, p<0.05). At 30 mg/kg/day, minimal to slight squamous cell hyperplasia along with hyperkeratosis was observed associated with minimal inflammation (one male and one female) in the forestomach. In the absence of erosion/ulcer, changes at this dose-level were considered not to be adverse. No test item-related changes were seen in kidneys of males. At 10 mg/kg/day, no test item-related changes were seen either in the forestomach or in kidneys of males.
In pups, there were no test item-related deaths, clinical signs or necropsy findings and no toxicologically relevanteffects on mean pup body weights, mean pup body weight gains or on the percentage of male pups at birth.
Based on the experimental conditions of this study:
- the NOEL for parental toxicity was considered to be 30 mg/kg/day based on forestomach adverse effects at the highest dose-level both in males and in females,
- the NOAEL for parental toxicity was considered to be 100 mg/kg/day in males and in females based on the lack of relevant systemic toxicity (excluding the local effects on the forestomach)
- the NOAEL for reproductive performance (mating and fertility) was considered to be 100 mg/kg/day,
- the NOAEL for toxic effects on progeny was considered to be 100 mg/kg/day.
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