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EC number: 218-827-2
CAS number: 2244-16-8
Summary table of the 2 generation study
Dose (mg/kg bw/day)
no toxicologically relevant effect
Body weight (gain)B
dr = dose related; i = increased; d = decreased; is = increased significantly; ds = decreased significantly, a= absolute, r=relative
A Animals were found dead or killed in extremis due to bad health or delivery difficulties. The deaths are not considered to be treatment-related.
B Females of the 30 mg/kg bw/day group showed small but significant decreases in body weight gain during lactation on days
4, 7 and 14, and body weight loss on day 4 during lactation.
C Females of the 30 mg/kg bw/day group showed a significant decrease in food consumption from day 1-4 during lactation.
D Males of all treated groups showed histopathological changes in the kidney consistent with accumulation ofα2u-globulin.
E Females of the 90 mg/kg bw/day group had in increased body weight and body weight gain. The study authors consider this finding not toxicologically relevant. The present reviewers endorse this view
2-Generation reproduction study of d-carvone(2244-16-8) was performed on male and female Wistar Crl : (WI) BR rat according to GLP and to OECD Guideline 416 (OECD, 2001). The test material soluble in corn oil in dose concentration 0, 3, 10 or 30 mg/kg/day and administered by oral gavage for 10 weeks prior to mating until termination.Groups of 25 male and 25 female per dose group were used in F0 generation.For the F1 generation the dose levels were revised to 0, 10, 30 and 90 mg/kg/day. Females were mated individually and remained with the litters during weaning. Pups were not treated during the weaning period. On day 4 after birth all litters of more than 8 pups were culled to approximately 4 males and 4 females. After weaning of the F1 generation, animals were selected and again treated for 10 weeks prior to mating and up to termination. F0 males were killed as soon as possible after successful mating while F1 males were only killed after successful delivery of the dams. Females from both generations were killed at day 21 post partum. All animals were checked at least once daily for clinical signs and condition. Body weight and food consumption measurements were recorded weekly. All parental animals were subject to a necropsy and some tissues weighed (adrenals, brain, epididymides, kidneys, liver, ovaries, pituitary, prostate, seminal vesicles, spleen, testes, thyroid, uterus with oviducts and cervix) also a range of tissues (adrenals, brain, coagulating glands, epididymides, identification marks, kidneys, liver, ovaries, pituitary, prostate, seminal vesicles, spleen, testes, thyroid, uterus with oviducts and cervix, vagina) preserved for histological examination. All pups not selected for mating were taken for necropsy at day 21 post partum or shortly thereafter; organ weights were recorded for brain, spleen and thymus.
For males surviving to scheduled necropsy, sperm was assessed for motility and morphology plus one testis and epididymis was frozen for enumeration of homogenisation-resistant spermatids and cauda epididymal sperm reserves. For females, the ovaries and uterus were examined prior to fixation and the number of corpora lutea and implantation sites recorded. Each litter was examined for number of live and dead pups as soon as possible after birth. The individual weights of all live pups were recorded at day 1, 4, 7, 14 and 21. The sex of all pups was recorded, as was the number with any physical or behavioural abnormality. For the F1 weanlings selected for mating the day of vaginal opening or balanopreputial separation was recorded. Reproductive parameters recorded were percentage mating, fertility index, conception rate, gestation index, duration of gestation, percentage live offspring by sex, percentage of post-natal loss, percentage of breeding loss, percentage live at weaning by sex, viability index, weaning index.
There were no differences between treated and control animals in any of the indices of reproductive performance or in the results of the sperm morphology and motility measurements. Males of the F0 generation given 30 mg/kg bw/day had increased relative kidney weights. Histopathology of the male kidneys showed changes typical of 2u -globulin nephropathy at all doses. No other histopathological changes were reported and no similar changes were observed in females. Males of the F1 generation given 30 and 90 mg/kg bw/day had increased mean relative liver and kidney weights. Histopathology of the male kidneys showed changes typical of 2u -globulin nephropathy at all doses. No differences were seen in females and no other histopathological changes were reported.Hence The NOAEL for systemic toxicity is 30 mg/kg bw/day. No effects on reproductive parameters were observed. Based on this the NOAEL for reproductive effects for treatment of two generations of rats is 90 mg/kg bw/day.When male and femaleWistar Crl : (WI) BR ratswere treated with d-carvone(2244-16-8)orally.
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