1-(allyloxy)-2-methyl-1-oxopropan-2-yl 2-chloro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl]benzoate
11 March 1996 to 22 December 1998
other: The study was performed to GLP and in line with the standardised guidelines OECD 416 and EPA OPP 83-4, with no deviations thought to impact the reliability of the presented results.
Test guidelineopen allclose all
Test guideline 1
EPA OPP 83-4 (Reproduction and Fertility Effects)
other: Japanese Ministry of Agriculture, Forestry and Fisheries 59 NohSan No. 4200, "Reproduction Study" January 28 1985
other: European Communities Commission Directive 87/302/EEC, "Two-Generation Reproduction Toxicity Test", OJ No L133/47, November 18, 1987
C20H18ClF3N2O6
migrated information: powder
- Storage condition of test material: room temperature
- Physical state: tan solid powder
other: Tif: RAI f, hybrids of RII/1 x RII/2
- Age at study initiation: (P) 6 - 7 weeks
- Weight at study initiation (mean): (P) Males: 218.5 - 219.9 g; Females: 160.8 - 163.9 g
- Housing: Individually
- Diet: pelleted, certified standard feed ad libitum
- Water: tap water ad libitum
- Acclimation period: at least 7 days
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 50 ± 20 %
- Air changes (per hr): about 16 air changer per hour
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light
oral: feed
DIET PREPARATION:
- Rate of preparation of diet : On average every 4 weeks
- Mixing appropriate amounts with: Ground feed pellets were mixed with the appropriate quantity of test material, hydrated and repressed to pellets
- Storage temperature of food: The diet was stored in un-opened sacks or in polyurethane of stainless steel bins with dust-tight lids, at room temperature.
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: up to 19 days
- Proof of pregnancy: presence of vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged: individually
- Samples: The stability of the test substance in feed mixtures was assessed after 6 weeks storage and content under actual conditions of administration, test substance content, homogeneity and stability were measured in the pellet samples.
- Sample storage: Before analysis, samples were frozen at approximately – 20 °C
- Preparation of samples: Depending on the nominal values, aliquots of the extracts were either directly diluted with the mobile phase or evaporated to dryness and the residues dissolved in mobile phase before injection.
- Conditions: The dimensions of the columns were 100 x 2 mm with a flow rate of 0.2/0.3 mL/min. The dimensions of the column used for the quantitation were 125 x 3 mm with a flow rate of 0.4-0.5/0.5 mL/min.
- Detection: UV
- Recoveries: The overall recovery percentages were 80 and 117 %
- Results: The content of the test material in the experimental diet was found to be in good agreement with the nominal concentrations.
Over two generations (until weaning of the F2 generation)
Daily (experimental diet was available ad libitum)
Details on study schedule:
- F1 parental animals not mated until 10 weeks after selected from the F1 litters.
- Selection of parents from F1 generation when pups were 4 days of age.
0, 30, 300, 1000 ppm
nominal in diet
yes, plain diet
- Dose selection rationale: doses were selected on the basis of results from a 3-month oral toxicity study in which rats were fed 20, 100, 300, 1000 or 4000 ppm test material in the diet. During the study there were 3 deaths in the male group dosed at 4000 ppm. Body weight gains were reduced by 17 % and 41 % in males and 12 % and 20 % in females dosed at 1000 and 4000 ppm, respectively. Haematology and blood chemistry parameters were affected at 1000 and 4000 ppm. Urinary levels of bilirubin and urobilirubin were increased at doses of 300 ppm and above. Liver and spleen weights were increased at 4000 ppm. The liver was confirmed microscopically as the target organ. There were areas of diffuse necrosis, necrosis of single hepatocytes, inflammatory cell infiltration, pigmentation of hepatocytes and Kupffer cells, cytoplasmic vacuolisation, extramedullary haematopoiesis, and hepatocellular hypertrophy at 1000 and 4000 ppm. The maximum tolerated dose was met or exceeded at 1000 ppm and clearly exceeded at 4000 ppm. The doses selected for this study were therefore 0, 30, 300 and 1000 ppm.
- Time schedule: twice daily checks for mortality
- Time schedule for examinations: weekly
FOOD CONSUMPTION AND COMPOUND INTAKE: Yes (measured weekly)
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
Estrous cycle stages were recorded daily during the mating period until there was positive evidence of mating.
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 8 pups/litter (4/sex/litter as nearly as possible); excess pups were killed and subjected to gross necropsy.
PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2] offspring: number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities and developmental landmarks (righting reflex and eye opening)
GROSS EXAMINATION OF DEAD PUPS: Yes
The gross necropsy examination consisted of a macroscopic examination of the body, limbs, and organs of the thoracic and abdominal cavities, with special attention directed to the organs of the reproductive system.
- All parent animals were necropsied after weaning and subjected to macroscopic examination, with histopathology of the sex and target organs
GROSS NECROPSY
- Gross necropsy consisted of examination of the following for gross pathological changes: vagina, uterus, ovaries, testes, epididymides, seminal vesicles, mammary area, prostate, pituitary gland, skin, spleen, mesenteric lymph node, axillary lymph node, popliteal lymph node, sternum with bone marrow, femur with joint, skeletal muscle, trachea, lung, heart, aorta, submandibular salivary glands, liver, pancreas, oesophagus, stomach, small intestine, large intestine, kidneys, urinary bladder, adrenals, thyroid with parathyroid, thymus, peripheral nerve, brain, spinal cord, eyes with optic nerves, orbital glands, extraorbital lacrimal glands, zymbal glands, muzzle, tongue and all gross lesions
- The following were weighed: ovaries, testes, spleen, heart, liver, kidneys, adrenals, thymus and brain
- The following were prepared for microscopic examination for all animals of the control and high dose F0 and F1 animals selected for mating: vagina, uterus, ovaries, testes, epididymides, seminal vesicles, prostate, pituitary gland, liver, mammary area and all gross lesions.
- In addition, the following organs were histopathologically examined in all groups: ovaries in non-pregnant positively mated females; testes, epididymides, seminal vesicles and prostate in males that failed to mate
- Additionally, to clarify the apparent differences in organ weights, the following organs were examined:
> F0 generation: liver (groups 2 and 3, all animals, both sexes), ovaries (groups 2 and 3, all females), spleen (groups 1 and 4, all males), heart (groups 1 and 4, all animals, both sexes), thymus (groups 1 and 4, all animals, both sexes), adrenals (groups 1 and 4, all males)
> F1 generation: liver (groups 2 and 3, all animals, both sexes), ovaries (groups 2 and 3, all females), adrenal (groups 1 and 4, all females)
- All pups in both generations (F1 pups not culled or selected for mating and F2 pups) were killed on or shortly after weaning of the last litter of that mating.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:
- Gross necropsy consisted of a macroscopic examination of the body, limbs, and organs of the thoracic and abdominal cavities, with special attention directed to the organs of the reproductive systems (pups that were found dead or moribund were also subjected to the same procedure).
Statistical analysis of continuous data was performed using the Analysis of Variance Procedure (ANOVA) followed by Dunnett's t-test in case of a significant result. Categorical data were analysed using Chi-square test followed by Fischer's Exact test in case of a significant result. Non-parametric data were analysed using the Kruskal-Wallis nonparametric analysis of variance test followed by the Dunn test.
All microscopic findings from F0 and F1 animals were subjected to statistical analysis using statistical software. Over all findings Cochran Armatage's linear trend test was performed. In all cases where an effect was found, further analyses were carried out by deleting the highest dose group and re-performing the analysis until a non-significant result was obtained.
Female mating: number of females positively mated as a percentage of the number of females used for mating
Female fertility (=fecundity): number of females pregnant as a percentage of the females mated
Male mating: number of males with positive mating as a percentage of the number of males used for mating
Male fertility: number of males inducing pregnancy as a percentage of the number of males with positive mating
Parturition: number of females with births as a percentage of the number of females with confirmed pregnancy
Gestation: number of females with liveborn as a percentage of the number of females with confirmed pregnancy
Live birth: mean number of pups born alive per litter as a percentage of the mean number of pups born per litter
Viability: mean number of pups alive on day 4 (pre-culling) per litter as a percentage of the mean number of pups born alive per litter
Lactation: mean number of pups alive on day 21 per litter as a percentage of the mean number of pups alive on day 4 (post-culling) per litter
effects observed, treatment-related
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
P Generation:
There were no treatment-related clinical signs and no treatment-related deaths among parental animals. One group 2 male (30 ppm) was found dead on day 111. Hypothermia, dyspnoea and hypoactivity had been noted for one day; haemorrhagic contents in the thoracic cavity was observed at necropsy. One group 4 female (1000 ppm) was found dead on gestation day 7. This female was pregnant, had no clinical signs and necropsy did not reveal any pathological findings. Incidental clinical signs observed occasionally among surviving animals included hair loss, wounds and/or crust, scurf, and chromodacryorrhea.
F1 Generation:
Furthermore, there were no treatment-related clinical signs among the F1 parent animals. Incidental clinical signs observed occasionally among surviving F1 animals included palpable masses, vaginal bloody discharge, hair loss and/or crust, and chromodacryorrhea.
There were no treatment-related deaths among the F1 parent animals. One 30 ppm male was found dead on day 43. At necropsy, dilatation and fibrinous adhesion of the small intestine were seen.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
During the premating period, males dosed at 300 and 1000 ppm, had 11 % and 22 % lower body weight gain compared to controls. Body weights were statistically significant from controls from day 68 and day 22, respectively. At 30 ppm for both sexes and at 300 and 1000 ppm for females, body weights and body weight gains were similar to control values.
For males at 1000 ppm, consumption was reduced by approximately 10 % from the start of the dosing period and differences from the control were statistically significant throughout the entire P generation. At 300 ppm, for males, differences from the control value attained statistical significance during weeks 2, 4 and 5 of the premating period; during the rest of the premating period, differences from the control value were minimal.
At 30 ppm, for both sexes and at 300 and 1000 ppm for females, food consumption was similar to that of the control group throughout the P generation. The only difference from the control value which attain statistical significance was for the females at 1000 ppm during the first week of the dosing period; differences from the control were minimal.
Group 300 and 1000 ppm F1 parent animals had significantly lower body weights on day 2, the first day of the F1 generation. Throughout the F1 generation, bodyweights in both groups remained lower than controls, but body weight gain was unusually similar to that of the control group.
Body weights for females were approximately 94 % of the controls (at 300 and 1000 ppm) during the premating period, weight gains were similar to controls.
In the low dose group (30 ppm), bodyweights and bodyweight gain were similar to that of the control group throughout the F1 generation. The only statistically significant changes were for the lower bodyweight and weight gain values for the males at 30 ppm on day 15 and during the second week of treatment (Days 8 -15) respectively.
Food consumption was reduced for both sexes at 300 and 1000 ppm throughout the premating period compared to the controls. This effect was more pronounced in males than in females. Food consumption for the females.
Food consumption in the females was similar in all groups throughout the gestation and lactation period.
Mean food consumption at 30 ppm for both sexes was similar to the control group throughout the F1 generation with the exception of a minimal reduction during the second week in males and an increase during weeks 6 and 10 in females.
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
Mean test material intake for the P males reduced as bodyweight increased. At the start of the study, it was 0, 3.3, 321.9 and 101.6 mg/kg bw/day in the 0, 30, 300 and 1000 ppm dose groups, respectively. By the end of the treatment period, substance intake had reduced to approximately half these initial values. Substance intake for the P females was similar to that of the males at the start of the study - 0, 3.1, 30.0 and 91.9 mg/kg bw/day in the 0, 30, 300 and 1000 ppm dose groups, respectively. By the end of the premating period, substance intake had reduced by up to 30 %. During gestation, substances intake was stable at values similar to those found at the end of the premating period. In contrast, during lactation, there was a marked increase in substance intake as a result of increased food intake by the dams and the pups feeding. At the end of the lactation period, values were 0, 6.3, 64.0 and 215.8 mg/kg bw/day in the 0, 30, 300 and 1000 ppm dose groups, respectively.
As in the P generation, mean test material intake reduced as body weight increased. In the first week of the F1 generation, values were 0, 4.1, 42.5 and 146.9 mg/kg bw/day for males and 0, 3.8, 39.7 and 143.1 mg/kg bw/day for females in 0, 30, 300 and 1000 ppm groups, respectively. By the end of the pre-mating period, substance intake had reduced by between 55 % and 65 %. For the females, substance intake remained stable during the gestation period but there was a marked increase during the lactation period as a result of increased food intake by the dams and the pups feeding. At the end of the lactation period, values were 0, 6.2, 65.4 and 209.4 mg/kg bw/day in the 0, 30, 300 and 1000 ppm groups, respectively. In comparison with the P generation, values for test material intake at the start of the F1 generation were higher because the animals were slightly younger and weighed less.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
There was no treatment-related effects on the number of animals mating, the number of females becoming pregnant or on the mean pre-coital time. Only 7 males failed to mate (one control, two 30 ppm, one 300 ppm and three 1000 ppm). Three mated females were not pregnant (one control, one 300 ppm and one 1000 ppm).
The mean duration of gestation was approximately 22 days in all groups. There was no indication of an adverse effect of treatment on any of the gestation or parturition indices. A total of 27, 28, 27 and 25 females in groups 1 to 4 were pregnant and gave birth to live young.
There were no treatment-related effects on the number of animals mating, the number of females becoming pregnant or on the mean pre-coital time.
Mating generally occurred within one estrous cycle for all mated females. Four, seven, two and three mated females were not pregnant in the control to 1000 ppm group.
There was no indication of an adverse effect of treatment on any of the gestation or parturition indices. A total of 26, 27 and 25 females in groups 1 to 4, respectively were pregnant and gave birth to live young. A total of four mated females (one group 2 female, one group 3 female and two group 4 females) did not deliver, but were pregnant by Salawski stain at necropsy.
REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
For all mated P females, mating generally occurred within one estrous cycle.
ORGAN WEIGHTS (PARENTAL ANIMALS)
At 300 amid 1000 ppm, exsanguinated body weights for males were lower (6 % and 13 %, respectively) and significantly different from controls. At 1000 ppm, most of the absolute organ weights were also lower, and the differences were significant for spleen, liver, adrenals, and thymus. At 300 ppm, absolute spleen and liver weights were significantly lower than controls. In contrast, at both dose levels, the majority of relative organ weights were similar or higher than those of the control group. At 1000 ppm heart, kidney, testes and brain were significantly higher than controls. At 300 ppm, heart and brain relative weights were significantly higher than controls and liver relative weights were slightly lower than controls. These findings were considered to be due to the treatment-related effect of body weight and not to be a specific toxic effect on target organs.
Exsanguinated bodyweights at 300 and 1000 ppm males were approximately 64 and 12 % lower respectively and significantly different from controls. At 1000 ppm most of the absolute organ weights were lower and the differences were significant for heart, liver and kidneys. At 300 ppm, some absolute organ weights were lower, but none of the differences were statistically significant.
In contrast, most of the relative organ weights were higher that the control. Spleen, heart, testes, thymus and brain were significantly higher at 1000 ppm and testes and brain at 300 ppm. These findings were considered to be a direct result of the reduced bodyweight and not specifically a toxic effect on target organs. All other changes were found to be within the historical control range and were not accompanied by any histopathological changes.
GROSS PATHOLOGY (PARENTAL ANIMALS)
No treatment-related macroscopic changes were observed at terminal necropsy.
HISTOPATHOLOGY (PARENTAL ANIMALS)
No treatment-related microscopic changes were observed following examination of the reproductive organs of the control and high dose groups or at microscopic examination of heart, adrenal, ovaries, spleen and thymus from selected groups. Treatment-related statistically significant findings were confined to the liver of 300 and 1000 ppm groups, and included: minimal/mild bile duct hyperplasia in males and females at 300 and 1000 ppm; minimal hepatocelular hypertrophy in males at 1000 ppm; and minimal/mild foci of necrosis in occasional animals (males at 300 and 1000 ppm, and females at 1000 ppm).
No treatment-related microscopic changes were observed at microscopic examination of the reproductive organs and adrenals (females) of the control and high dose groups or at microscopic examination of ovaries from selected groups. Treatment-related statistically significant findings were confined to the liver of 300 and/or 1000 ppm groups, and included: minimal/mild bile duct hyperplasia in males and females at 300 and 1000 ppm; minimal hepatocellular hypertrophy in males at 1000 ppm; and minimal/mild foci of necrosis in occasional animals (males at 300 and 1000 ppm and females at 1000 ppm).
(reprotoxic effects)
1 000 ppm (nominal)
other: There were no treatment-related effects on any of the reproductive parameters
other: Generation: P and F1 (migrated information)
(systemic effects)
30 ppm (nominal)
other: Based on body weight gain reduction and liver histopathology.
LITTER INDICES
F1 Pups:
At birth, mean litter size was comparable in all groups. At 300 ppm, the incidence of pup loss between days 1 and 4 post-partum, prior to culling, was higher than that of the control group. After culling on day 4, mean litter size and pup loss during the lactation period were similar in all groups to that of the control group. The sex ratios of the F1 pups on days 0 to 21 post-partum were similar in all groups.
All F1 pregnant females which gave birth reared their young to weaning on day 21 post partum. In all test groups, both the viability index and the lactation index, mean litter size and pup loss during the lactation period were similar to that of the control group. The sex ratios of the pups on days 0 and 21 post partum were similar in all groups.
VIABILITY (OFFSPRING)
Differences from the control value attained statistical significance for the lower percentage of pups surviving days 0 to 4 however this was attributed to a dam failing to wean her litter (not treatment related)
The percentage of pups surviving days 0 to 4 were similar to the control group.
CLINICAL SIGNS (OFFSPRING)
During lactation, there were no clinical signs for the F1 pups which were considered to be related to treatment.
During lactation, there were no clinical signs for the F2 pups which were considered to be related to treatment of the dams with the test material.
BODY WEIGHT (OFFSPRING)
At 300 and 1000 ppm, from birth to day 14, mean F1 pup weight was similar to that of the control group. However, there was a retardation in weight gain in both groups, particularly between days 14 and 21, such that mean pup bodyweights were lower than controls on day 21 by up to 9 % in the 1000 ppm group.
Mean body weight of F2 pups was similar in all groups. At 1000 ppm there was an approximate 10 % retardation in weight gain between days 7 and 21 post partum.
GROSS PATHOLOGY (OFFSPRING)
No treatment-related findings were noted at necropsy of the F1 of F2 pups.
Any other information on results incl. tables
Table 1: Mean body weights for P Males
Dose (ppm)
370.7**
* = p < 0.05
** = p < 0.01
Table 2: Mean body weights P females
Premating
Table 3: Mean body weights F1 males
Table 4: Mean body weights F1 females
Table 5: Incidence of treatment-related liver findings
P Generation
Hepatocelular hypertrophy (minimal)
Bile duct hyperplasia (minimal/mild)
Foci of necrosis (minimal/mild)
F1 Generation
Under the conditions of the study, none of the reproductive parameters - gonadal function, mating behaviour, conception, parturition, lactation and weaning - were affected by the administration of the test material to the parent animals at any dose level, in either the P or F1 generation. Based on the results of this study there was no evidence of reproductive toxicity through 1000 ppm. Based on the body weight gain reduction and liver histopathology, the no observed effect level for systemic toxicity was 30 ppm. The no observed effect level for reproductive toxicity was determined to be 1000 ppm.
The reprotoxicity of the test material was investigated in accordance with standardised guidelines OECD 416, EC OJ No L133/47, Japanese MAFF 59 No 4200 and EPA OPP 83 -4. In two successive generations (P and F1), male and female rats were continuously exposed to the test material admixed in diet at nominal concentrations of 0, 30, 300 and 1000 ppm. At 10 weeks premating dietary exposure to the test material, animals were paired 1:1 within each dose group (30 animals per sex and dose) until there was evidence of positive mating or for 19 days, whichever occurred first. Dams were allowed to litter and suckle their pups naturally. Litter were culled to 4 male and 4 female pups, where possible, on day 4 post partum. After weaning, selected F1 young (30 animals per sex and dose) were continuously exposed to the test material in the diet as in the P generation. After 10 weeks exposure, these F1 animals w4ere cohabited 1:1 within each dose group for up to 19 days. Resulting F2 litters were necropsied after weaning. Clinical signs, body weights, food consumption, mating, gestation and delivery parameters, pup survival and physical and behavioural developmental landmarks were recorded. A gross necropsy examination was performed on all pups not selected for mating. All parent animals were necropsied after weaning and subjected to macroscopic examination, with histopathology of the sex and target organs.
There were no treatment-related clinical signs or treatment-related deaths among the P animals. At 300 and 1000 ppm, for P males, food consumption was reduced and body weight gain was retarded from the start of the dosing period. As a result, body weights were significantly lower than those of the control group. Male and female mating and fertility indices, maternal gestation and parturition indices and the duration of gestation were unaffected by treatment. Mean weight gain of the pups was retarded during lactation days 14 to 21 at 300 ppm (93 % of control) and 1000 ppm (84 % of control); and body weights were reduced at weaning. For all test groups, no treatment-related effects were noted in the F1 offspring in terms of the sex ratios, clinical signs, or macroscopic findings at necropsy. For P parent animals there were no treatment-related findings at terminal necropsy, in organ weights or in the histopathological examination of the adrenals, thymus, spleen, heart or reproductive organs. Microscopic examination of the liver revealed increased incidence of males and females at 300 and 1000 ppm with bile duct hyperplasia, hepatocellular hypertrophy and necrosis.
There were no treatment-related clinical signs or treatment-related deaths among the F1 parent animals. At 300 and 1000 ppm, body weights of the selected F1 animals were significantly lower than those of the control group. During the premating period, for both sexes, body weights and food consumption in these groups were significantly lower than controls, but body weight gain was unusually similar to that of the control group. Male and female mating and fertility indices, maternal gestation and parturition indices and the duration of gestation were unaffected by treatment. At 1000 ppm, mean pup body weight gain was retarded by approximately 10 % during lactation days 7 to 21 and body weights were reduced at weaning. At 30 and 300 ppm, pup weights from birth, through lactation to weaning were no affected by treatment. For all groups, litter size, post-natal loss were not affected by treatment. For all test groups, no treatment-related effects were noted in the F2 offspring in terms of the sex ratios, the development of physical landmarks, clinical signs, or the macroscopic findings noted at necropsy. For F1 parent animals, there were no treatment-related findings at terminal necropsy, in the organ weights or in the histopathological examination of the adrenals or reproductive organs. Microscopic examination of the liver showed similar findings as in P parents.
At 300 and 1000 ppm, food consumption was reduced and body weight gain was retarded in both P and F1 males and in F1 females. Additionally, at both of these dose levels, in both generations, body weight gain of the pups was retarded during the lactation period. Increased incidence of liver pathology were observed in males and females in the P and F1 generations - minimal/mild bile duct hyperplasia in both sexes at 300 and 1000 ppm, minimal hepatocellular hypertrophy in males at 1000 ppm, and minimal/mild foci of necrosis at 300 and 1000 ppm and in few females at 1000 ppm.
None of the reproductive parameters - gonadal function, mating behaviour, conception, parturition, lactation and weaning - were affected by the administration of the test material to the parent animals at any dose level, in either the P or F1 generation. Based on the results of this study there was no evidence of reproductive toxicity through 1000 ppm. Based on the body weight gain reduction and liver histopathology, the no observed effect level for systemic toxicity was 30 ppm. The no observed effect level for reproductive toxicity was determined to be 1000 ppm.
The available data are deemed to be relevant, reliable and adequate for the purposes of risk assessment.
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