| filename |
-
43935801.DER2.pdf
-
43935801
-
Ziram Reproduction Toxicity
-
137-30-4
-
034805
-
Nemec, M. (1996) A Dietary Two-Generation Reproduction and Developmental Neurotoxicity Study of Ziram in Rats: Final Report: Lab Project Number: WIL-223003. Unpublished study prepared by WIL Research Labs, Inc. 2607 p.
-
1996.0
-
1) reproduction study
Ziram (97.8% a.i.) was administered to male and female Sprague-Dawley CD rats in the diet at concentrations of 0, 72, 207, or 540 ppm for two generations (MRID 43935801). Premating doses for the F0 males were 5.3, 14.8, and 37.5 mg/kg, respectively and for the F0 females were 6.1, 16.8, and 42.8 mg/kg, respectively. Premating doses for the F1 males were 5.6, 16.7, and 42.7 mg/kg, respectively, and for the F1 females were 6.3, 18.4, and 47.5 mg/kg, respectively. Each generation contained 30 animals/sex/dose which were given test or control diet for at least 10 weeks then mated within the same dose group. F1 animals were weaned on the same diet as their parents. Sibling matings were avoided and at least 23 litters were produced in each generation. All animals were exposed to test material either in the diet or during lactation until sacrifice. The time course for the study was as follows: weeks 1-10, F0 premating; weeks 11-18, F0 breeding, gestation, and lactation; weeks 19-30, F1 premating; week 39, end of study.
All F0 and F1 parental animals survived to scheduled necropsy. Generalized, clinical signs in the adult animals, such as hair loss and sores, were observed in the control and treated animals equally and there was no correlation with dose. No treatment-related effects were seen in the 72 or 207 ppm groups of either generation as compared with controls. High-dose F0 males initially had lower body weights (90-93%) than controls at weeks 1, 2 (p <= 0.01), and 3 (p <= 0.05) due to a significantly (p <= 0.01) lower body weight gain (71%) during week 0-1. Throughout the remainder of the study, there were no significant differences in absolute body weights of the treated F0 male groups as compared to controls. Food consumption by the high-dose F0 males was significantly (p <= 0.01) less than controls for the first 4 weeks of the study and at weeks 8-9, 9-10 (p <= 0.05), and 10-11. Body weights of the high-dose F0 females were significantly (p <= 0.01) less than the controls for the entire premating period (92-94%). However, body weight gains were significantly less than controls only during week 0-1 (44%; p <= 0.01), week 1-2 (76%; p <= 0.05), and week 6-7 (67%; p <= 0.01). High-dose F0 females ate significantly (p <= 0.01) less than the controls throughout the entire premating period. High-dose F1 males had significantly (p <= 0.01) lower body weights (97-90%) as compared to controls throughout the entire premating period and continuing until study termination. Body weight gains in the high-dose males were significantly less than the controls during study weeks 18-19, 20-21 (83%; p <= 0.01), and 21-22 (90%; p <= 0.05) of the premating period. Food consumption was significantly less than the controls for the high-dose F1 males (p <= 0.01) throughout the entire premating period. Absolute body weights of the high-dose F1 females were significantly lower than the controls for the entire premating period (89-92%; study weeks 19-23, p <= 0.05; weeks 24-30, p <= 0.01); significantly lower body weight gains (67-87%) occurred only during study weeks 18-19 (p <= 0.05), 23-24, and 24-25 (p <= 0.01). Food consumption by the high-dose F1 females was also significantly less than the controls throughout premating (p <= 0.01; weeks 21-22 and 28-29, p <= 0.05). There were no treatment-related gross- or histological abnormalities observed in either generation. Differences in absolute and relative organ weights of the high-dose male and female F0 and F1 groups as compared to controls are consistent with reduced body weights of these animals. Therefore, the systemic toxicity LOAEL is 540 ppm (37.5 mg/kg/day) based on reduced body weights, body weight gains, and decreased food consumption by F0 and F1 males and females. The systemic toxicity NOAEL is 207 ppm (14.8 mg/kg/day).
High-dose F0 animals had significantly (p <= 0.01) lower body weights as compared to controls throughout gestation and until day 14 of lactation; body weight gains were significantly (p <= 0.05) less than controls during the day 10-14 interval of gestation. Some recovery was apparent in the high-dose F0 females with body weight gains significantly (p <= 0.01) greater than the controls during lactation days 14-21; this resulted in overall body weight gains during lactation significantly greater than the controls. On gestation day 20 and lactation day 21 body weights of the high-dose F0 animals were 90% and 98% of the control level. High-dose F0 females also had significantly (p <= 0.01) lower food consumption as compared to controls throughout gestation and during days 4-7 (p <= 0.05) and 7-14 of lactation. The high-dose F1 females had significantly lower body weights throughout gestation (days 0 and 7, p <= 0.05; day 10, 14, and 20, p <= 0.01) and lactation (p <= 0.01) as compared to controls. Body weight gains were significantly lower in the high-dose (p <= 0.01) group as compared to controls during days 14-20 of gestation. No significant differences occurred for body weight gains during lactation for any treated group as compared to controls. On gestation day 20 and lactation day 21 body weights of the high-dose F1 animals were 89% and 93% of the control level. Food consumption was significantly (p <= 0.05 or p <= 0.01) lower than controls by the high-dose group throughout gestation and lactation.
No dose- or treatment-related effects were noted on the reproductive performance of adults from either generation. F1 pups from high-dose group dams had consistently lower body weights than controls beginning at day 4 precull with significance (92%; p <= 0.01) reached on day 14. High-dose F2 pups also had lower body weights than the controls throughout lactation with significance reached on days 1, 4 precull (92-93%; p <= 0.05), 14, and 21 (88-91%; p <= 0.01). Therefore, the LOAEL for offspring toxicity is 540 ppm (42.8 mg/kg/day) based on reduced pup body weights at birth in F2 pups and during lactation in both F1 and F2 pups. The corresponding NOAEL for offspring toxicity is 207 ppm (16.8 mg/kg/day).
This study is classified as Acceptable/Guideline and satisfies the guideline requirements for a multigeneration reproduction feeding study (83-4) in rats.
2) developmental neurotoxicity
Ziram (97.8% a.i.) was evaluated for developmental neurotoxicity during the conduct of a two-generation reproduction study. Test article was administered to male and female Sprague-Dawley CD rats in the diet at concentrations of 0, 72, 207, or 540 ppm for two generations (MRID 43935801). These concentrations resulted in F1 maternal doses of 5, 13, and 32 mg/kg/day, respectively, during gestation and 11, 30, and 79 mg/kg/day, respectively, during lactation. The developmental neuro-toxicity of ziram was evaluated in the F2 offspring. Behavioral alterations, motor activity measures, auditory startle response, learning and memory, and the age of sexual maturation (vaginal perforation and balanopreputial separation) were examined. Brain weights and dimensions were recorded, and gross and histopathological evaluation of the nervous system tissue was conducted.
No treatment-related maternal or offspring toxicity was observed in the 72 or 207 ppm groups as compared with controls. All F1 dams survived until scheduled sacrifice and there were no treatment-related clinical signs of toxicity or neurobehavioral alterations. The high-dose F1 females had significantly lower body weights throughout gestation (p <= 0.05 or 0.01) and lactation (p <= 0.01) as compared to controls. Body weight gains were significantly lower in the high-dose (p <= 0.01) group as compared to controls during days 14-20 of gestation. No significant differences occurred for body weight gains during lactation for any treated group as compared to controls. On gestation day 20 and lactation day 21 body weights of the high-dose F1 animals were 89% and 93%, respectively of the control level. Food consumption was significantly (p <= 0.05 or p <= 0.01) lower than controls in the high-dose group throughout gestation and lactation. At necropsy, there were no treatment-related gross- or histopathological abnormalities observed in the dams, and differences in absolute and relative organ weights of the high-dose group as compared to controls were consistent with reduced body weights of these animals. High-dose F2 pups also had lower body weights than the controls throughout lactation, with significance reached on postnatal days 1, 4 precull (92-93%; p <= 0.05), 14, and 21 (88-91%; p <= 0.01). Mean body weights of the high-dose F2 males and females were also statistically signifi-cantly (p <= 0.05 or 0.01) less than the controls throughout the post-weaning period. However, final (postnatal day 70) body weights of F2 males and females were 93 and 96%, respectively, of the control values. Overall body weight gain of the high-dose males was 94% of the controls while overall weight gain of the high-dose females was 99% of the control value. The age of sexual maturation for F2 pups was not affected by treatment.
No clinical signs of neurotoxicity were observed in the F2 offspring during daily cageside observations- or at detailed physical examinations. Motor activity (total and/or ambulatory counts) was increased at all treatment levels, often 2 to 3-fold greater than control and in a dose-related manner, in pups of both sexes. At the low dose, these increases are apparent beginning at postnatal day 17 and continuing through postnatal day 21, while at the mid and high doses, they initiate at postnatal day 13 and continue through both days 17 and 21. Motor activity counts for postnatal day 60 were similar for control and treated rats of both sexes. Mean peak startle response was decreased (approximately 30% from control) in an apparently dose and treatment-related manner in high-dose pups of both sexes at postnatal day 22; this finding was not observed on postnatal day 60. Mean latency to peak response, response duration, and average response values appeared to be unaffected in treated animals as compared with controls on postnatal days 22 and 60. Learning and memory evaluations (in a water T-maze) at postnatal days 11 and 70 were similar for control and treated offspring. Brain weights (whole and regional) and dimensions (length and width) were not affected by treatment at postnatal days 11 or 70. Qualitative histopathological evaluation of the nervous system tissues did not reveal any treatment-related findings.
The maternal LOAEL is 540 ppm (32 mg/kg/day) based on reduced body weights and/or body weight gains, and decreased food consumption during gestation and lactation. The maternal NOAEL is 207 ppm (13 mg/kg/day).
The offspring LOAEL is 72 ppm (5 mg/kg/day) based on increased motor activity on postnatal days 17 and 21 for both sexes. The offspring NOAEL is <72 ppm (5 mg/kg/day).
Although this study contains useful information regarding the developmental neurotoxic potential of ziram, it is classified as Guideline Unacceptable (§83-6; OPPTS 870.6300) due to the following major deficiencies: 1) Neurobehavioral data (motor activity, startle response, and cognitive function) were not presented as percent change from control or analyzed statistically. 2) Simple morphometric analysis of representative locations within the neocortex, hippocampus, and cerebellum was not performed for F2 offspring during histopathological examination of the brain at postnatal days 11 and 70. This study can be upgraded upon the submission and review of acceptable statistical analysis and morphometric data.
-
Reproduction
-
NA [83-4, 2-generation repro.-rat|83-6, Developmental Neurotoxicity]
-
Oral
-
Treatment Duration: 2 Generations; also Developmental Neurotoxicity
-
14277.0
-
2000-08-03
-
2021-06-02
-
Reproduction DER (same MRID as DNT study, but separate review)
|
Added by
Madison Feshuk
on Apr 25, 2022
|
|