Chronic mixture toxicity study of Clophen A60 and diethyl phthalate in male rats

2008 ◽  
Vol 90 (2) ◽  
pp. 349-359 ◽  
Author(s):  
Contzen Pereira ◽  
Kranti Mapuskar ◽  
C. Vaman Rao
2013 ◽  
Vol 32 (2) ◽  
pp. 113-122 ◽  
Author(s):  
John T. Houpt ◽  
Glenn J. Leach ◽  
Larry R. Williams ◽  
Mark S. Johnson ◽  
Gunda Reddy

4-Amino-2-nitrotoluene (4A2NT; CAS 119-32-4) is a degradation product of 2,4-dinitrotoluene. The toxicity data on 4A2NT are limited. Therefore, we collected toxicity data from rats to assess environmental and human health effects from exposures. The approximate lethal dose for both sexes was 5000 mg/kg. A 14-day toxicity study in rats was conducted with 4A2NT in the feed at concentrations of 0, 125, 250, 500, 1000, and 2000 ppm. Based on a 14-day oral dose range toxicity study with 4A2NT in the feed, 2000 ppm was selected as highest concentration for a subsequent 90-day study. An oral 90-day subchronic toxicity study in rats was conducted with concentrations of 0, 500, 1000, or 2000 ppm of 4A2NT in the feed. The calculated consumed doses of 4A2NT in the feed were 0, 27, 52, or 115 mg/kg/d for males and 0, 32, 65, or 138 mg/kg/d for females. A no-observed adverse effect level could not be determined. The lowest observed adverse effect level was 27 mg/kg/d for males and 32 mg/kg/d for female rats based upon decreased body weight gain. The decreased body weight gain in male rats was the most sensitive adverse event observed in this study and was used to derive a benchmark dose (BMD). A BMD of 23.1 mg/kg/d and BMD with 10% effect level of 15.5 mg/kg/d were calculated for male rats, which were used to derive an oral reference dose (RfD). The human RfD of 1.26 μg/kg/d was derived using current United States Environmental Protection Agency guidelines.


2008 ◽  
Vol 27 (3_suppl) ◽  
pp. 101-118 ◽  
Author(s):  
Eri Watanabe ◽  
Terutaka Kodama ◽  
Takeshi Masuyama ◽  
Shoji Tsubuku ◽  
Akira Otabe ◽  
...  

Dihydrocapsiate, (4-hydroxy-3-methoxybenzyl 8-methylnonanoate; CAS No. 205687-03-2) is a naturally occurring capsinoid compound found in nonpungent chili peppers. Although the safety of synthetically produced dihydrocapsiate has been previously evaluated, the purpose of this 13-week gavage toxicity study is to evaluate dihydrocapsiate produced with a slightly modified manufacturing process. Sprague-Dawley rats, 10 rats/sex/group, 6 weeks of age at study initiation, were administered the dihydrocapsiate daily by gavage at dose levels of 0 (vehicle), 100,300, or 1000 mg/kg/day. The rats were observed for antimortem and postmortem signs of toxicity, including changes in clinical signs, body weights, food consumption, water intake, ophthalmology, clinical pathology (clinical chemistry, hematology, urinalysis), tissue findings (macroscopic and microscopic examination), as well as organ weights. There were no changes observed in clinical signs, body weight, food consumption, water intake, ophthalmology, urinalysis, hematology, or blood chemistry that were attributable to the administration of dihydrocapsiate. The only change observed attributable to the dihydrocapsiate administration involved the liver and that change occurred only at the high dose (1000 mg/kg). Both sexes had an increase in organ weights, but this increase correlated with a change in histopathology (i.e., hepatocyte hypertrophy) only in the males. No dihydrocapsiate-related histopathological changes were observed in males at doses ≤300 mg/kg or in females at any of the doses tested (≤1000 mg/kg). It was concluded that the no observed adverse effect level (NOAEL) of dihydrocapsiate was 300 mg/kg/day for male rats and 1000 mg/kg/day for female rats in this 13 week gavage study.


2020 ◽  
Vol 39 (8) ◽  
pp. 1079-1094 ◽  
Author(s):  
H Rehman ◽  
S Jahan ◽  
I Ullah ◽  
P-O Thörnqvist ◽  
M Jabbar ◽  
...  

The present study investigated the reproductive toxicity of furan in an Extended One-Generation Reproductive Toxicity Study in rats. Sprague Dawley F0 weaning rats (30 per sex per group) were exposed to furan orally at 0, 1, 2.5, 5, and 10 mg kg−1 for 10 weeks (males) and 2 weeks (females) and then mated. Results of F0 indicated that in the furan-treated groups (5 mg kg−1 and 10 mg kg−1), body weight (bw) gain decreased during prebreed and gestational period while increased during lactation periods. F0 animals prebreeding exposure resulted in head tilt and foot splay at 10 mg kg−1. Number of live pups at birth were decreased ( p < 0.001) at 10 mg kg−1. At postnatal day (PND) 70, a significant ( p = 0.03) decrease in testosterone levels of male rats and estrogen levels of female rats ( p = 0.05) was observed in 10 mg kg−1 furan-treated group in F1 generation. Luteinizing hormone, follicle-stimulating hormone, and progesterone levels were also reduced, but their reduction was not statistically significant in all groups. In higher dose furan group (10 mg kg−1), testicular and ovarian weights were reduced in F1 generation at PND 70, with decreased daily sperm production ( p = 0.01) and disturbed estrous cyclicity ( p < 0.01). Some histopathological changes were also observed in testis and ovaries in groups whose parents were previously exposed to 10 mg kg−1 bw of furan group. Based on the above results, it is suggested that exposure to food-based contaminant furan induced remarkable changes in the F0 (parental stage) and F1 (offspring, pubertal, and adult stage) generations of Sprague Dawley rats.


2003 ◽  
Vol 28 (2) ◽  
pp. 95-107 ◽  
Author(s):  
Osamu SAWAMOTO ◽  
Sadakatsu KYO ◽  
Shinya KANEDA ◽  
Miwa HARADA ◽  
Sanae KISHIMOTO ◽  
...  

1987 ◽  
Vol 7 (1) ◽  
pp. 15-16 ◽  
Author(s):  
J. W. G. M. Wilmer ◽  
R. A. Woutersen ◽  
L. M. Appelman ◽  
W. R. Leeman ◽  
V. J. Feron

2020 ◽  
Vol 44 ((E0)) ◽  
pp. 106-112
Author(s):  
Mohammed A. Aboktifa ◽  
Duraid A. Abbas

An interaction toxicity study was performed to evaluate and compare the effect of P-glycoprotein (P-gp) inhibitor (captopril) and inducer (spironolactone) on their common substrate (lovastatin) that were done by comparing LD50 of the acute study with their chronic form then with those combined therapeutic doses administered for 90 days. Therefore, isobolographic analysis and chronicity index were used as the parameters for this study. Forty rats were allocated into five groups according to the used treatment into: captopril, spironolactone, lovastatin, captopril + lovastatin and spironolactone + lovastatin using up and down method to determine their acute exposure LD50 while ninety rats were used to perform the chronic stage of the study divided equally into six groups according to daily dosing regimen as following G1- control group administered distilled water orally; G2 administered captopril 0.7 mg/kg BW orally; G3-administered spironolactone 1.4 mg/kg BW orally; G4- administered lovastatin 0.57 mg/kg BW orally; G5-administered spironolactone1.4 mg/kg BW orally and lovastatin 0.57 mg/kg BW, G6- administered captopril 0.7 mg/kg BW and lovastatin 0.57 mg/kg BW orally. The results of isobolographic analysis showed that the sort of interaction between P-gp inhibitor (captopril) and lovastatin alone and as combined administration showed to be antagonistic after acute administration while it was synergistic after chronic administration; for P-gp inducer, spironolactone and lovastatin were additive after acute administration and antagonistic after chronic administration. Chronicity index results showed that both captopril and lovastatin accumulated after administered each alone and showed more accumulation after their combined administration while the chronicity index for P-gp inducer (spironolactone) and lovastatin showed less total concentration in the body burden after their combined administration than alone one. In conclusion, it seems that P-gp inhibitor (captopril) causes accumulation of itself and substrate (lovastatin), while P-gp inducer (spironolactone) causes reduction on the body burden of itself as well as lovastatin possibly due to their effects on the kinetics of the body and this may affect the efficacy and safety of drugs.


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