National Toxicology Program

National Toxicology Program

Abstract for RACB94001 - Thiophenol II (CAS No 108-98-5)

http://ntp.niehs.nih.gov/go/7823

The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program (NTP). The findings may or may not have been peer reviewed and were not evaluated in accordance with the Explanation of Levels of Evidence for Reproductive Toxicity criteria (see http://ntp.niehs.nih.gov/ntp/htdocs/levels/09_3566_NTP_ReproTOX_R1.pdf or with the Explanation of Levels of Evidence for Developmental Toxicity criteria (see http://ntp.niehs.nih.gov/ntp/Test_info/NTP_DevTox20090507.pdf) established by the NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of the NTP or the US Government.

Reproductive Toxicity of Thiophenol II (CAS No: 108-98-5) Administered by Gavage to Sprague-Dawley Rats

NTP Report # RACB94001

Abstract

The potential reproductive toxicity of thiophenol in Sprague-Dawley rats was evaluated using the Reproductive Assessment by Continuous Breeding (RACB) protocol. Based on acute oral LD50 of 46.2 mg/kg and the increased mortality in the 40 mg/kg/day females and the increased liver weights at 30 mg/kg/day noted during a previous RACB study with thiophenol, dose levels for the continuous breeding phase for this study were set at 9, 18, and 35 mg/kg.

Male and female Sprague-Dawley rats were exposed to thiophenol in corn oil by oral gavage. During 16 weeks of cohabitation, live pup weight adjusted for litter size was decreased by 4 and 6% in the 9 and 35 mg/kg dose groups, respectively. The number of live pups was slightly but not significantly decreased (7%) at 35 mg/kg. No differences were observed in the pregnancy index, cumulative days to litter, mean average litters per pair, proportion of pups born alive, or sex ratio of pups.

A crossover mating trial (Task 3) revealed the females as the affected sex. When naive males were mated with control or 35 mg/kg females, the mean live pup weight and adjusted live pup weight were reduced in the 35 mg/kg group by 8-9%. No other treatment-related effects were seen. When naive females were mated with control or 35 mg/kg males, reproductive parameters were comparable between dose groups.

Throughout the study, the body weights of the F0 35 mg/kg males were 7-15% less than controls. F0 female body weights were not adversely effected by thiophenol. At necropsy, liver and kidney weights increased with increasing dose: liver weights (relative to body weight) of the 9, 18, and 35 mg/kg animals were increased by 20, 35, and 50% (males) and 11, 18, 36% (females), respectively. Relative kidney weights of the 9, 18, and 35 mg/kg animals were increased by 30, 53, and 104% (males) and 8, 5, 20% (females), respectively. There was a treatment-related increase in the incidence of enlarged and pitted kidneys in the F0 males at necropsy. Increased incidences of renal tubule degeneration (30%, 35%, and 40%, respectively) were observed in 9, 18, and 35 mg/kg F0 males and females. Centrilobular hepatocellular hypertrophy was observed in the 18 and 35 mg/kg F0 males and 9, 18, and 35 mg/kg F0 females.

Evaluation of epididymal computer-assisted sperm analysis (CASA) data revealed treatment-related decreases (5-6%) in percent motile sperm in the 18 and 35 mg/kg groups compared to controls. Other reproductive endpoints at necropsy were comparable among dose groups.

In Task 4 (second generation evaluation), the pup weights of the 35 mg/kg F1 males and females were decreased by 13-16% during Postnatal Day (PND) 4 and 7 of lactation; however, no differences were observed on PND 1, 14 or 21. There was no treatment-related increase in pre-weaning mortality of the F1 animals.

In the F1 mating trial, live F 2 pup weight was decreased by 9 and 12% in the 18 and 35 mg/kg dose groups, respectively, when compared to controls. Other endpoints were unchanged.

Body weights of the 35 mg/kg F1 males were 11-17% less than controls on Task Weeks 2 and 4, and at delivery and necropsy. At necropsy, the liver and kidneys were also enlarged in a treatment-related fashion for both sexes in the F1 animals: relative liver weights of the 9, 18, and 35 mg/kg animals were increased by 18, 37, and 62% (males) and 14, 17, 43% (females), respectively. Relative kidney weights of the 9, 18, and 35 mg/kg animals were increased by 52, 67, and 163% (males) and 12, 6, 26% (females), respectively. There was a treatment-related increase in the incidence of enlarged, pale, and soft kidneys in the F1 males at necropsy. As observed in the F0 animals, renal tubule degeneration was observed in 9, 18, and 35 mg/kg F1 males and 18 and 35 mg/kg F1 females. Centrilobular hepatocellular hypertrophy was observed in the 9, 18, and 35 mg/kg F1 males and females. Microscopic evaluation of the left testis from F1 males revealed a treatment-related increase in inhibited spermiation of the stage VIII-X tubules. No F1 sperm endpoints were significantly changed.

Results of this study show that thiophenol is not a selective reproductive toxicant, because the minor effects on development (decreased live pup weight during the crossover mating) occurred concomitant with, or at doses greater than, those doses that produce hepatic or renal effects. The no-observable-adverse-effect level (NOAEL) was not established in this study as the 9 mg/kg animals displayed increased liver and kidney weights (absolute and relative) and treatment-related microscopic lesions. A maximum tolerated dose (MTD) was reached for the 35 mg/kg F0 and F1 generation animals, based on decreased body weights (males only), increased liver and kidney weights, and treatment-related renal and hepatic lesions.

 


 

SUMMARY OF RESULTS
THIOPHENOL: REPRODUCTIVE ASSESSMENT BY CONTINUOUS BREEDING
WHEN ADMINISTERED TO SPRAGUE-DAWLEY RATS BY ORAL GAVAGE
        Treatment Group (mg/kg)
        _________________________________________________
Parameters   Control(0) Low(9) Mid(18) High(35)
         
General Toxicity (Tasks 2 and 3)
Terminal Body Weight   - - - decreaseM
Feed Consumption (g/animal/day) - - increaseM increaseM
Absolute Kidneys Weight   - increaseM increaseM increaseM,F
Relative Kidneys Weight   - increaseM,F increaseM increaseM,F
Absolute Liver Weight - increaseM increaseM,F increaseM,F
Relative Liver Weight   - increaseM,F increaseM,F increaseM,F
Mortality   0M,0F 0M,4F 1M,2F 2M,5F
Reproductive Parameters (Task 2)
Average Litters per Pair   - - - -
Average Live Pups per Litter - - - -
Proportion of Pups Born Alive - - - -
Adjusted Live Pup Weighta   - decreaseM - decreaseM,F
Cumulative Days to Litter   - - - -
Progression of Toxicity (Task 2)
Mean Live Pups per Litter   - - - -
Pregnancy Index   - - - -
Male Crossover Mating - Naive Females x Treated Males (Task 3)
Mating Index   -     -
Pregnancy Index   -     -
Fertility Index   -     -
Live Pups per Litter   -     -
Proportion of Pups Born Alive -     -
Adjusted Live Pup Weighta   -     -
Gestation Length   -     -
Number of Resorptions per Litter -     -
Post-implantation Loss   -     -
Female Crossover Mating - Naive Males x Treated Females (Task 3)
Mating Index   -     -
Pregnancy Index   -     -
Fertility Index   -     -
Live Pups per Litter   -     -
Proportion of Pups Born Alive -     -
Adjusted Live Pup Weighta -     decrease
Gestation Length   -     -
Estrous Cycle Length   -     -
Necropsy (Tasks 2/3)
Ovarian Weight   - - - -
Right Testis Weight   - - - -
Right Epididymis Weight - - - -
Right Caudal Epididymis Weight - - - decrease
Prostate Weight   - - - -
Seminal Vesicles Weight - - - -
Epididymal Sperm Density - - - -
Epididymal Sperm Morphology, % Abnormal   - - - -
Epididymal Sperm Motion Parameters (CASA) - - decrease decrease
No. Spermatids per mg Testis - - - -
Total No. Spermatid Heads per Testis - - - -
Renal Tubule Degeneration/
Regeneration
- increaseM,F increaseM,F increaseM,F
Centrilobular Hepatocellular Hypertrophy - increaseF increaseM,F increaseM,F
Inhibited Spermiation   - - - -
Second Generation (Task 4)
Pup Survival   - - - -
Body Weight (21 days)   - - - -
Body Weight (81±10 days) - - - -
General Toxicity (Task 4)
Terminal Body Weight   - - - decreaseM
Feed Consumption (g/animal/day) - - - -
Absolute Kidneys Weight - increaseM increaseM increaseM,F
Relative Kidneys Weight - increaseM,F increaseM,F increaseM,F
Absolute Liver Weight   - increaseM increaseM,F increaseM,F
Relative Liver Weight   - increaseM,F increaseM,F increaseM,F
Mortality   0M,1F 0M,0F 0M,0F 0M,5F
Reproductive Parameters (Task 4)
Pregnancy Index   - - - -
Live Pups per Litter   - - - -
Proportion of Pups Born Alive - - - -
Adjusted Live Pup Weighta - - - -
Days to Litter   - - - -
Estrous Cycle Length   - - - -
Necropsy (Task 4)
Ovarian Weight   - - - -
Right Testis Weight   - increase increase increase
Right Epididymis Weight - - -  
Right Caudal Epididymis Weight - - - -
Prostate Weight   - - - -
Seminal Vesicles Weight - - - -
Epididymal Sperm Motion Parameters (CASA) - - - -
Epididymal Sperm Density - - - -
Epididymal Sperm Morphology, % Abnormal - - - -
No. Spermatids per mg Testis - - - -
Total No. Spermatid Heads per Testis - - - -
Renal Tubule Degeneration/Regeneration - increaseM increaseM increaseM,F
Centrilobular Hepatocellular Hypertrophy - increaseM,F increaseM,F increaseM,F
Inhibited Spermiation - increase increase increase
______________________________________________
a Live pup weight adjusted for litter size

KEY: M = Male increase = Significant increase in the parameter
  F = Female decrease= Significant decrease in the parameter
    - = No effect

MTD: A maximum tolerated dose (MTD) was reached for the F0 and F1 generation animals, based on decreased body weights (males only), increased liver and kidney weights, and treatment-related renal and hepatic lesions.


REPRODUCTIVE TOXICANT:

 

Male - Yes, slight, based on an increased incidence of inhibited spermiation in all treated F1 males, and decreased epididymal sperm motility in the 18 and 35 mg/kg F0 males.

 

Female - Yes (developmental), slight, based on decreased pup weights.

CLASSIFICATION:

      9 mg/kg 18 mg/kg 35 mg/kg
  Males Reproductive Toxicity + + +
    General Toxicity + + +
 
  Females Developmental Toxicity - - +
    General Toxicity + + +

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Report Date: June 28, 1996

NTIS# PB96-211735

 


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