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Abstract for RACB20103, RACB20104, RACB20105, RACB20106, and RACB20203

Abstract

Pubertal Toxicity Study of Vinclozolin (Cas No. 50471-44-8), Flutamide (Cas No. 13311-84-7)and Phenobarbital (Cas No. 50-06-6)in Male Sprague Dawley Rats and Methoxychlor (Cas No. 72-43-5), Ethinyl Estradiol (Cas No. 57-63-6)and Phenobarbital in Female Sprague Dawley Rats when Administered in Corn Oil by Oral Gavage

NTP Report Numbers RACB20103, RACB20104, RACB20105, RACB20106, and RACB20203

Summary

The purpose of this study was to examine the sensitivity of the pubertal assay to an estrogen (Methoxychlor), anti-androgen (Vinclozolin and Flutamide), and a thyroid-active agent (Phenobarbital) in intact juvenile/peripubertal male and female rats. Fifty-five time-mated female (F0) Sprague Dawley Rats were received from Charles River Laboratories and allowed to litter at TherImmune. After weaning on Postnatal Day (PND) 21, 135 F1 males and 135 F1 females were assigned to male and female cohort studies, respectively. The F1 males were dosed with corn oil (0 mg/kg), or the test articles: Phenobarbital (25, 50, and 100 mg/kg/day), Vinclozolin (10, 30, and 100 mg/kg/day), or Flutamide (25 and 50 mg/kg/day), once daily via oral gavage from PND 23-53/54. The F1 females were dosed with corn oil (0 mg/kg), or the test articles: Ethinyl Estradiol (0.0025 and 0.0050 mg/kg/day), Methoxychlor (12.5, 25, and 50 mg/kg/day), or Phenobarbital (25, 50 and 100 mg/kg/day), once daily via oral gavage from PND 22-42/43.

Parameters evaluated include mortality and clinical observations, body weights, day of preputial separation, day of vaginal opening, estrous cyclicity, gross pathology, organ weights and histopathology.

Males
Test Article Concentration
(mg/kg/day)
Body
Weight
Age of Preputial
Separation
Organ Weights Histology
Phenobarbital 25 - - ⇑liver -
  50 - - ⇑liver -
  100 ⇑liver
⇓pituitary
-
Vinclozolin 10 - - -
  30 - ⇓repro. organs
⇑ testis,
-
  100 - ⇓repro. organs
⇑ testis
-
Flutamide 25 - ⇓repro. organs
⇑ testis,
⇓ kidneys
-
  50 - ⇓repro. organs
⇑ testis,
⇓ kidneys,
⇑adrenal glands
testis lesions
- = no effect; ⇑ = higher than control means; ⇓ = lower than control means
repro. = reproductive

Females
Test Article Concentration
(mg/kg/day)
Age at Vaginal
Opening
Age at First
Estrus
Irregular
Estrous Cycles
Organ
Weights
Phenobarbital 25 - - - ⇑liver
⇑ adrenal
  50 - - - ⇑ liver
⇑ adrenal
  100 - - ⇑ liver
⇑ adrenal
⇓ thyroid
Methoxychlor 12.5 - -
  25 X -
  50 X ⇓ liver
⇓ ovary
⇓ pituitary
Ethinyl
Estradiol
0.0025 - - - ⇑adrenal
  0.005 X ⇑adrenal
- = no effect; ⇑ = higher than control means; ⇓ = lower than control means; X =present
repro. = reproductive

The lowest observable effect level (LOEL) for an endocrine effect was 25 mg/kg/day for Flutamide, 10 mg/kg/day for Vinclozolin, 100 mg/kg/day for Phenobarbital, 12.5 mg/kg/day for Methoxychlor, and 0.005 mg/kg/day for Ethinyl Estradiol.


Report Date: May 2004

NTIS # PB2004-105924


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