Developmental Toxicity Study of Pentachlorophenol in the Rabbit

Bernard, Bruce K.; Ranpuria, Anish K.; Hoberman, Alan M.

doi:10.1080/109158101753333622

Cited by 5 publications

(5 citation statements)

References 13 publications

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“…The results of this study reported herein support and expand upon the results obtained in other studies (Bernard et al 2001a(Bernard et al , 2001b. Technical grade penta caused reproductive effects in the rodent and developmental effects in the rodent and nonrodent only at doses that are clearly maternally toxic.…”

Section: Discussionsupporting

confidence: 89%

“…3 (1.7) 2 (1.0) 0 0 Manubrium Fused Litter incidence (0, 0), a N (%) 0 0 0 1 (4.3) Fetal incidence (0, 0), a N (%) 0 0 0 1 (0.6) Sternal centra summarization (includes incompletely and not ossi ed sternebrae) Litter incidence (0-9, 0-36.0), a N (%) 1 (4.5) 4 (16.7) 1 (4.3) 18 (78.3) ¤¤ Fetal incidence (0-12, 0-6.7), a N (%) 1 (0.6) 4 (2.0) 1 (0. Tarsals (mean § SD) 0.00 § 0.00 0.00 § 0.00 0.00 § 0.00 0.00 § 0.00 Metatarsals (mean § SD) 4.00 § 0.00 4.00 § 0.00 4.00 § 0.00 3.96 § 0.12 ¤ Digits (mean § SD) 5.00 § 0.00 5.00 § 0.00 5.00 § 0.00 5.00 § 0.00 Phalanges (mean § SD) 4.97 § 0.13 5.00 § 0.00 5.00 § 0.00 The second study, also using RPAR-compliant penta, employed daily doses of 7.5, 15, and 30 mg/kg/day from days 6 to 18 of gestation (Bernard, Ranpuria, and Hoberman 2001a) and reported that penta was not a developmental toxicant in nonrodent mammalians (i.e., rabbits). This conclusion was based upon data showing that the mid and high doses reduced maternal body weight gain and that the high dose caused transient weight loss and reduced feed consumption.…”

Section: Discussionmentioning

confidence: 99%

“…In the multigeneration study, the LOAEL and the NOAEL (10 and 30 mg/kg/day, respectively) were the same for reproductive effects and general toxicity (Bernard et al 2001b). In the rabbit developmental study, penta was not a developmental toxicant because the developmental NOAEL, 30 mg/kg/day, was greater than the maternal NOAEL, 7.5 mg/kg/day (Bernard, Ranpuria, and Hoberman et al 2001a).…”

mentioning

confidence: 96%

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A Study of the Developmental Toxicity Potential of Pentachlorophenol in the Rat

Bernard

Hoberman

2001

Int J Toxicol

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Pentachlorophenol (penta, CAS #87-86-5) is primarily used as a wood preservative. As part of the USEPA pesticide reregistration process, the developmental toxicity (embryo-fetal toxicity and teratogenic potential) of commercially available penta was studied following oral gavage to presumed pregnant female Sprague-Dawley rats (Crl:CD BR VAF/Plus Subdivision F, 83-3). Both study design and penta purity met the requirements of the USEPA. Doses of 0 (corn oil), 10, 30, and 80 mg/kg/day were administered to the rats at concentrations of 0, 2, 6, and 16 mg/ml, respectively from day 6 to day 15 of presumed gestation. The dosage volume was 5 ml/kg, adjusted on each day of dosage based on individual body weights recorded immediately before intubation. The rats were sacrificed on day 20 of presumed gestation and necropsied. The number of corpora lutea in each ovary was recorded. The uterus was examined for pregnancy, number and distribution of implantations, early and late resorptions and live and dead fetuses. Each fetus was weighed, sexed, and examined for gross external, soft tissue and skeletal alterations. The no-observable-adverse-effect-level (NOAEL) for maternal toxicity in rats was determined to be 30 mg/kg/day of penta. The developmental NOAEL for penta in rats was also found to be 30 mg/kg/day. The lowest-observable-adverse-effect-level (LOAEL) for penta developmental toxicity (80 mg/kg/day) was associated with increased resorptions, reduced live litter size and fetal body weights, and caused increased malformations and variations. These NOAELs, derived using USEPA approved study designs, are higher than those previously reported using penta that is no longer commercially available in studies with non-approved experimental designs. Penta should not be identified as a selective developmental toxicant in the rat because adverse effects on development of rat conceptuses occurred only at maternally toxic dosages.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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confidence: 96%

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A Study of the Developmental Toxicity Potential of Pentachlorophenol in the Rat

Bernard

Hoberman

2001

Int J Toxicol

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“…For this study, the NOAEL for general toxicity, excluding metabolic effects resulting in increased liver weight and centrilobular hypertrophy, was 10 mg/kg/day. The NOAEL for developmental toxicity, a component of reproductive toxicity, is also 10 mg/kg/day (Bernard, Ranpuria, and Hoberman 2001;, whereas the NOAEL for adult reproductive toxicity associated with developmental toxicity is 30 mg/kg/day. Thus, the lowest reproductive NOAEL of 10 mg/kg/day is two to three times higher than the highest NOAEL, 3 mg/kg/day, observed in the previous one-generation tests.…”

Section: Discussionmentioning

confidence: 99%

“…Penta is supplied as a tan to grey solid. The same lot of commercially available penta (CAS 87-86-5, Lot EL-064) that was provided by the Pentachlorphenol Task Force for testing in two developmental toxicity studies (Bernard, Ranpuria, and Hoberman 2001; was employed throughout the study. This lot contained >97.5% chlorinated phenols, of which approximately 89% was penta.…”

Section: Test Substance Characterizationmentioning

confidence: 99%

Oral (Gavage) Two-Generation (One Litter Per Generation) Reproduction Study of Pentachlorophenol (Penta) in Rats

Bernard

Hoberman

Brown³

et al. 2002

Int J Toxicol

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The potential for pentachlorophenol (penta) to induce general and reproductive/developmental toxicity was evaluated in Crl Sprague-Dawley rats, employing a two-generation reproduction toxicity study. Penta was administered by gavage at doses of 0, 10, 30, and 60 mg/kg/day. In both generations, the parental animals (30/sex/group) were intubated daily for 10 weeks before cohabitation and continuing through cohabitation, gestation, and lactation periods. Intubation of the F1 generation was begun 28 days postpartum. Animals were evaluated daily for mortality and general toxicity (clinical observations, body weights and gains, feed consumption). Organ weights were recorded and histopathological evaluations were made. Specific indices of reproductive function evaluated included estrous cycles, mating and fertility, parturition, lactation, viability, and growth and development of offspring, including sexual maturation, sperm parameters, and numbers of ovarian primordial follicles. All deaths in the parental rats were unrelated to penta. Expected metabolic effects of penta, sporadic increased liver weights associated with hepatocellular centrilobular hypertrophy and vacuolation and lipofuscin pigmentation, were evident in the 10-, 30-, and 60-mg/kg/day dose group P1 and F1 animals. Toxicity, in the form of liver pathology (single cell necrosis), reduced body weights and associated reductions in organ weights, and reduced feed consumption were noted in both generations at the 30- and 60-mg/kg/day doses. Developmental toxicity associated with these doses included reduced pup weights and viability. The 60-mg/kg/day dose also resulted in delayed sexual maturation, decreased spermatid counts, small prostates and testes, decreased implantations, reduced fertility, and increased resorptions of embryos. Based on these results, it was concluded that 30 mg/kg/day is the lowest-observable-adverse-effect level (LOAEL) and 10 mg/kg/day is the no-observable-adverse-effect level (NOAEL) for both reproductive and general toxicity. These findings are consistent with results from previously conducted studies wherein reproductive/developmental toxicity was observed only at doses that also induced general toxicity. It differs from previous findings in that the NOAEL for general toxicity is two to three times higher for the more pure product than for products produced and tested previously. In addition, the results did not indicate bioaccumulation of penta. Thus, penta did not selectively affect reproduction or development of the offspring of rats at a dose of 10 mg/kg/day, a dose that is 7000 to 20,000 times higher than human exposure.

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