Developmental Toxicity Study of Pentachlorophenol in the Rabbit

2001 ◽  
Vol 20 (6) ◽  
pp. 345-352 ◽  
Author(s):  
Bruce K. Bernard ◽  
Anish K. Ranpuria ◽  
Alan M. Hoberman
Keyword(s):  
Corn Oil ◽  
Body Weight Gain ◽  
Developmental Toxicity ◽  
Feed Consumption ◽  
High Dose ◽  
Corpora Lutea ◽  
New Zealand White Rabbits ◽  
Adverse Effect Level ◽  
Effect Level ◽  
High Doses

The potential for developmental toxicity of pentachlorophenol (penta) was studied in New Zealand white rabbits at doses of 0 (corn oil), 7.5, 15, and 30 mg/kg/day administered by gavage on days 6 to 18 of gestation. The rabbits were sacrificed on day 29 of presumed gestation and necropsied. Measurements included number of corpora lutea, pregnancy, number and distribution of implantations, early and late resorptions, live and dead fetuses, fetal weight, gender, and gross external, soft tissue, and skeletal alterations. The mid and high doses reduced maternal body weight gain; the high dose caused transient weight loss and reduced feed consumption. There were no effects on embryofetal development at any of the doses evaluated. Based on these data, the maternal no-observable-adverse-effect level (NOAEL) is 7.5 mg/kg/day, while the developmental NOAEL is 30 mg/kg/day. Penta is not a developmental toxicant in a nonrodent animal model.

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

2001 ◽  
Vol 20 (6) ◽  
pp. 353-362 ◽  
Author(s):  
Bruce K. Bernard ◽  
Alan M. Hoberman
Keyword(s):  
Adverse Effect ◽  
Corn Oil ◽  
Developmental Toxicity ◽  
Wood Preservative ◽  
Corpora Lutea ◽  
Sprague Dawley ◽  
Fetal Toxicity ◽  
Body Weights ◽  
Adverse Effect Level ◽  
Effect Level

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.

Evaluation of the Developmental Toxicity of Linalool in Rats

2008 ◽  
Vol 27 (2) ◽  
pp. 183-188 ◽  
Author(s):  
Valerie T Politano ◽  
Elise M Lewis ◽  
Alan M Hoberman ◽  
Mildred S Christian ◽  
Robert M Diener ◽  
...  
Keyword(s):  
Body Weight ◽  
Developmental Toxicity ◽  
Clinical Signs ◽  
Feed Consumption ◽  
Corpora Lutea ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Weight Gains ◽  
Adverse Effect Level ◽  
Effect Level

The developmental toxicity of linalool, a widely used fragrance ingredient, was evaluated in presumed pregnant Sprague-Dawley rats (25/group). Oral dosages of 0, 250, 500, or 1000 mg/kg/day linalool were administered by gavage on gestational days 7 to 17. The presence of spermatozoa and/or a copulatory plug in situ was designated as gestational day 0. Rats were observed for viability, clinical signs, body weights, and feed consumption. Caesarean sectioning and necropsy occurred on gestational day 21. Uteri were examined for number and distribution of implantations, live and dead fetuses, and early and late resorptions. Numbers of corpora lutea were also recorded. Fetuses were weighed and examined for gender, gross external changes, and soft tissue or skeletal alterations. There were no maternal deaths, clinical signs, or gross lesions that were considered related to linalool. During the dosage period, mean relative feed consumption was significantly reduced by 7% and mean body weight gains were reduced by 11% at 1000 mg/kg/day. During the postdosage period, feed consumption values at 1000 mg/kg/day were significantly higher than vehicle control values, which corresponded to the increase in body weight gains during this period. Caesarean section and litter parameters, as well as fetal alterations, were not affected by linalool at any of the three dosages tested. On the basis of these data, the maternal no observed adverse effect level (NOAEL) of linalool is 500 mg/kg/day, whereas the developmental NOAEL is ≥ 1000 mg/kg/day. It is concluded that linalool is not a developmental toxicant in rats at maternal doses of up to 1000 mg/kg/day.

scholarly journals Palmitoylethanolamide: Prenatal Developmental Toxicity Study in Rats

2021 ◽  
pp. 109158182098607
Author(s):  
Narendra S. Deshmukh ◽  
Shailesh Gumaste ◽  
Silma Subah ◽  
Nathasha Omal Bogoda
Keyword(s):  
Body Weight ◽  
Developmental Toxicity ◽  
Reproductive Toxicity ◽  
Toxicity Study ◽  
High Dose ◽  
Pregnant Rats ◽  
Human Dose ◽  
Adverse Effect Level ◽  
Female Wistar Rats ◽  
Effect Level

Palmitoylethanolamide (PEA) is an endogenous ethanolamine playing a protective and homeodynamic role in animals and plants. Prenatal developmental toxicity of PEA was tested following oral administration to pregnant female Wistar rats, from days 0 to 19 of gestation, at dosage of 250, 500, or 1,000 mg/kg body weight, according to Organisation for Economic Co-operation and Development Test Guideline No. 414. On gestation day 20, cesarean sections were performed on the dams, followed by examination of their ovaries and uterine contents. The fetuses were further examined for external, visceral, and skeletal abnormalities. Palmitoylethanolamide did not cause any alterations at any of the given dosages in the measured maternal parameters of systemic toxicity (body weight, food consumption, survival, thyroid functions, organ weight, histopathology), reproductive toxicity (preimplantation and postimplantation losses, uterus weight, number of live/dead implants and early/late resorptions, litter size and weights, number of fetuses, their sex ratio), and fetal external, visceral, or skeletal observations. Any alterations that were recorded were “normal variations” or “minor anomalies,” which were unrelated to treatment with PEA. Under the condition of this prenatal study, the no-observed-adverse-effect level of PEA for maternal toxicity, embryotoxicity, fetotoxicity, and teratogenicity in rats was found to be >1,000 mg/kg body weight/d. It indicates that PEA is well tolerated by and is safe to pregnant rats even at a high dose of 1,000 mg/kg body weight/d, equivalent to a human dose of greater than 9.7 g/d. This prenatal developmental toxicity study contributes greatly in building a robust safety profile for PEA.

Developmental Toxicity Studies of Triethylene Glycol Monomethyl Ether Administered Orally to Rats and Rabbits

1996 ◽  
Vol 15 (5) ◽  
pp. 349-370 ◽  
Author(s):  
A. M. Hoberman ◽  
W. J. Krasavage ◽  
M. S. Christian ◽  
C. R. Stack
Keyword(s):  
Developmental Toxicity ◽  
Clinical Signs ◽  
Triethylene Glycol ◽  
Monomethyl Ether ◽  
Feed Consumption ◽  
Corpora Lutea ◽  
Maternal Body ◽  
Body Weights ◽  
Effect Level ◽  
Dose Levels

Triethylene glycol monomethyl ether (TGME) was administered orally via gavage stomach tube to mated Caesarean delivered (CD) rats and artificially inseminated New Zealand white rabbits on days 6–15 and 6–18 of gestation, respectively, at dose levels of 0, 625, 1,250, 2,500, or 5,000 mg/kg/day (rats) and 0, 250, 500, 1,000, or 1,500 mg/kg/day (rabbits). Clinical signs, maternal body weights, and feed consumption were monitored throughout the treatment period. The surviving rats and rabbits underwent Caesarean section on day 20 and day 29 of gestation, respectively. Fetuses were weighed, sexed, and examined externally and for soft tissue and skeletal alterations. In rats, the high dose significantly reduced maternal body weights, feed consumption, and gravid uterine weights. One dam in this group died on day 13 of gestation. Treatment-related clinical signs were seen only at the highest dose tested. Maternal feed consumption was significantly reduced at 5,000 and 2,500 mg/kg and slightly, but not significantly, reduced at 1,250 mg/kg. Doses as high as 5,000 mg/kg/day did not affect pregnancy rate, implantations, corpora lutea, live fetuses, or fetal sex ratios. Resorptions were significantly increased at 5,000 mg/kg, and fetal body weights were slightly reduced at 1,250 mg/kg and significantly reduced at 2,500 and 5,000 mg/kg. The incidences of malformations and external or internal soft tissue variations were not increased at doses as high as 5,000 mg/kg. Incidences of skeletal variations were increased at doses of 1,250 mg/kg and higher. The no-observable-effect level (NOEL) in rats, for both maternal and developmental toxicity, was 625 mg/kg, while 1,250 mg/kg was a no-observable-adverse-effect level (NOAEL) for maternal toxicity and may be very near the NOAEL for developmental toxicity. In rabbits, 1,500 mg/kg/day reduced maternal body weights and feed consumption and caused death, abortions, treatment-related clinical signs of toxicity, and reduced gravid uterine weights. One doe in the 1,000 mg/kg group died on day 18 of gestation, but no treatment-related signs were seen in the other animals in this group. Doses as high as 1,500 mg/kg did not significantly affect pregnancy rate, implantations, corpora lutea, resorptions, live fetuses, fetal body weights, or sex ratio. Incidences of malformations or external and internal variations were not increased at any of the dose levels. The only developmental toxicity seen in the rabbit was an increase in the incidence of two common skeletal variations, angulated hyoid alae and delayed ossification of the xiphoid process, at the highest dose tested. For maternal toxicity, the NOEL and NOAEL were 250 mg/kg and 500 mg/kg, respectively, and for developmental toxicity the NOEL and NOAEL were 1,000 mg/kg and 1,500 mg/kg, respectively. These studies indicate that TGME was not selectively toxic to developing rat or rabbit conceptuses.

scholarly journals Developmental Toxicity Study of Orally Administered Resorcinol Bis-Diphenylphosphate (RDP) in Rabbits

2000 ◽  
Vol 19 (4) ◽  
pp. 257-264 ◽  
Author(s):  
B. M. Ryan ◽  
R. Henrich ◽  
R. I. Freudenthal
Keyword(s):  
Body Weight ◽  
Corn Oil ◽  
Body Weight Gain ◽  
Developmental Toxicity ◽  
Clinical Signs ◽  
Lubricant Additive ◽  
Control Group ◽  
Vehicle Control Group ◽  
New Zealand White Rabbits ◽  
Ester Product

Fyrolflex resorcinolbis-diphenylphosphate (RDP) is a nonhalogenphosphate ester product that is widely used as a flame retardant for petrochemicalplastics and high-temperature lubricant additive applications. The potential developmental toxicity of RDP was evaluated in rabbits. Groups of 27 sperm-positive New Zealand white rabbits (Hazelton Research Products Inc., Denver, PA) were administered graded concentrations of 50, 200, or 1000 mg/kg/day of RDP in corn oil. A vehicle control group of equal size was administered corn oil alone. Rabbits were dosed daily (1.5 ml/kg) on gestationdays 6 to 28 and sacrificed on gestationday 29. The fetuses were removed by cesarean section and examined for gross external, visceral, cephalic, and skeletal anomalies. No treatment-related clinical signs of toxicity were observed. No treatment-related effects in maternal food consumption, body weight, body weight gain, or on uterus, liver, kidney, and spleen weights were detected. Fetal viability and body weight, as well as developmental end points were also unaffected by treatment. Accordingly, exposure of pregnant rabbits to doses ranging from 50 to 1000 mg/kg/day of RDP during the periods of major organogenesis and histogenesis did not result in any biologically significant toxic or teratogenic/developmental effect in the dams or fetuses.

Prenatal Oral (Gavage) Developmental Toxicity Study of Decabromodiphenyl Oxide in Rats

2002 ◽  
Vol 21 (2) ◽  
pp. 83-91 ◽  
Author(s):  
M. L. Hardy ◽  
R. Schroeder ◽  
J. Biesemeier ◽  
O. Manor
Keyword(s):  
Body Weight ◽  
Flame Retardant ◽  
Corn Oil ◽  
Body Weight Gain ◽  
Developmental Toxicity ◽  
Clinical Signs ◽  
Toxicity Study ◽  
Wide Range ◽  
Effect Level ◽  
Effect Of Treatment

Decabromodiphenyl oxide (DBDPO) is a highly effective flame retardant that is primarily used in electrical and electronic equipment with a secondary, but important, application in upholstery textiles. DBDPO, the second largest volume brominated flame retardant in use today, has undergone a wide range of toxicology tests in mammalian species with the results indicating a no-adverse-effect level of ∼1000 mg/kg/day in oral repeated-dose studies. An oral prenatal developmental toxicity study of the commercial DBDPO product (97% purity) was performed under current EPA OPPTS and OECD guidelines. Female Sprague-Dawley rats (25 mated females/group) received 0, 100, 300 or 1000 mg DBPDO/kg/day via gavage in corn oil during gestation days 0 through 19. All females survived until scheduled sacrifice. No clinical signs of toxicity were observed. Pregnancy rates in the control and treated groups ranged from 96% to 100% and provided 23 or more litters in each group for evaluation on gestation day 20. No effect of treatment was seen in maternal gestational parameters (body weight, body weight gain, and food consumption), uterine implantation data, liver weight, or necropsy findings. Likewise, no effect of treatment was seen in fetal body weights, fetal sex distribution, or during the fetal external, visceral, or skeletal examinations. The NOEL (noobservable-effect level) for maternal and developmental toxicity was 1000 mg DBPDO/kg/day, the highest dose level administered on gestation days 0 to 19.

Developmental Toxicity of Clarified Slurry Oil Applied Dermally to Rats

1989 ◽  
Vol 5 (3) ◽  
pp. 587-599 ◽  
Author(s):  
Maureen H. Feuston ◽  
Stacy L. Kerstetter ◽  
Edward J. Singer ◽  
Myron A. Mehlman
Keyword(s):  
Body Weight Gain ◽  
Developmental Toxicity ◽  
Test Material ◽  
Residual Fraction ◽  
Pregnant Rats ◽  
Viable Offspring ◽  
Adverse Effect Level ◽  
Effect Level ◽  
Dose Levels ◽  
External Development

Clarified Slurry Oil (CSO), the heavy residual fraction from the fluidized catalytic cracker, was applied to the shaven backs of groups of 10 pregnant rats at doses of 0, 4, 8, 30, 125, and 250 mg/kg I day. All groups received the test material on gestation days 0–19. CSO was applied undiluted and left uncovered on the skin; collars were placed on the rats to minimize ingestion of the test material. Signs of maternal toxicity, some of which were seen at dose levels as low as 8 mg/kg/day, included vaginal bleeding, decreased body weight gain, reduced food consumption, death, increased relative liver weights, atrophy of the thymus, and aberrant serum chemistry. The number of fetal resorptions / deaths was markedly increased and the number of viable offspring decreased by CSO at dosages of 30 mg/kg/day and above. The group receiving 250 mg/kg/day carried no viable offspring. Fetuses from pregnant females exposed to CSO at dose levels in excess of 8 mg/kg/day were smaller than those from control and 4 mg/kg/day groups, and their skeletons showed decreased ossification. Abnormal external development and visceral development were observed in living and dead fetuses exposed in utero to CSO at dose levels as low as 8 mg/kg/day. Based on these data, 4 mg/kg/day represents the No-Observed-Adverse-Effect-Level for both maternal and developmental toxicity.

Evaluation of the Developmental Toxicity of Acetyl Cedrene

2006 ◽  
Vol 25 (5) ◽  
pp. 423-428 ◽  
Author(s):  
Aurelia Lapczynski ◽  
Daniel A. Isola ◽  
Mildred S. Christian ◽  
Robert M. Diener ◽  
Anne Marie Api
Keyword(s):  
Body Weight ◽  
Soft Tissue ◽  
Corn Oil ◽  
Developmental Toxicity ◽  
Clinical Signs ◽  
Feed Consumption ◽  
Corpora Lutea ◽  
Sprague Dawley ◽  
Body Weights ◽  
Weight Gains

The developmental toxicity of acetyl cedrene (AC), a widely used fragrance ingredient, was evaluated in pregnant Sprague-Dawley rats (25/group). Gavaged dosages of 0 (corn oil), 25, 50, or 100 mg/kg/day were administered on days 7 through 17 of gestation (GDs 7 to 17). First and last day dosing suspensions were analyzed for AC content. All rats were observed daily for viability, clinical signs, abortions, and premature deliveries. Body weights were recorded at frequent intervals. Cesarean-sectioning and necropsy examinations were performed on GD 21. Uteri were examined for number and distribution of implantations, live and dead fetuses, and early and late resorptions. The number of corpora lutea in each ovary was also recorded. Fetuses were weighed and examined for gender and gross external changes and soft tissue or skeletal alterations. Totals of 25, 23, 21, and 24 rats became pregnant in the 0 (control), 25, 50 and 100 mg/kg/day groups, respectively, and analysis of dosage preparations verified that administered dosages reflected calculated dosages ±10%. No deaths or premature deliveries occurred in the study. Clinical signs included excessive salivation, which was attributed to the administration of AC. When compared to controls, significant reductions in feed consumption and body weight gains occurred only at 100 mg/kg/day. Both absolute (g/day) and relative (g/kg/day) feed consumption values were significantly decreased on GDs 7 to 12. Relative values were decreased significantly on GDs 15 to 18. Body weight gains were significantly reduced on GDs 7 to 10. Mean maternal body weights remained significantly lower than controls on GDs 9 to 14, but a marked compensatory increase in feed consumption on GDs 15 to 18 prevented further deterioration in body weight gains. No cesarean-sectioning or litter parameters were affected by dosages of AC and necropsy of the dams after cesarean section did not reveal any gross changes attributable to AC. No gross external, soft tissue, or skeletal fetal alterations (malformations or variations) were attributed by dosages AC. The average number of ossifications sites per fetus per litter did not differ among the groups. Based on these data, maternal and developmental no-observable-adverse-effect levels (NOAELs) of 50 and 100 mg/kg/day, respectively, were established for AC.

Evaluation of the Developmental Toxicity of α-Methyl-3,4-Methylene-Dioxyhydrocinnamic Aldehyde in Rats

2006 ◽  
Vol 25 (2) ◽  
pp. 127-132 ◽  
Author(s):  
Anne Marie Api ◽  
Elise M. Lewis ◽  
Alan M. Hoberman ◽  
Mildred S. Christian ◽  
Robert M. Diener
Keyword(s):  
Corn Oil ◽  
Developmental Toxicity ◽  
Clinical Signs ◽  
Feed Consumption ◽  
Corpora Lutea ◽  
Sprague Dawley ◽  
Pregnant Rats ◽  
Excessive Salivation ◽  
Sprague Dawley Rats ◽  
Body Weights

The developmental toxicity of α-methyl-3,4-methylene-dioxyhydrocinnamic aldehyde (MMDHCA), a widely used fragrance ingredient, was evaluated for developmental toxicity in Sprague-Dawley rats (25/group; cesarean-sectioning identified 21 to 25 pregnant rats/group). Oral dosages of 0 (corn oil), 62, 125, or 250 mg/kg/day were administered by gavage on days 7 through 17 of gestation (GDs 7 through 17). Rats were observed for viability, clinical signs, body weights, and feed consumption. Necropsy and cesarean sectioning occurred on GD 21. Uteri were examined for number and distribution of implantations, live and dead fetuses, and early and late resorptions. Numbers of corpora lutea were also recorded. Fetuses were weighed and examined for gender, gross external changes, and soft tissue or skeletal alterations. Analysis of dosage preparations verified calculated dosages ±10%. No deaths occurred. Excessive salivation occurred in all groups, but the incidence was increased at 250 mg/kg/day. The 250 mg/kg/day dosage also was associated with a significant increase in the incidences of a clear, red or yellow perioral and/or red perivaginal substance and significant reductions in mean feed consumption and body weight gains (11.6% and 7.4%, respectively) during the entire dosage period. No gross changes attributable to MMDHCA were observed at necropsy. Cesarean section or litter parameters, as well as fetal alterations, were not affected by MMDHCA at 250 mg/kg/day or either of the lower dosages tested. Based on these data, maternal and developmental no-observable-effect levels (NOAELs) of 125 and >250 mg/kg/day, respectively, were established for MMDHCA. It is concluded that MMDHCA is not a developmental toxicant in rats under the conditions of this study and dosing regimen.

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

2002 ◽  
Vol 21 (4) ◽  
pp. 301-318 ◽  
Author(s):  
Bruce K. Bernard ◽  
Alan M. Hoberman ◽  
W. Ray Brown ◽  
Anish K. Ranpuria ◽  
Mildred S. Christian
Keyword(s):  
Adverse Effect ◽  
Sexual Maturation ◽  
Developmental Toxicity ◽  
Metabolic Effects ◽  
Feed Consumption ◽  
Organ Weights ◽  
General Toxicity ◽  
Body Weights ◽  
Adverse Effect Level ◽  
Effect Level

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 centrilob-ular 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 bioaccu-mulation 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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