Evaluation of the Developmental Toxicity of Dihydromyrcenol in Rats

2009 ◽  
Vol 28 (2) ◽  
pp. 80-87 ◽  
Author(s):  
Valerie T. Politano ◽  
Elise M. Lewis ◽  
Alan M. Hoberman ◽  
Mildred S. Christian ◽  
Robert M. Diener ◽  
...  
Keyword(s):  
Body Weight ◽  
Corn Oil ◽  
Developmental Toxicity ◽  
Clinical Signs ◽  
Lumbar Vertebrae ◽  
Feed Consumption ◽  
Exposure Level ◽  
Dosage Group ◽  
Sprague Dawley ◽  
Metatarsal Bones

Dihydromyrcenol, a widely used fragrance ingredient, was evaluated for developmental toxicity in pregnant Sprague-Dawley rats (25/group). Oral dosages of 0, 250, 500, or 1000 mg/kg/d in corn oil were administered on gestational days 7 to 17. Rats were observed for viability, clinical signs, body weights, and feed consumption. Caesarean sectioning and necropsy occurred on gestational day 21. Fetuses were weighed and examined for sex, gross external changes, and soft tissue or skeletal alterations. All rats survived until scheduled termination. No clinical signs were attributed to dihydromyrcenol. There were no gross tissue changes at necropsy. The 1000-mg/kg/d dosage group had reduced mean maternal body weight gains of 5% compared with controls, whereas absolute and relative feed consumption were significantly reduced during the dosage period. This threshold systemic maternal toxicity was associated with threshold developmental toxicity in the 1000-mg/kg/d dosage group. Fetal effects included a minimal ∼3% reduction in fetal body weight; reversible variations in ossification, including retarded ossification of the metatarsal bones in the hindpaws; and an increase in supernumerary thoracic ribs with associated increases or decreases in thoracic and lumbar vertebrae, respectively. Based on these data, maternal and developmental no observable effect levels of 500 mg/kg/d and maternal and developmental no observable adverse effect levels of 1000 mg/kg/d were established for dihydromyrcenol. It was concluded that dihydromyrcenol is not a selective developmental toxicant in rats under the conditions of this study and that a margin of safety of 25 000 exists between reversible developmental delays in rats and the estimated daily human exposure level of 0.02 mg/kg/d.

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.

scholarly journals Evaluation of the Developmental Toxicity of 1-(1,2,3,4,5,6,7,8-Octahydro-2,3,8, 8-Tetramethyl-2-Naphthalenyl) Ethanone (OTNE) in Rats

2009 ◽  
Vol 28 (3) ◽  
pp. 213-218 ◽  
Author(s):  
Valerie T. Politano ◽  
Charlene S. Letizia ◽  
Mildred S. Christian ◽  
Robert M. Diener ◽  
Anne Marie Api
Keyword(s):  
Body Weight ◽  
Soft Tissue ◽  
Developmental Toxicity ◽  
Clinical Signs ◽  
Significant Degree ◽  
Feed Consumption ◽  
Exposure Level ◽  
Sprague Dawley ◽  
Body Weights ◽  
Weight Gains

The developmental toxicity of 1-(1,2,3,4,5,6,7,8-Octahydro-2,3,8,8-tetramethyl-2-naphthalenyl) ethanone (OTNE), a widely used fragrance ingredient, was evaluated in pregnant Sprague-Dawley rats (25/group) gavaged with dosages of 0 (water), 96, 240, or 480 mg/kg/d on days 7 through 17 of gestation (GDs 7–17). Rats were observed for clinical signs, abortions, premature deliveries, body weights, and feed intake. Caesarean section and necropsy were performed on GD 21. Fetuses were weighed and examined for gender, gross external changes, and soft tissue or skeletal alterations. No deaths or premature deliveries were attributed to OTNE. OTNE-related clinical signs included significantly increased incidences of excessive salivation in all 3 treatment groups, and urine-stained abdominal fur in the high dosage group. Mean body weight gains were significantly reduced by all OTNE dosages on GDs 7–10, while at 480 mg/kg/d, significant reductions continued through the remainder of the dosage period. Feed consumption generally paralleled body weight gains. Fetal body weights were reduced by 480 mg/kg/d, but not to a statistically significant degree. No fetal gross external, soft tissue, or skeletal malformations or variations were attributable to OTNE. Based on these data, maternal and developmental no-observable-adverse-effect-levels (NOAELs) of 240 mg/kg/d were established for OTNE. It was concluded that OTNE is not a developmental toxicant in rats under the conditions of this study, and that a margin of safety greater than 2700 exists between reversible developmental delays in rats and the calculated daily human exposure level of 0.086 mg/kg/d.

Evaluation of the Developmental Toxicity of Methyl Dihydrojasmonate (MDJ) in Rats

2008 ◽  
Vol 27 (3) ◽  
pp. 295-300 ◽  
Author(s):  
Valerie T. Politano ◽  
Elise M. Lewis ◽  
Alan M. Hoberman ◽  
Mildred S. Christian ◽  
Robert M. Diener ◽  
...  
Keyword(s):  
Body Weight ◽  
Soft Tissue ◽  
Corn Oil ◽  
Developmental Toxicity ◽  
Clinical Signs ◽  
Feed Consumption ◽  
Sprague Dawley ◽  
Body Weights ◽  
Adverse Effect Level ◽  
Sparse Hair

Methyl dihydrojasmonate (MDJ) is a widely used fragrance ingredient. MDJ was evaluated for developmental toxicity in presumed pregnant Sprague-Dawley rats (25/group) at oral dosages of 0, 40, 80 or 120 mg/kg/day in corn oil administered on gestational days 7–20. Dams were observed for viability, clinical signs, body weights, and feed consumption. Caesarean-sectioning and necropsy occurred on gestational day 21. Fetuses were weighed and examined for gender, gross external changes, and soft tissue or skeletal alterations. No maternal or fetal deaths occurred. MDJ-related maternal clinical signs included an increased incidence of sparse hair coat and ungroomed appearance at 120 mg/kg/day. Two dams in this group also had tan areas in the liver and a pale spleen. The 120 mg/kg/day dosage also caused reduced mean maternal body weight gains and body weights during the dosage period and reduced absolute and relative maternal feed consumption for the entire dosage period. No Caesarean-sectioning or litter parameters were affected by dosages of MDJ as high as 120 mg/kg/day, although at the highest dosage a tendency toward slightly reduced, but not statistically significant, fetal mean body weight was observed. No fetal gross external, soft tissue or skeletal changes were attributable to dosages of MDJ as high as 120 mg/kg/day. Based on these data, maternal No-Observable-Adverse-Effect-Level (NOAEL) of 80 and developmental NOAEL of equal to or greater than 120 mg/kg/day were established for MDJ. It is concluded that MDJ is not a developmental toxicant in rats under the conditions of this study.

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.

scholarly journals Evaluation of the Developmental Toxicity of Alpha-iso-methylionone in Rats

2007 ◽  
Vol 26 (3) ◽  
pp. 271-276 ◽  
Author(s):  
Valerie T. Politano ◽  
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 ◽  
Sprague Dawley Rats ◽  
Body Weights ◽  
Tissue Changes

Alpha-iso-methylionone, a widely used fragrance ingredient, was evaluated for developmental toxicity in presumed pregnant Sprague-Dawley rats (25/group). Oral dosages of 0, 3, 10, or 30 mg/kg/day alpha-iso-methylionone in corn oil 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. 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. No maternal or fetal deaths occurred. No fragrance ingredient–related clinical signs were observed. Feed consumption, body weight gains, gross tissue changes at necropsy, and caesarean section or litter parameters, as well as fetal developmental morphology, were unaffected by dosages of alpha-iso-methylionone as high as 30 mg/kg/day. Based on these data, maternal and developmental no observed adverse effect levels of equal to or greater than 30 mg/kg/day were established for alpha-iso-methylionone. It is concluded that alpha-iso-methylionone is not a developmental toxicant in rats at maternal doses of up to 30 mg/kg/day.

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 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.

Subchronic Toxicity and Developmental Toxicity Studies in Rats With Aquateric® Aqueous Enteric Coating

1999 ◽  
Vol 18 (2) ◽  
pp. 109-116 ◽  
Author(s):  
Lois A. Kotkoskie ◽  
Christine Freeman ◽  
Mark A. Palmieri
Keyword(s):  
Developmental Toxicity ◽  
Dose Range ◽  
Clinical Signs ◽  
Study Groups ◽  
Feed Consumption ◽  
Histological Evaluation ◽  
Sprague Dawley ◽  
Enteric Coating ◽  
Toxicological Effects ◽  
Sprague Dawley Rats

Studies were conducted to evaluate the subchronic and developmental toxicity of Aquateric® Aqueous Enteric Coating. Homogeneity and stability studies were conducted over a range of 5,000 to 50,000 ppm Aquateric in the diet. In the subchronic study, groups of Sprague-Dawley rats (20/sex/group) received 0 (control), 5,000, 25,000, or 50,000 ppm Aquateric in the diet for 90 consecutive days. No mortality, clinical signs of toxicity or adverse toxicological effects on hematology or serum chemistry parameters, body weights, feed consumption, ophthalmological examinations, or histological evaluation of tissues were noted in any treatment group. In the developmental toxicity study, groups of pregnant Sprague-Dawley rats (25/group) received 0 (control), 5,000, 25,000 or 50,000 ppm Aquateric in the diet on gestational days 6-15. No evidence of maternal toxicity or fetotoxicity or embryotoxicity was noted. The no observed adverse effect level (NOAEL) exceeds 50,000 ppm in the diet, which represents a dose range of approximately 3600 to 4100 mg/kg/day. The results of these studies demonstrate the low toxicity of Aquateric. The estimated human intake is approximately 4 mg/kg/day. Based on the NOAEL from the subchronic study of 3604 mg/kg/day, the margin of safety is 900.

scholarly journals Developmental Toxicity of Levo-Alpha-Acetylmethadol (LAAM) in Tolerant Rats

2002 ◽  
Vol 21 (2) ◽  
pp. 147-159 ◽  
Author(s):  
Raymond G. York ◽  
Kevin H. Denny ◽  
David E. Moody ◽  
Mario E. Alburges
Keyword(s):  
Body Weight ◽  
Body Weight Gain ◽  
Fetal Liver ◽  
Developmental Toxicity ◽  
Clinical Signs ◽  
Fetal Brain ◽  
Female Rats ◽  
Feed Consumption ◽  
Fetal Plasma ◽  
Range Finding

Mated Crl:CD VAF/Plus female rats, in a range-finding study ( n = 5–6 per dose) and a subsequent definitive study ( n = 30 per dose) were used to determine the developmental toxicity, including the teratogenic potential of levo-alpha-acetyhnethadol (LAAM) hydrochloride, in tolerant rats. Tolerance was induced by initially administering the drug by gavage (10 ml/kg) at 2 mg/kg/day and increasing the dose every 2 weeks for 12 weeks until the doses of 2, 6, 9, 12, and 15, or 2, 6, and 12 mg/kg/day were achieved in the range-finding or definitive study, respectively. Females were then mated to stock males and treated throughout mating and gestation. Controls received distilled water on a similar regimen. The range-finding experiment was used for initial clinical evaluations and to determine tissue concentrations of LAAM and metabolites. In plasma, liver, and brain collected from dams and fetuses pooled by litter on gestation day 20, LAAM and its two N-demethylated metabolites, norLAAM and dinorLAAM, showed dose-dependent increases in concentration and in tissue to plasma ratios. Tissue to dam plasma ratios were highest in dam liver (17–60), intermediate in fetal liver (3–16), and fetal brain (3–14), and lowest in dam brain (0.8–5.6) and fetal plasma (0.3–2.1). In the definitive study, caesarean section examinations were performed following euthanization on gestation day 20 on all surviving females followed by teratologic examination of the fetuses. Drug-related outcomes, including increased activity, secondary hair loss, scabbing, focal swelling, and material around the nose, were exhibited by all groups receiving LAAM. Maternal toxicity was evident as decreased body weights, with maximum reduction at the 6-mg/kg/day dose, and reduction in feed consumption. There was also evidence of developmental toxicity in the form of postimplantaüon losses at all doses of LAAM. There were no deaths attributable to LAAM. No grossly observable visceral or skeletal anomalies related to LAAM were observed in the fetuses. In conclusion, the no-observable-effect level when administered to tolerant rats was less than 2 mg/kg/day with regard to clinical signs, body weight, body weight gain, and feed consumption, and with regard to developmental toxicity as reflected by postimplantaüon losses. Despite maternal and developmental toxicity, there was no evidence of selective fetal toxicity or teratogenic activity attributable to LAAM.

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