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.

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.

Subchronic Hepatotoxicity Evaluation of 1,2,4-Tribromobenzene in Sprague-Dawley Rats

2012 ◽  
Vol 31 (3) ◽  
pp. 250-256 ◽  
Author(s):  
Darol E. Dodd ◽  
Linda J. Pluta ◽  
Mark A. Sochaski ◽  
Kathleen A. Funk ◽  
Russell S. Thomas
Keyword(s):  
Adverse Effect ◽  
Body Weight ◽  
Exposure Time ◽  
Clinical Signs ◽  
Liver Weight ◽  
Sprague Dawley ◽  
Significant Incidence ◽  
Sprague Dawley Rats ◽  
Adverse Effect Level ◽  
Effect Level

Male Sprague-Dawley rats were exposed to 1,2,4-tribromobenzene (TBB) by gavage for 5 days, 2, 4, and 13 weeks at 0, 2.5, 5, 10, 25, or 75 mg/kg per d. There were no TBB exposure-related clinical signs of toxicity or changes in body weight. Liver weight increases were dose and exposure time related and statistically significant at ≥10 mg/kg per d. Incidence and severity of centrilobular cytoplasmic alteration and hepatocyte hypertrophy were dose and time related. The 75 mg/kg per d group had minimally increased mitoses within hepatocytes (5 days only). Hepatocyte vacuolation was observed (13 weeks) and was considered TBB exposure related at ≥25 mg/kg per d. Concentrations of blood TBB increased linearly with dose and at 13 weeks, ranged from 0.5 to 17 µg/mL (2.5-75 mg/kg per d). In conclusion, rats administered TBB doses of 10-75 mg/kg per d for 13 weeks had mild liver effects. A no observed adverse effect level of 5 mg/kg per d was selected based on the statistically significant incidence of hepatocyte hypertrophy at doses ≥10 mg/kg per d.

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.

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.

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.

Oral (Drinking Water) Developmental Toxicity Study of Ammonium Perchlorate in Sprague-Dawley Rats

2003 ◽  
Vol 22 (6) ◽  
pp. 453-464 ◽  
Author(s):  
Raymond G. York ◽  
Kathleen A. Funk ◽  
Michael F. Girard ◽  
David Mattie ◽  
Joan E. Strawson
Keyword(s):  
Drinking Water ◽  
Ammonium Perchlorate ◽  
Developmental Toxicity ◽  
Thyroid Stimulating Hormone ◽  
Toxicity Study ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Adverse Effect Level ◽  
Effect Level ◽  
Maternal Thyroid

A developmental toxicity study was conducted with ammonium perchlorate (AP) in the drinking water at doses of 0.0, 0.01, 0.1, 1.0, and 30.0 mg/kg-day beginning 14 days before cohabitation and continuing through sacrifice. Twenty-four rats/group were cesarean-sectioned on day of gestation (DG) 21 and fetuses examined for visceral and skeletal alterations. An additional 16 litters/group were sacrificed on DG 21 for maternal and fetal serum TSH, T3, and T4 (thyroid-stimulating hormone, triiodothyronine, and thyroxine) levels and thyroid histopathology. Clinical and necropsy observations, body weights, feed and water consumption, and cesarean-sectioning parameters were comparable among the groups with only delays in ossification observed in the 30 mg/kg-day group. Maternal thyroid weights were increased in the 30.0 mg/kg-day group. Decreased colloid was present in male and female fetal thyroids in the 1.0 and 30.0 mg/kg-day groups. Maternal TSH was increased and T4 was decreased at all levels, and T3 was reduced at 30.0 mg/kg-day. Fetal TSH was increased at 1.0 and 30.0 mg/kg-day, T4 was reduced at 30.0 mg/kg-day, and T3 was decreased at all levels. The maternal no-observable-adverse-effect level (NOAEL) was 1.0 mg/kg-day; exposures of 30.0 mg/kg-day increased absolute and relative maternal thyroid weights and histopathology findings. The developmental NOAEL was 1.0 mg/kg-day; developmental delays in ossification occurred in the 30.0 mg/kg-day group. The colloid depletion in the thyroids and increased TSH and decreased T3 and T4 levels at lower exposures were considered adaptive and not adverse. No adverse effects on development at occurred levels that did not cause maternal toxicity. AP is not a selective developmental toxicant.

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.

Studies of the Toxicological Potential of Capsinoids: IV. Teratology Studies of CH-19 Sweet Extract in Rats and Rabbits

2008 ◽  
Vol 27 (3_suppl) ◽  
pp. 41-57 ◽  
Author(s):  
Bruce K. Bernard ◽  
Eri Watanabe ◽  
Terutaka Kodama ◽  
Shoji Tsubuku ◽  
Akira Otabe ◽  
...  
Keyword(s):  
Body Weight ◽  
Sex Ratio ◽  
Food Consumption ◽  
Clinical Signs ◽  
Pathological Finding ◽  
High Dose ◽  
Corpora Lutea ◽  
Test Substance ◽  
Sprague Dawley ◽  
Adverse Effect Level

In order to evaluate the safety of CH-19 Sweet extract that contains capsinoids, teratology studies were conducted in pregnant Sprague-Dawley rats (20 rats per group) and pregnant New Zealand white rabbits (17 to 22 animals per group). The test substance was administered to rats by gavage for 11 days on gestation days 7 to 17 at doses of 0 (vehicle), 1.25, 2.5, and 5.0 ml/kg and to rabbits for 13 days on gestation days 6 to 18 at doses of 0 (vehicle), 0.25, 0.5, and 1.0 ml/kg. As the concentration of capsinoids in CH-19 Sweet extract was 72.2 to 75.05 mg/ml, the resulting dose of capsinoids administered to rats was 90.25, 180.5, and 361 mg/kg, and to rabbits was 18.76, 37.53, and 75.05 mg/kg in the vehicle, low-, mid-, and high-dose groups, respectively. In the rat study, no deaths occurred in any group and there were no test substance–related changes or abnormalities in clinical signs, body weight, food consumption, or gross pathological findings. There were no test substance–related changes in the number of corpora lutea, number or index of implantations, index of embryofetal deaths, number of live fetuses, sex ratio, fetal body weight at the end of the gestation period, or abnormalities in the placenta of live fetuses. There were no test substance–related abnormalities or variations in the external, skeletal, or visceral examinations of live fetuses. It was concluded that the test article caused neither teratogenic effects nor abnormalities in the progression of ossification. In the rabbit study, there were no test substance–related effects on clinical signs, body weight, food consumption, or necropsy findings. There were neither test substance–related abortions nor test substance–related effects on the number of corpora lutea, or number or index of implantations. There were no test substance–related effects on the number of dead embryos/fetuses, the number of live fetuses, sex ratio, body weight of live fetuses, or gross pathological finding in the placentas. There were no test substance–related external abnormalities or incidences of visceral or skeletal abnormalities or variations, and there were no test substance–related effects on the progress of ossification in any group. The authors concluded the no observed adverse effect level (NOAEL) of CH-19 Sweet extract containing capsinoids on pregnant animals and fetal development/growth was >5.0 ml/kg/day (>361 mg/kg/day as capsinoids) in rats and >1.0 ml/kg/day (>75.05 mg/kg/day as capsinoids) in rabbits.

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