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Reproductive toxicity of isobornyl acetate (IA), a widely used fragrance ingredient, was investigated in a 1-generation reproduction study in which 25 Crl: CD (Sprague-Dawley) rats/sex/group were gavaged with dosages of 0 (corn oil vehicle), 30, 100, or 300 mg/kg/d during premating, mating, gestation, and lactation. After weaning, 25 F1 generation pups/sex/dosage group were randomly selected for evaluation until sexual maturity. The following parameters were evaluated in P generation males and females: viability, clinical signs, body weights, feed consumption, mating and fertility, organ weights, gross and microscopic observations, sperm assessments (motility and concentration), natural delivery and litter observations, and ovarian follicle counts. In F1 generation pups, viability, body weights, sexual maturation, anogenital distance (days 1 and 22 postpartum), nipple eruption (day 12 postpartum), and gross necropsy observations were recorded. Isobornyl acetate did not adversely affect any of the investigated parameters. Based on the results of this investigation, the no observable adverse effect level (NOAEL) for toxicity of IA is considered to be 300 mg/kg/d. Increased incidences of excess salivation occurred in P generation male and female rats at 100 and/or 300 mg/kg/d throughout the dosage period, and low incidences of urine-stained abdominal fur were seen in females at 300 mg/kg/d during the gestation period. These clinical signs were not considered as adverse effects of IA administration. Thus, the NOAEL for reproductive toxicity in the P generation rats and the NOAEL for viability and growth of the F1 generation offspring is considered to be ≥300 mg/kg/d. [ABSTRACT FROM AUTHOR]

The estrogenic potential of lavender oil was evaluated in a percutaneous uterotrophic bioassay in immature female rats. Four groups of 10 immature female rats each were randomly selected on postpartum day (PPD) 16. During the 3-day treatment period (PPDs 19-21), the immature rats were separated from the dams, caged in groups of 5 in a litter box for 6 hours, and administered the vehicle control article (corn oil) or lavender oil at 20 or 100 mg/kg per day. All dosages were administered as a 5 mL/kg volume in a Hilltop Chamber (25 mm diameter; absorbent material removed) placed on the shaved back of each immature rat, and secured with micropore tape and Vetrap. A positive control group was gavaged twice daily with 2.5 μg/kg per day of 17α-ethinyl estradiol. Daily observations included viability, clinical signs, body weights, and body weight gains. All rats were euthanized 24 hours after the third and final treatment, the uteri and ovaries were removed, and the paired ovaries and wet and blotted uterine weights were recorded. No unscheduled deaths occurred. No skin reactions were observed. Both dosages of lavender oil significantly reduced body weight gains after the third day of treatment, but terminal body weights and mean absolute and relative uterine weights did not differ significantly from vehicle control values. Positive controls showed significant increases in body weight and increased mean absolute and relative uterine weights as expected. Based on these data, lavender oil, at dosages of 20 or 100 mg/kg, was not active in the rat uterotrophic assay and gave no evidence of estrogenic activity. [ABSTRACT FROM AUTHOR]

The fragrance ingredient 4-tert-butylcyclohexyl acetate (4-tBCHA) was evaluated for potential developmental toxicity in pregnant rats at oral dosages of 0, 40, 160, or 640 mg/kg per d in corn oil on gestational days 7 to 20. Increased salivation was observed at 160 and 640 mg/kg per d. The 640 mg/kg per d dosage was associated with the presence of a red perioral substance, ungroomed, sparse hair coat on the limbs, localized alopecia, reduced feed and body weight gains, or body weight losses, and mortality. Fetal body weights also were reduced at 640 mg/kg per d. This effect was associated with transient delays in fetal development, including significant increases in fetal incidences of moderate enlargement of the renal pelvis and reversible delays in ossification of the caudal vertebrae, fore and hind limb phalanges, and hind limb metatarsals. Maternal and developmental no observable adverse effect levels (NOAELs) were 160 mg/kg per d. It was concluded that 4-tBCHA is not a developmental toxicant in rats. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]