NTP developmental and reproductive toxicity technical report on the modified one-generation study of 2-Ethylhexyl p-Methoxycinnamate (CASRN 5466-77-3) administered in feed to Sprague Dawley (Hsd:Sprague Dawley(r) sD(r)) rats with prenatal, reproductive performance, and subchronic assessments in f1\sOffspring
EHMC exposure did not induce any specific fetal malformations.SYNONYMS: octinoxate; ethylhexyl methoxycinnamate; octyl methoxycinnamate; 2-propenoic acid, 3-(4-methoxyphenyl)-, 2-ethylhexyl ester; 2-ethylhexyl 3-(4-methoxyphenyl)prop-2-enoate
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| Format: | eBook |
| Language: | English |
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Research Triangle Park, North Carolina, USA
National Toxicology Program, Public Health Service, U.S. Department of Health and Human Services
June 2022, 2022
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| Series: | DART report
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| Online Access: | |
| Collection: | National Center for Biotechnology Information - Collection details see MPG.ReNa |
| Summary: | EHMC exposure did not induce any specific fetal malformations.SYNONYMS: octinoxate; ethylhexyl methoxycinnamate; octyl methoxycinnamate; 2-propenoic acid, 3-(4-methoxyphenyl)-, 2-ethylhexyl ester; 2-ethylhexyl 3-(4-methoxyphenyl)prop-2-enoate The timing of weaning weight-adjusted vaginal opening (VO) and balanopreputial separation (BPS) was significantly delayed by approximately 2.1\sdays and 2.2\sdays, respectively, in the 6,000\sppm group. F1\srats exposed to 6,000\sppm EHMC displayed slightly more time in estrus. Reproductive performance (fertility and fecundity) was not affected by EHMC exposure. The numbers of live fetuses and pups were not affected. EHMC exposure was not associated with any effects on fetal weight or the incidences of external, visceral, or skeletal malformations. The 6,000\sppm group did exhibit a higher combined fetal incidence of lumbar\s1 rudimentary rib variants (approximately 10% versus 4% in the control group). In the subchronic cohort, no gross findings, changes in organ weights, or histopathological findings were attributed to EHMC exposure. Upon sexual maturity, F1\smating and pregnancy indices were evaluated. In the prenatal cohort, F2\sprenatal development (litter size, fetal weight, and morphology) was assessed on GD\s21. In the reproductive performance cohort, littering indices, F2\sviability, and growth were assessed until PND\s28. The likelihood of identifying potential EHMC-induced adverse effects (similarity and magnitude thereof) at any phase of growth or development was increased by examining related endpoints and multiple pups within a litter throughout life, across cohorts, and across generations. EHMC did not induce overt F0\sor F1\smaternal toxicity or affect mating or pregnancy indices. Dam feed consumption and body weights were slightly lower during lactation in the 6,000\sppm group. EHMC exposure at 6,000\sppm was associated with significantly decreased F1\sand F2\spreweaning mean body weights, with an onset at approximately PND\s13, consistent with the beginning of pup feed consumption. EHMC intake by F0\sfemales in the 1,000, 3,000, and 6,000\sppm EHMC groups, based on feed consumption and dietary concentrations from GD\s6 through GD\s21, was approximately 70, 207, and 419\smg/kg/day, respectively; from LD\s1 through LD\s13, EHMC intake was approximately 161, 475, and 920\smg/kg/day, respectively. EHMC intake by the F1\sgeneration postweaning (PND\s28 through PND\s91) in the 1,000, 3,000, and 6,000\sppm groups was approximately 80, 242, and 491\smg/kg/day (males) and 87, 263, and 528\smg/kg/day (females), respectively. EHMC intake by the adult F1\sfemales in the 1,000, 3,000, and 6,000\sppm groups was approximately 73, 220, and 435\smg/kg/day (GD\s0 through GD\s21) and 139, 418, and 842\smg/kg/day (LD\s1 through LD\s13), respectively. EHMC exposure did not alter anogenital distance or areola/nipple retention. Significantly decreased F1\spreweaning mean body weights were observed in males and females exposed to 3,000 or 6,000\sppm, whereas only F2\smale and female preweaning mean body weights of the 6,000\sppm group were significantly decreased relative to their respective control groups. Although mean body weight gains of males (PND\s28-105) and females (PND\s28-\s91) in all EHMC-exposed groups were similar to those of the respective control groups, postweaning F1\smale and female mean body weights of the 6,000\sppm group were significantly decreased by 5%-14% relative to the respective control animals. Both male and female mean body weights of the 3,000\sppm groups were significantly decreased by approximately 5% on PND\s28, but by PND\s56, their mean body weights were comparable to those of the control groups. Lower F1\spostweaning body weights were not associated with concurrent lower feed consumption. The dietary route of administration was selected to approximate continual exposure in group-housed animals. EHMC exposure via the diet, rather than topical application, was selected for this study to sustain internal exposure; if applied topically, the internal dose would have been influenced by intra- and interanimal grooming behavior. Exposure concentration selection for the MOG study was based on a dose range-finding study in which time-mated rats were exposed to 0, 2,250, 5,000, 10,000, or 20,000\sppm EHMC in the diet from gestation day (GD)\s6 through lactation day (LD)\s28. Dams exposed to 20,000\sppm displayed significantly decreased mean body weights on GD\s21 and body weight gain from GD\s6 through GD\s21. Dams exposed to 20,000\sppm displayed lower live litter size, and pups in this group displayed significantly decreased PND\s1 weights and lower postnatal viability resulting in the group being removed from study on postnatal day (PND)\s14. CONCLUSIONS: Under the conditions of this modified one-generation (MOG) study, there was no evidence of reproductive toxicity of 2-ethylhexyl p-methoxycinnamate (EHMC) in Hsd:Sprague Dawley(r) SD(r) rats at exposure concentrations of 1,000, 3,000, or 6,000\sppm. Mating and littering were not affected significantly by EHMC exposure. Under the conditions of this MOG study, there was equivocal evidence of developmental toxicity of EHMC in Hsd:Sprague Dawley(r) SD(r) rats based on the observed postnatal effects on body weight that showed some indication of recovery by study end, delays in postnatal day\s28-adjusted vaginal opening and balanopreputial separation, which could have been influenced by the apparent transient effects on body weight, and time in estrus was slightly longer in EHMC-exposed females relative to that of the control group. No other signals consistent with alterations in estrogenic, androgenic, or antiandrogenic action were observed. Pup body weights of the 10,000\sppm group were also lower than those in the control group. Therefore, exposure concentrations of 0, 1,000, 3,000, and 6,000\sppm were selected for the subsequent MOG study. Test article consumption was exposure concentration-proportional. EHMC intake for F0\sfemales in the 2,250, 5,000, 10,000, and 20,000\sppm groups, based on feed consumption and dietary concentrations for GD\s6 through GD\s21, was approximately 161, 365, 714, and 1,841\smg EHMC/kg body weight/day (mg/kg/day), respectively; from LD\s1 through LD\s14, EHMC intake was approximately 410, 925, and 1,615\smg/kg/day for the 2,250, 5,000, and 10,000\sppm groups, respectively.MODIFIED ONE-GENERATION STUDY: F0\sexposure began on GD\s6 and was continual. At weaning on PND\s28, F1\soffspring were assigned to the reproductive performance (up to 2/sex/litter, when available), prenatal (1/sex/litter), or subchronic cohort (1/sex from 10 litters). 2-Ethylhexyl p-methoxycinnamate (EHMC), also known as octinoxate and octyl methoxycinnamate, is a common component of sunscreens, cosmetics, and personal care products. Mechanistic screening studies have purported that EHMC, and its metabolites, are capable of activating the estrogen receptor to varying degrees. The objective of this study was to characterize the potential for EHMC to adversely affect any phase of rat development, maturation, and ability to reproduce. The potential for EHMC to induce subchronic toxicity in the F1\sgeneration, to adversely affect the ability of the F1\sgeneration to reproduce viable F2\soffspring, and to adversely affect the F2\sembryo-fetal development was assessed in Sprague Dawley (Hsd:Sprague Dawley(r) SD(r)) rats administered EHMC in 5K96 feed, a diet low in phytoestrogens, using the National Toxicology Program modified one-generation (MOG) study design. |
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| Physical Description: | 1 PDF file (various pagings) illustrations |