NTP developmental and reproductive toxicity technical report on the modified one-generation study of 2-hydroxy-4-methoxybenzophenone (CASRN 131-57-7) administered in feed to Sprague Dawley (Hsd:Sprague Dawley(r) sD(r)) rats with prenatal and reproductive performance assessments in f1\soffspring / National Toxicology Program, Public Health Service, U.S. Department of Health and Human Services

2-Hydroxy-4-methoxybenzophenone (2H4MBP), also known as oxybenzone and benzophenone-3, is approved by the U.S. Food and Drug Administration for use in sunscreens and other personal care products in concentrations of <6%, either alone or in combination formulations, and as an indirect food additive in acrylic and modified acrylic plastics that come into contact with food. Mechanistic screening studies have shown that 2H4MBP and its metabolites are capable of activating the estrogen receptor and antagonizing the androgen receptor to varying degrees. The objective of the present study was to characterize the potential for 2H4MBP to adversely affect any phase of development, maturation, and ability to reproduce in Sprague Dawley (Hsd:Sprague Dawley(r) SD(r)) rats administered 2H4MBP in 5K96\sfeed, a diet low in phytoestrogens, using the National Toxicology Program (NTP) modified one-generation (MOG) study design. 2H4MBP exposure via 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 concentrations were based on a dose range-finding study that demonstrated 25,000\sppm 2H4MBP did not induce excessive maternal toxicity or affect parturition, litter size, or pup viability. 2H4MBP intake by F0\sfemales in the 3,000, 10,000, 25,000, and 50,000\sppm 2H4MBP groups, based on feed consumption and dietary concentrations from gestation day (GD)\s6 through GD\s21, was approximately 215, 695, 2,086, and 6,426\smg 2H4MBP/kg body weight/day (mg/kg/day), respectively; from lactation day (LD)\s1 through LD\s14, 2H4MBP intake was approximately 577, 1,858, 4,460, and 12,029\smg/kg/day, respectively. Exposure concentrations of 3,000, 10,000, and 30,000 ppm\swere selected for the subsequent MOG study; ethinyl estradiol (EE), a synthetic form of estrogen, was included at 0.05\sppm as a positive reference control.MODIFIED ONE-GENERATION STUDY: F0\sexposure began on GD\s6 and was continual. At weaning on postnatal day (PND)\s28, F1\soffspring were assigned to either reproductive performance (2/sex/litter), prenatal (1/sex/litter), or biological sampling (1/sex/litter) cohorts. 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 2H4MBP-induced adverse effects (similarity and magnitude thereof) at any phase of growth or development was increased by examining related endpoints in multiple pups within a litter throughout life, across cohorts, and across generations. 2H4MBP exposure at the tested concentrations did not induce any effects on mating or pregnancy indices. In the prenatal cohort, exposure to 30,000\sppm was associated with a slight but significant decrease in the mean numbers of corpora lutea and F2\simplants and a slightly lower number of live fetuses on GD\s21 than in the control group. In the reproductive performance cohort, total F2\smean litter size on PND\s0 was also significantly decreased compared to the control group. 2H4MBP exposure might have affected litter size, although the effect was small in magnitude. Collectively, given the minimal apparent response that may or may not be a direct effect of 2H4MBP, this was considered equivocal evidence of an adverse effect on reproductive performance. EE exposure did not affect F1\slive litter size on PND\s0, but significantly decreased mean number of corpora lutea and total F2\simplants were observed. 2H4MBP was associated with lower F1\sand F2\spreweaning and F1\spostweaning mean body weights. At 30,000\sppm 2H4MBP, preweaning F1\smean body weights of both males and females were progressively lower over time, relative to their respective control groups. The response was lessened in F2\smales and even more so in F2\sfemales. The significantly decreased F1\spostweaning mean body weights were not associated with concurrent lower feed consumption. The effects on body weights associated with exposure to 2H4MBP were considered some evidence of developmental toxicity. 2H4MBP intake by F0 females in the 3,000, 10,000, and 30,000\sppm 2H4MBP groups, based on feed consumption and dietary concentrations from GD 6 through GD 21 was approximately 205, 697, and 2,644\smg/kg/day, respectively; from LD 1 through LD 13, 2H4MBP intake was approximately 484, 1,591, and 5,120\smg/kg/day, respectively. 2H4MBP intake by the F1 generation postweaning (PND 28 through PND 91) in the 3,000, 10,000, and 30,000\sppm groups was approximately 267, 948, and 3,003\smg/kg/day (males) and 287, 983, and 3,493\smg/kg/day (females), respectively. 2H4MBP intake by the adult F1 females in the 3,000, 10,000, and 30,000\sppm groups was approximately 240, 825, and 2,760\smg/kg/day (GD 0 through GD 21) and 426, 1,621, and 5,944\smg/kg/day (LD 1 through LD 13), respectively. Diaphragmatic hernias were observed at a low incidence in 2H4MBP-exposed animals in both the F1\sand F2\sgenerations but were not observed in any control animals. Most of the diaphragmatic hernias were associated histologically with hepatodiaphragmatic hernias. Low incidences of diaphragmatic and hepatodiaphragmatic hernias have been reported in control groups in other NTP MOG studies. Therefore, it is unclear whether the occurrences of diaphragmatic and hepatodiaphragmatic hernias in both the F1\sand F2\sgenerations were related to 2H4MBP exposure. 2H4MBP did not alter estrogen or androgen-mediated developmental markers, and no gross lesions were observed at adult necropsy consistent with perturbation of normal estrogen receptor- or androgen-receptor-mediated development. Expected estrogenic responses were observed in the EE group. In the 30,000\sppm group, adult weights of male androgen-dependent reproductive tissues were slightly lower than those of the control males, likely secondary to the apparent growth retardation, and occurred in the absence of histopathological findings. Sperm and spermatid counts were not affected by 2H4MBP exposure. The ability of F1\smales in either cohort to successfully mate, resulting in pregnancy, also was not affected. Unlike findings reported for in vitro cell models, 2H4MBP had no apparent effect on estrogen receptor- or androgen-receptor-dependent processes, nor did it affect mating or pregnancy indices. 2H4MBP exposure in F1\srats was associated with significantly increased kidney weights, renal tubule epithelial regeneration, interstitial chronic active inflammation, renal tubule and pelvic concretions, renal tubule dilation, papillary necrosis, urothelial hyperplasia, and urothelial ulcers. F1\sfemales also displayed renal tubule epithelial degeneration, pelvic dilation, chronic progressive nephropathy, and mineralization. 2H4MBP-exposed F1\smales and females displayed significantly increased liver weights relative to their respective control groups. The absolute weight of the adrenal glands was significantly decreased in the 30,000\sppm female group relative to the control group in the reproductive performance cohort. Several other decreases in organ weights were not associated with histological correlates and were considered related to changes in body weights. F2\sfetal findings of hydronephrosis of the kidney and enlarged liver were observed in the 30,000\sppm group. F2\soffspring in the 30,000\sppm group exhibited dilation of the renal pelvis. The observed fetal, PND\s28, and adult necropsy findings were consistent with previously reported studies that identified the kidney and liver as target tissues of 2H4MBP-mediated toxicity. CONCLUSIONS: Under the conditions of this modified one-generation (MOG) study, there was equivocal evidence of reproductive toxicity of 2-hydroxy-4-methoxybenzophenone (2H4MBP) in Hsd:Sprague Dawley(r) SD(r) rats based on a decrease in F2\slitter size in both the prenatal and reproductive performance cohorts. Under the conditions of this MOG study, there was some evidence of developmental toxicity of 2H4MBP in Hsd:Sprague Dawley(r) SD(r) rats based on the observed postnatal growth retardation. The relationship of the increased occurrence of diaphragmatic and hepatodiaphragmatic hernias in F1\sadults and F2\spups to 2H4MBP exposure is unclear..

Exposure to 2H4MBP was not associated with signals consistent with alterations in estrogenic, androgenic, or antiandrogenic action. Exposure to 2H4MBP was associated with lower F1\sand F2\smean body weights; this effect on body weight contributed to the apparent 2H4MBP-related decreases in male reproductive organ weights. Mating and littering were not significantly affected by 2H4MBP exposure. Exposure to 2H4MBP was associated with nonneoplastic kidney lesions in the F0, F1, and F2\sgenerations. Expected estrogenic responses were observed in the EE\sgroup.SYNONYMS: benzophenone-3; (2-hydroxy-4-methoxyphenyl)-phenylmethanoneoxybenzone; oxybenzone..

Medienart:	E-Book

Erscheinungsjahr:	June 2022
Erschienen:	Research Triangle Park, North Carolina, USA: National Toxicology Program, Public Health Service, U.S. Department of Health and Human Services ; June 2022

Reihe:	DART report - 05

Sprache:	Englisch

Links:	www.ncbi.nlm.nih.gov [teilw. kostenfrei]

Themen:	Benzophenones Embryonic Development Mice Rats, Sprague-Dawley Reproduction Sunscreening Agents Technical Report Toxicity Tests

Anmerkungen:	Includes bibliographical references. - Description based on online resource; title from PDF title page (viewed December 29, 2022)

Umfang:	1 online resource (1 PDF file (various pagings)) ; illustrations.

Förderinstitution / Projekttitel:

PPN (Katalog-ID):	1830419382