A Two-Generation Reproductive Toxicity Study of Butyl Benzyl Phthalate in Rats

Aso, Sunao; Ehara, Hatsune; Miyata, Katsumi; Hosyuyama, Satsuki; Shiraishi, Keiji; Umano, Takaaki; Minobe, Yasusi

doi:10.2131/jts.30.s39

Cited by 26 publications

(17 citation statements)

References 28 publications

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“…Other authors have reported changes in the time of vaginal opening by prenatal plus prepubertal exposure to BBP by administration to the mothers of 1g/L in drinking water [27], as well as modifications in the anogenital distance of rats exposed prenatally by oral gavage to the pregnant dams with 100 mg BBP/kg body weight [28]. Another indicator of sexual maturity is the morphological and cellular changes of mammary gland.…”

Section: Discussionmentioning

confidence: 99%

In utero exposure to butyl benzyl phthalate induces modifications in the morphology and the gene expression profile of the mammary gland: an experimental study in rats

et al. 2011

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BackgroundEnvironmental estrogens are exogenous estrogen-mimicking compounds that can interfere with endogenous endocrine systems. Several of these endocrine disruptors have been shown to alter normal development and influence tumorigenesis in experimental models. N-butyl benzyl phthalate (BBP), a widely used plasticizer, is a well-known endocrine disruptor. The aim of this study was to elucidate the effect of prenatal exposure to BBP on the morphology, proliferative index, and genomic signature of the rat mammary gland at different ages.MethodsIn utero exposure was performed by gavage of pregnant Sprague Dawley CD rats with 120mg or 500mg BBP/kg/day from day 10 post-conception to delivery. Female litters were euthanized at 21, 35, 50 and 100 days. The morphology and proliferative index of the mammary gland were studied from whole mount preparations and BrdU incorporation, respectively. Gene expression profile was assessed by microarrays. Several genes found differentially expressed and related to different functional categories were further validated by real time RT-PCR.ResultsPrenatal exposure of BBP induced delayed vaginal opening and changes in the post-natal mammary gland long after the end of the treatment, mainly by 35 days of age. Exposure to the high dose resulted in modifications in architecture and proliferative index of the mammary gland, mostly affecting the undifferentiated terminal end buds. Moreover, the expression profiles of this gland in the exposed rats were modified in a dose-dependent fashion. Analysis of functional categories showed that modified genes were related to immune function, cell signaling, proliferation and differentiation, or metabolism.ConclusionsOur data suggest that in utero exposure to BBP induced a delayed pubertal onset and modified morphology of the mammary gland. These alterations were accompanied by modifications in gene expression previously associated with an increased susceptibility to carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

In utero exposure to butyl benzyl phthalate induces modifications in the morphology and the gene expression profile of the mammary gland: an experimental study in rats

et al. 2011

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“…It is important to note that these studies did not consider litter effects, meaning their results may be affected by similarities between animals from the same litter. Other studies reported no change in the onset of sexual maturity using oral doses from 20 to 500 mg/kg/d in Sprague–Dawley rats (Aso et al, 2005; Nagao et al, 2000). The reasons for the contradictory results in these studies are difficult to resolve.…”

Section: Animal Studiesmentioning

confidence: 94%

“…Further, decreased ovarian weights were found in 500 mg/kg/d treated Sprague–Dawley rats (Nagao et al, 2000). BBP exposure (200 mg/kg/d orally) also decreased uterine weights in treated Sprague–Dawley rats (Aso et al, 2005). …”

Section: Animal Studiesmentioning

confidence: 98%

Reproductive and developmental effects of phthalate diesters in females

Kay

Chambers

Foster

2013

Critical Reviews in Toxicology

275

176

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Phthalate diesters, widely used in flexible plastics and consumer products, have become prevalent contaminants in the environment. Human exposure is ubiquitous and higher phthalate metabolite concentrations documented in patients using medications with phthalate-containing slow release capsules raises concerns for potential health effects. Furthermore, animal studies suggest that phthalate exposure can modulate circulating hormone concentrations and thus may be able to adversely affect reproductive physiology and the development of estrogen sensitive target tissues. Therefore, we conducted a systematic review of the epidemiological and experimental animal literature examining the relationship between phthalate exposure and adverse female reproductive health outcomes. The epidemiological literature is sparse for most outcomes studied and plagued by small sample size, methodological weaknesses, and thus fails to support a conclusion of an adverse effect of phthalate exposure. Despite a paucity of experimental animal studies for several phthalates, we conclude that there is sufficient evidence to suggest that phthalates are reproductive toxicants. However, we note that the concentrations needed to induce adverse health effects are high compared to the concentrations measured in contemporary human biomonitoring studies. We propose that the current patchwork of studies, potential for additive effects and evidence of adverse effects of phthalate exposure in subsequent generations and at lower concentrations than in the parental generation support the need for further study.

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“…ECHA combined the LOAELs of 100 mg BBP/kg bw per day from the studies of Aso et al. () and Ahmad et al. (), and the NOAEL of 100 mg BBP/kg bw per day from the study of Nagao et al.…”

Section: Hazard Identification and Characterisationmentioning

confidence: 99%

Update of the risk assessment of di‐butylphthalate (DBP), butyl‐benzyl‐phthalate (BBP), bis(2‐ethylhexyl)phthalate (DEHP), di‐isononylphthalate (DINP) and di‐isodecylphthalate (DIDP) for use in food contact materials

Silano¹,

Baviera²,

Bolognesi³

et al. 2019

EFS2

110

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The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP Panel) was asked by the European Commission to update its 2005 risk assessments of di-butylphthalate (DBP), butylbenzyl-phthalate (BBP), bis(2-ethylhexyl)phthalate (DEHP), di-isononylphthalate (DINP) and diisodecylphthalate (DIDP), which are authorised for use in plastic food contact material (FCM). Dietary exposure estimates (mean and high (P95)) were obtained by combining literature occurrence data with consumption data from the EFSA Comprehensive Database. The highest exposure was found for DINP, ranging from 0.2 to 4.3 and from 0.4 to 7.0 lg/kg body weight (bw) per day for mean and high consumers, respectively. There was not enough information to draw conclusions on how much migration from plastic FCM contributes to dietary exposure to phthalates. The review of the toxicological data focused mainly on reproductive effects. The CEP Panel derived the same critical effects and individual tolerable daily intakes (TDIs) (mg/kg bw per day) as in 2005 for all the phthalates, i.e. reproductive effects for DBP (0.01), BBP (0.5), DEHP (0.05), and liver effects for DINP and DIDP (0.15 each). Based on a plausible common mechanism (i.e. reduction in fetal testosterone) underlying the reproductive effects of DEHP, DBP and BBP, the Panel considered it appropriate to establish a group-TDI for these phthalates, taking DEHP as index compound as a basis for introducing relative potency factors. The Panel noted that DINP also affected fetal testosterone levels at doses around threefold higher than liver effects and therefore considered it conservative to include it within the group-TDI which was established to be 50 lg/kg bw per day, expressed as DEHP equivalents. The aggregated dietary exposure for DBP, BBP, DEHP and DINP was estimated to be 0.9-7.2 and 1.6-11.7 lg/kg bw per day for mean and high consumers, respectively, thus contributing up to 23% of the group-TDI in the worst-case scenario. For DIDP, not included in the group-TDI, dietary exposure was estimated to be always below 0.1 lg/kg bw per day and therefore far below the TDI of 150 lg/kg bw per day. This assessment covers European consumers of any age, including the most sensitive groups. Based on the limited scope of the mandate and the uncertainties identified, the Panel considered that the current assessment of the five phthalates, individually and collectively, should be on a temporary basis. ):5838 related chronic hepatic and renal effects in rats was identified. An uncertainty factor of 100 was applied for deriving the TDI of 0.15 mg/kg bw per day for DINP.-For DIDP, a NOAEL of 15 mg DIDP/kg bw per day for liver effects in dogs wasidentified. An uncertainty factor of 100 was applied for deriving the TDI of 0.15 mg/kg bw per day for DIDP. 1 ECHA (2017a) used a factor of 3 (total UF 300) for the extrapolation from LOAEL to NAEL.The CEP Panel considers that the effect on the liver is still the most sensitive endpoint for these two phthalates. However, the possibility to establish HBGVs for re...

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A Two-Generation Reproductive Toxicity Study of Butyl Benzyl Phthalate in Rats

Cited by 26 publications

References 28 publications

In utero exposure to butyl benzyl phthalate induces modifications in the morphology and the gene expression profile of the mammary gland: an experimental study in rats

In utero exposure to butyl benzyl phthalate induces modifications in the morphology and the gene expression profile of the mammary gland: an experimental study in rats

Reproductive and developmental effects of phthalate diesters in females

Update of the risk assessment of di‐butylphthalate (DBP), butyl‐benzyl‐phthalate (BBP), bis(2‐ethylhexyl)phthalate (DEHP), di‐isononylphthalate (DINP) and di‐isodecylphthalate (DIDP) for use in food contact materials

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