Reproductive toxicity evaluation of dietary butyl benzyl phthalate (BBP) in rats

Tyl, Rochelle W.; Myers, Christina; Marr, Melissa C.; Fail, Patricia A.; Seely, John C.; Brine, Dolores R.; Barter, R. A.; Butala, John H.

doi:10.1016/j.reprotox.2003.10.006

Cited by 135 publications

(103 citation statements)

References 55 publications

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“…One of the possible interpretations is that 2,4-DCP might alter endogenous sex hormone concentrations by a specific mechanism through which the estrogenic phenotype appears in treated animals. Steroidogenic enzymatic mechanisms have indeed been suggested to be implicated in endocrine disruption by certain phthalates and/ or azole fungicides (Ema et al, 1998;Ema and Miyawaki, 2002;Gray et al, 1997;Tyl et al, 2004). However, the present study failed to show any changes in serum concentrations of pituitary or sex steroid hormones in the treated females at necropsy after weaning of their offspring.…”

Section: Vol 30 Special Issuecontrasting

confidence: 80%

A Two-Generation Reproductive Toxicity Study of 2,4-Dichlorophenol in Rats

Aoyama¹,

Hojo²,

Takahashi³

et al. 2005

J. Toxicol. Sci.

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-A two-generation reproductive toxicity study was conducted with 2,4-dichlorophenol (2,4-DCP), an agent suspected of exerting endocrine disrupting effects. Wistar-Hannover rats, 24/sex/ group, were given diet containing 2,4-DCP at dose levels of 0, 500, 2000 or 8000 ppm to examine the potential effects of the test substance on parental animals and their offspring over 2 successive generations. Neither clear systemic nor reproductive toxicity of 2,4-DCP was apparent in the 500 ppm group. In the 2000 ppm group, mean body weight gain and food consumption of females were lowered significantly during the treatment period. Effects on body weights and food consumption were more serious in the 8000 ppm group, both males and females being significantly affected. Reproductive effects of the test substance were also observed in the 2000 and 8000 ppm groups dose-dependently. Observations included significantly increased uterine weights of F1 and/or F2 female weanlings and reduced numbers of implantation sites and live births of F1 parental females. These results suggest that 2,4-DCP has weak reproductive toxicity, possibly based on endocrine activity. However, the basic mechanisms for apparent estrogenic effects of 2,4-DCP remain to be elucidated.

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Section: Vol 30 Special Issuecontrasting

confidence: 80%

A Two-Generation Reproductive Toxicity Study of 2,4-Dichlorophenol in Rats

Aoyama¹,

Hojo²,

Takahashi³

et al. 2005

J. Toxicol. Sci.

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“…DnBP and BBzP produce a number of reproductive abnormalities like malformations of the epididymis and the external genitalia (hypospadias), undescended testicles (cryptorchidism), impaired spermatogenesis and a general reduction of male fertility (Wine et al, 1997;Mylchreest et al, 2000). DnBP and BBzP cause signs of feminization (retention of nipples/areolae in male rodents) and a reduced anogenital distance (AGD) as a first indication of general demasculinization (Lee et al, 2004;Tyl et al, 2004;Foster, 2006). On a cellular level, both phthalates lead to decreased fetal testicular levels of testosterone and insulinlike factor 3 (Insl3) and to increased serum levels of the follicle-stimulating hormone (FSH) (Nagao et al, 2000;Wilson et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…The TDI for BBzP was set at 500 mg/kg bw/day based on the end points testicular toxicity and reduction of the AGD (Tyl et al, 2004;EFSA, 2005b). The Reference Dose (RfD) of the US EPA for DnBP of 100 mg/kg bw/day (Smith, 1953;EPA, 1990) and for BBzP of 200 mg/kg bw/day (NTP, 1985;EPA, 1993) have not yet been updated with the most recent science.…”

Section: Introductionmentioning

confidence: 99%

Di-n-butylphthalate and butylbenzylphthalate — urinary metabolite levels and estimated daily intakes: pilot study for the German Environmental Survey on children

Koch

Becker

Wittassek

et al. 2006

J Expo Sci Environ Epidemiol

140

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We analysed urine samples from the 2001/2002 pilot study of the German Environmental Survey on Children (GerES IV) for the concentrations of the di-n-butylphthalate (DnBP) metabolite mono-n-butylphthalate (MnBP) and the butlybenzylphthalate (BBzP) metabolite mono-benzyl-phthalate (MBzP). The study population consisted of 239 children (106 boys, 133 girls) aged between 2 and 14 years (median 8.5 years). We applied two calculation models to estimate the daily intake for the two parent phthalates from metabolite excretion. One was based on the creatinine-related metabolite concentrations; the other was based on the volume-related metabolite concentrations. Median urinary metabolite concentrations were 174 mg/l (136 mg/g creatinine) for MnBP and 19.7 mg/l (15.3 mg/g creatinine) for MBzP. Such levels have been determined in German children before. Compared to the USA, German median MnBP levels were about 3-10 times higher, whereas MBzP levels were in the same range. Median daily intakes calculated with the creatinine-based model were 4.07 (range: 0.66-76.4; 95th percentile: 14.9) mg/kg body weight (bw)/day for DnBP and 0.42 (range: 0.06-13.9; 95th percentile: 2.57) mg/kg bw/day for BBzP. Daily intakes calculated with the volume-based model were approximately two times higher with a median of 7.61 (range: 0.91-110; 95th percentile: 30.5) mg/kg bw/day for DnBP and a median of 0.77 (range: 0.05-31.3; 95th percentile: 4.48) mg/kg bw/day for BBzP. Using the creatinine model, 28 (11.7%) of the 239 children exceeded the TDI for DnBP of 10 mg/kg bw/day defined by the European Union. Employing the volume model, 89 (37.2%) children exceeded the TDI. For BBzP, no preventive limit values (TDI or RfD) were exceeded. For both phthalates and independent of the model, we found increasing daily intakes with decreasing age. Between 25% (creatinine model) and 50% (volume model) of the 2-4-year old children had daily intakes for DnBP above the TDI.

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“…However, already at the low and mid dose a decrease in epididymis weight in the F1 was noted, as well as a decreased anogenital distance. An earlier multi-generation study (Tyl et al, 2004) showed missing testes in one F2 male pup at the study LEL whereas no testes effects were observed in other generations. At the high dose mating and fertility effects were noted in the P1 as well as a decreased litter size in the F2, both of which were not noted in the P0/F1 generation.…”

Section: Bbpmentioning

confidence: 68%