Subacute oral toxicity study of diethylphthalate based on the draft protocol for “Enhanced OECD Test Guideline no. 407”

Shiraishi, Keiji; Miyata, Katusi; Houshuyama, Satsuki; Imatanaka, Nobuya; Umano, Takaaki; Minobe, Yasushi; Yamasaki, Kanji

doi:10.1007/s00204-005-0008-6

Cited by 10 publications

(17 citation statements)

References 23 publications

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“…In addition, serum and testicular testosterone levels were statistically significantly decreased in young rats exposed to DEP for 7 days ( Oishi and Hiraga 1980 ), although this data was presented as a percentage of control without a measure of variance and is considered low confidence . In contrast to other findings, no effect on serum testosterone or gonadotropin levels was observed in a high confidence study in Wistar rats following exposures up to 1000 mg/kg-day DEP for 28 days ( Shiraishi et al 2006 ), although those authors did observe a statistically significant decrease in serum estradiol for males in the 1000 mg/kg-day dose group. No effects on serum testosterone were observed in a medium confidence study in Swiss albino mice following exposures up to 10 mg/kg-day in diet for 3 months ( Mondal et al 2019 ).…”

Section: Resultscontrasting

confidence: 70%

“…The medium confidence study by Mondal et al (2019) reported a statistically significant decrease in epididymal sperm count, motility, and viability and increased sperm morphological abnormalities in adult mice dosed with 1 or 10 mg/kg-day for three months, and provided supporting mechanistic evidence demonstrating oxidative stress in germ cells and apoptosis in testicular sections. Conversely, the medium confidence study by Shiraishi et al (2006) reported no effects on epididymal sperm counts or morphology in adult rats following 28-day DEP exposure at doses up to 1000 mg/kg-day, although the authors provided no quantitative data. Although effects varied across studies, alterations in sperm quality were observed across most studies including three considered high confidence , and therefore the evidence for effects on sperm parameters is considered moderate.…”

Section: Resultsmentioning

confidence: 97%

“…The remaining studies evaluated rats or mice following peripubertal or adult exposure. Oishi and Hiraga (1980) , Mondal et al (2019) , and Jones et al (1993) focused on male reproductive effects (testosterone, sperm parameters, and/or testicular histology), and Shiraishi et al (2006) evaluated reproductive effects in both male and female rats including hormone levels, sperm parameters, and estrous cyclicity. Kwack et al (2010) and Kwack et al (2009) evaluated general toxicity (organ weights, serum biochemistry, urinalysis) in DEP- and MEP-exposed rats, with a sperm evaluation also conducted in Kwack et al (2009) .…”

Section: Resultsmentioning

confidence: 99%

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Hazards of diethyl phthalate (DEP) exposure: A systematic review of animal toxicology studies

Weaver

Beverly

Keshava

et al. 2020

Environment International

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Background: Diethyl phthalate (DEP) is widely used in many commercially available products including plastics and personal care products. DEP has generally not been found to share the antiandrogenic mode of action that is common among other types of phthalates, but there is emerging evidence that DEP may be associated with other types of health effects. Objective: To inform chemical risk assessment, we performed a systematic review to identify and characterize outcomes within six broad hazard categories (male reproductive, female reproductive, developmental, liver, kidney, and cancer) following exposure of nonhuman mammalian animals to DEP or its primary metabolite, monoethyl phthalate (MEP). Methods: A literature search was conducted in online scientific databases (PubMed, Web of Science, Toxline, Toxcenter) and Toxic Substances Control Act Submissions, augmented by review of online regulatory sources as well as forward and backward searches. Studies were selected for inclusion using PECO (Population, Exposure, Comparator, Outcome) criteria. Studies were evaluated using criteria defined a priori for reporting quality, risk of bias, and sensitivity using a domain-based approach. Evidence was synthesized by outcome and life stage of exposure, and strength of evidence was summarized into categories of robust , moderate , slight , indeterminate , or compelling evidence of no effect , using a structured framework. Results: Thirty-four experimental studies in animals were included in this analysis. Although no effects on androgen-dependent male reproductive development were observed following gestational exposure to DEP, there was evidence including effects on sperm following peripubertal and adult exposures, and the overall evidence for male reproductive effects was considered moderate . There was moderate evidence that DEP exposure can lead to developmental effects, with the major effect being reduced postnatal growth following gestational or early postnatal exposure; this generally occurred at doses associated with maternal effects, consistent with the observation that DEP is not a potent developmental toxicant. The evidence for liver effects was considered moderate based on consistent changes in relative liver weight at higher dose levels; histopathological and biochemical changes indicative of hepatic effects were also observed, but primarily in studies that had significant concerns for risk of bias and sensitivity. The evidence for female reproductive effects was considered slight based on few reports of statistically significant effects on maternal body weight gain, organ weight changes, and pregnancy outcomes. Evidence for cancer and effects on kidney were judged to be...

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Section: Resultscontrasting

confidence: 70%

Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

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Hazards of diethyl phthalate (DEP) exposure: A systematic review of animal toxicology studies

Weaver

Beverly

Keshava

et al. 2020

Environment International

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“…In a study investigating MPB exposure and estrogenic effects, MPB was administered by oral gavage from PND 21 to 40 in oral doses ranging from 62.5 to 1,000 mg/kg/day ( Vo et al 2010 ). In another investigation of DEP exposure and endocrine-mediated properties, the chemical was administered by oral gavage for 28 days in doses ranging from 40 to 1,000 mg/kg/day ( Shiraishi et al 2006 ). In most cases, the lowest doses far exceeded the highest doses (0.25 mg/kg/day for triclosan, 5.25 mg/kg/day for MPB, 8.675 mg/kg/day for DEP) used in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, to evaluate risks or investigate the biological effects of environmental chemicals, it is critical to employ doses in animal experiments that are comparable to the human experience. However, the dose ranges used for DEP, MPB, and triclosan in animal studies have been wide and often orders of magnitude higher than humans are likely to encounter ( Shiraishi et al 2006 ; Stoker et al 2010 ; Vo et al 2010 ). On the basis of increasing evidence suggesting low-dose health effects of these chemicals, there is an urgent need for studies that utilize doses in the range of typical human exposure ( Birnbaum 2012 ; Casals-Casas and Desvergne 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Paired Serum and Urine Concentrations of Biomarkers of Diethyl Phthalate, Methyl Paraben, and Triclosan in Rats

Teitelbaum

Lambertini

et al. 2016

Environ Health Perspect

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BackgroundExposure to environmental chemicals, including phthalates and phenols such as parabens and triclosan, is ubiquitous within the U.S. general population.ObjectiveThis proof-of-concept rodent study examined the relationship between oral doses of three widely used personal care product ingredients [diethyl phthalate (DEP), methyl paraben (MPB), and triclosan] and urine and serum concentrations of their respective biomarkers.MethodsUsing female Sprague-Dawley rats, we carried out two rounds of experiments with oral gavage doses selected in accordance with no observed adverse effect levels (NOAELs) derived from previous studies: 1,735 (DEP), 1,050 (MPB), 50 (triclosan) mg/kg/day. Administered doses ranged from 0.005 to 173 mg/kg/day, 10–100,000 times below the NOAEL for each chemical. Controls for the MPB and triclosan experiments were animals treated with olive oil (vehicle) only; controls for the DEP serum experiments were animals treated with the lowest doses of MPB and triclosan. Doses were administered for 5 days with five rats in each treatment group. Urine and blood serum, collected on the last day of exposure, were analyzed for biomarkers. Relationships between oral dose and biomarker concentrations were assessed using linear regression.ResultsBiomarkers were detected in all control urine samples at parts-per-billion levels, suggesting a low endemic environmental exposure to the three chemicals that could not be controlled even with all of the precautionary measures undertaken. Among the exposed animals, urinary concentrations of all three biomarkers were orders of magnitude higher than those in serum. A consistently positive linear relationship between oral dose and urinary concentration was observed (R2 > 0.80); this relationship was inconsistent in serum.ConclusionsOur study highlights the importance of carefully considering the oral dose used in animal experiments and provides useful information in selecting doses for future studies.CitationTeitelbaum SL, Li Q, Lambertini L, Belpoggi F, Manservisi F, Falcioni L, Bua L, Silva MJ, Ye X, Calafat AM, Chen J. 2016. Paired serum and urine concentrations of biomarkers of diethyl phthalate, methyl paraben, and triclosan in rats. Environ Health Perspect 124:39–45; http://dx.doi.org/10.1289/ehp.1409586

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Repeated 28-day oral toxicity study of ketoconazole in rats based on the draft protocol for the “Enhanced OECD Test Guideline No. 407” to detect endocrine effects

et al. 2006

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We performed a 28-day repeated-dose toxicity study of ketoconazole, a widely used an antimycotic drug, based on the draft protocol of the "Enhanced OECD Test Guideline 407" (Enhanced TG407) to investigate whether ketoconazole has endocrine-mediated properties according to this assay. Seven-week-old SD rats were administered with ketoconazole daily by oral gavage at doses of 0, 6.25, 25 or 100 mg kg(-1) day(-1) for at least 28 days. The ketoconazole-treated male rats showed reduction of epididymis and accessory sex organ weights, spermatid retention in the seminiferous tubules, decrease of testosterone and increases of estradiol, luteinizing hormone (LH) and follicular stimulating hormone (FSH). A prolongation of the estrous cycle and increases of estradiol, LH and FSH were observed in the treated female rats. Thyroxin and triiodothyronine were decreased and thyroid-stimulating hormone was increased in both sexes; however, there were no compound-related microscopic lesions in the thyroid gland or changes in the thyroid weight. The endocrine-related effects of ketoconazole could be detected by the parameters examined in the present study based on the Organization for Economic Cooperation and Development (OECD) protocol, suggesting that the Enhanced TG407 protocol should be a suitable screening test for detection of endocrine-mediated effects of chemicals.

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Subacute oral toxicity study of diethylphthalate based on the draft protocol for “Enhanced OECD Test Guideline no. 407”

Cited by 10 publications

References 23 publications

Hazards of diethyl phthalate (DEP) exposure: A systematic review of animal toxicology studies

Hazards of diethyl phthalate (DEP) exposure: A systematic review of animal toxicology studies

Paired Serum and Urine Concentrations of Biomarkers of Diethyl Phthalate, Methyl Paraben, and Triclosan in Rats

Repeated 28-day oral toxicity study of ketoconazole in rats based on the draft protocol for the “Enhanced OECD Test Guideline No. 407” to detect endocrine effects

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