Two-generation reproduction studies in Rats fed di-isodecyl phthalate

Hushka, Leslie J.; Waterman, Stacey J.; Keller, Laura; Trimmer, Gary W.; Freeman, James J.; Ambroso, Jeffrey L.; Nicolich, Mark J.; McKee, Richard H.

doi:10.1016/s0890-6238(01)00109-5

Cited by 26 publications

(16 citation statements)

References 30 publications

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“…Alternatively, reported individual litter average data (one mean response per litter) could be used. In the case of the critical studies and effects selected, the data were reported as summary data (mean) of all litters per dose, not individual litter data (Nagao et al, 2000;Tyl et al, 2004;Aso et al, 2005 andChristiansen et al, 2010;Clewell et al, 2013a), or unprocessed data were not available (Hushka et al, 2001) which prevented the reanalysis of the data for BMD modelling. In the case of the critical effects with histopathological data, the problems of integrating them into the BMD model were related to no clear dose-response relationship (Nagao et al, 2000;Wolfe and Layton, 2003) or to the difficulty to interpret the data and the dose-response without an integrated quantitative severity scale of the histopathological findings in the case of Lee et al (2004).…”

Section: Derivation Of Health-based Guidance Values For Reproductive mentioning

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

104

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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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Section: Derivation Of Health-based Guidance Values For Reproductive mentioning

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

104

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“…The estrous cycle and number of oocytes in Sprague–Dawley rats were unaffected after exposure to DiDP at doses from 0.02% to 0.8% in the diet over two generations (Hushka et al, 2001). On the other hand, the number of pups and pup survival was decreased at 0.8% in the first generation and at 0.4% and 0.8% in the second generation, and vaginal opening was delayed in the 0.4% and 0.8% exposure groups (Hushka et al, 2001). Despite a paucity of studies, we suggest that DiDP exposure can adversely affect pregnancy and female reproductive health.…”

Section: Animal Studiesmentioning

confidence: 99%

Reproductive and developmental effects of phthalate diesters in females

Kay

Chambers

Foster

2013

Critical Reviews in Toxicology

274

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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“…Recently, attention has been given to the potential for some phthalates, including DINP, to affect reproductive outcomes and the development of the male reproductive tract (Adamsson et al 2009; Borch et al 2006; Gray and Gangolli 1986; Gray et al 2000; Howdeshell et al 2007; Kavlock et al 2002b; Masutomi et al 2003; Waterman et al 2000); these phthalates can alter sexual differentiation of the male rat by inhibiting fetal testicular testosterone synthesis (Foster 2006; Gray et al 2000; Lee et al 2004; Sharpe and Irvine 2004; Tyl et al 2004). Other phthalates, such as DIDP, can also produce rodent liver effects (European Commission 2003a) but have not been shown to affect reproductive outcomes (Hushka et al 2001; Kavlock et al 2002a). Compared with the large body of experimental evidence suggesting reproductive or developmental toxicity of phthalates, human data are rather limited (Hauser and Calafat 2005; Meeker et al 2009).…”

mentioning

confidence: 99%

Selecting Adequate Exposure Biomarkers of Diisononyl and Diisodecyl Phthalates: Data from the 2005–2006 National Health and Nutrition Examination Survey

Calafat

Wong

Silva

et al. 2011

Environ Health Perspect

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BackgroundHigh-molecular-weight phthalates, such as diisononyl phthalate (DINP) and diisodecyl phthalate (DIDP), are used primarily as polyvinyl chloride plasticizers.ObjectivesWe assessed exposure to DINP and DIDP in a representative sample of persons ≥ 6 years of age in the U.S. general population from the 2005–2006 National Health and Nutrition Examination Survey (NHANES).MethodsWe analyzed 2,548 urine samples by using online solid-phase extraction coupled to isotope dilution high-performance liquid chromatography–tandem mass spectrometry.ResultsWe detected monocarboxyisooctyl phthalate (MCOP), a metabolite of DINP, and monocarboxyisononyl phthalate (MCNP), a metabolite of DIDP, in 95.2% and 89.9% of the samples, respectively. We detected monoisononyl phthalate (MNP), a minor metabolite of DINP, much less frequently (12.9%) and at concentration ranges (> 0.8 μg/L–148.1 μg/L) much lower than MCOP (> 0.7 μg/L– 4,961 μg/L). Adjusted geometric mean concentrations of MCOP and MCNP were significantly higher (p < 0.01) among children than among adolescents and adults.ConclusionsThe general U.S. population, including children, was exposed to DINP and DIDP. In previous NHANES cycles, the occurrence of human exposure to DINP by using MNP as the sole urinary biomarker has been underestimated, thus illustrating the importance of selecting the most adequate biomarkers for exposure assessment.

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Two-generation reproduction studies in Rats fed di-isodecyl phthalate

Cited by 26 publications

References 30 publications

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

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

Reproductive and developmental effects of phthalate diesters in females

Selecting Adequate Exposure Biomarkers of Diisononyl and Diisodecyl Phthalates: Data from the 2005–2006 National Health and Nutrition Examination Survey

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