An assessment of the toxicity of phthalate esters to freshwater benthos. 1. Aqueous exposures

Tests were performed with the freshwater invertebrates Hyalella azteca, Chironomus tentans, and Lumbriculus variegatus to determine the acute toxicity of six phthalate esters, including dimethyl phthalate (DMP), diethyl phthalate (DEP), di-n-butyl phthalate (DBP), butylbenzyl phthalate (BBP), di-n-hexyl phthalate (DHP), and di-2-ethylhexyl phthalate (DEHP). It was possible to derive 10-d LC50 (lethal concentration for 50% of the population) values only for the four lower molecular weight esters (DMP, DEP, DBP, and BBP), for which toxicity increased with increasing octanol-water partition coefficient (Kow) and decreasing water solubility. The LC50 values for DMP, DEP, DBP, and BBP were 28.1, 4.21, 0.63, and 0.46 mg/L for H. azteca; 68.2, 31.0, 2.64, and > 1.76 mg/L for C. tentans; and 246, 102, 2.48, and 1.23 mg/L for L. variegatus, respectively. No significant survival reductions were observed when the three species were exposed to either DHP or DEHP at concentrations approximating their water solubilities.     

Effects of Phthalate Ester Treatment on Seed Germination and Antioxidant Enzyme Activities of Phaseolus radiatus L.

Effects of di-(2-ethylhexyl) phthalate and di-n-butyl phthalate on seed germination rate and antioxidant enzymes activities of mung bean (Phaseolus radiatus L.) were investigated. Results showed that under the treatment with 10 mg/kg of phthalate esters (PAEs), superoxide dismutase (SOD), peroxidase and catalase (CAT) activities were higher than those of the control (p > 0.05). But SOD and CAT activities decreased with the PAEs concentrations and the treatment duration, and were significantly lower than those of the control (p < 0.05). Effect of PAEs stress on SOD activity in germinating seeds of mung bean displayed a significant dose–effect relationship.     

Decreased serum free testosterone in workers exposed to high levels of di-n-butyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP): a cross-sectional study in China

BACKGROUND: Observations of adverse developmental and reproductive effects in laboratory animals and wildlife have fueled increasing public concern regarding the potential for various chemicals to impair human fertility. OBJECTIVE: Our objective in this study was to assess the effect of occupational exposure to high levels of phthalate esters on the balance of gonadotropin and gonadal hormones including luteinizing hormone, follicle-stimulating hormone, free testosterone (fT), and estradiol. METHODS: We examined urine and blood samples of 74 male workers at a factory producing unfoamed polyvinyl chloride flooring exposed to di-n-butyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP) and compared them with samples from 63 male workers from a construction company, group matched for age and smoking status. RESULTS: Compared to the unexposed workers, the exposed workers had substantially and significantly elevated concentrations of mono-n-butyl phthalate (MBP; 644.3 vs. 129.6 microg/g creatinine, p < 0.001) and mono-2-ethylhexyl phthalate (MEHP; 565.7 vs. 5.7 microg/g creatinine, p < 0.001). fT was significantly lower (8.4 vs. 9.7 microg/g creatinine, p = 0.019) in exposed workers than in unexposed workers. fT was negatively correlated to MBP (r = -0.25, p = 0.03) and MEHP (r = -0.19, p = 0.095) in the exposed worker group. Regression analyses revealed that fT decreases significantly with increasing total phthalate ester score (the sum of quartiles of MBP and MEHP; r = -0.26, p = 0.002). CONCLUSION: We observed a modest and significant reduction of serum fT in workers with higher levels of urinary MBP and MEHP compared with unexposed workers.     

Mortality during heat waves in New York City July, 1972 and August and September, 1973.

Twelve phthalic acid esters, including those commonly used as plasticizers for biomedical devices, were subjected to various biological tests for acute, short-term, and chronic toxicity. Certain aspects of subtle toxicity were investigated as well as overt toxic manifestations. The acute ip LD₅₀ for these compounds in mice ranged from 3.22 to more than 100 g/kg. A comparison of acute LD₅₀ to chronic LD₅₀ reveals that most of these phthalates are 2–4 times more toxic chronically. However, the chronic toxicity of di-n-octyl phthalate was 21.74 times greater than its acute toxicity, while for di-2-ethylhexyl phthalate the chronic toxicity was 27.99 times greater. Most of these compounds produced a prolongation of pentobarbital sleeping time in mice pretreated with a phthalate ester.     

气相色谱-质谱法测定饮用水中19种农药残留及邻苯二甲酸二（2-乙基己基）酯

目的 建立饮用水中19种农药残留及邻苯二甲酸二（2-乙基己基）酯的气相色谱-质谱测定方法。方法 水样用 1∶1正己烷-二氯甲烷混合溶剂萃取、旋蒸浓缩后进样分析。以保留时间、特征离子定性,外标法定量。结果 方法线性范围为0.05～5 mg/L,相关系数为0.9953～0.9998,检出限为0.0009～0.007 mg/L,回收率为86.4%～101.9%,相对标准差为1.8%～8.5%。结论 本方法操作简单、准确快速、灵敏度高、精密度高,满足饮用水中农药和邻苯二甲酸二（2-乙基己基）酯残留的测定要求。     

Toxicoanthropology: Phthalate exposure in relation to market access in a remote forager-horticulturalist population

Phthalates are a class of plasticizing chemicals produced in high volume and widely found in consumer products. Evidence suggests that phthalates may have non-monotonic effects on reproductive hormone activity. With exposure to phthalates virtually ubiquitous among industrialized populations, identifying unexposed and/or minimally exposed human populations is essential for understanding the effects of low level exposures. Our primary objective was to quantify urinary phthalate metabolite concentrations in the Tsimane’, a remote population of Bolivian forager-horticulturalists. Our secondary objectives were to determine if phthalate metabolite concentrations vary in relation to access to market goods; and to explore relationships between phthalate and reproductive hormone metabolite concentrations. Given that phthalate exposure is of particular concern during fetal development, we focused on reproductive age women in the current analyses. Phthalate metabolites were assayed in urine samples from 59 naturally cycling, reproductive age Tsimane’ women. Market access was assessed as: (1) distance from residence to the largest nearby town (San Borja, Bolivia) and (2) Spanish fluency. Urinary reproductive hormone metabolite concentrations were quantified using enzyme immunoassays. We fit linear models to examine: (1) predictors of phthalate exposure; and (2) relationships between urinary phthalate and reproductive hormone metabolite concentrations. Eight phthalate metabolites were detectable in at least 75% of samples. Median concentrations were up to an order of magnitude lower than industrialized populations. Proximity to San Borja and Spanish fluency were strong predictors of exposure. In exploratory analyses, the sum of the di-2-ethylhexyl phthalate metabolites (∑DEHP) and Mono-isobutyl phthalate (MiBP) were significantly associated with altered concentrations of urinary reproductive hormone metabolites. Remote, subsistence populations, like the Tsimane’, offer a unique window into the health effects of endocrine active compounds because: (1) exposures are low and likely to be first generation; (2) a natural fertility lifestyle allows for exploration of reproductive effects; and (3) ever-increasing globalization will result in increasing exposure in the next decade.     

Estimating the contribution of inhalation exposure to di-2-ethylhexyl phthalate (DEHP) for PVC production workers,using personal air sampling and urinary metabolite monitoring

Because of troubling reports of high urinary metabolite levels and adverse reproductive health effects in workers exposed to di(2-ethylhexyl)phthalate (DEHP) in occupational settings, concern about exposure to DEHP in occupational settings is increasing. However, the contributions of different routes of exposure to DEHP are unclear. We used personal air sampling and biomonitoring to determine the contribution of inhalation exposure to the body burden of DEHP in the workplace. Eighty-nine workers (high-exposure group: 66 raw-materials workers; low-exposure group: 23 administrative workers) were recruited from three polyvinyl chloride (PVC) factories. Urinary levels of mono(2-ethylhexyl) phthalate (MEHP), (mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) were measured in pre-shift and post-shift samples. The geometric means of airborne concentrations of DEHP were 5.3 μg/m³ (low-exposure group) and 32.7 μg/m³ (high-exposure group) (P < 0.01). Correlation analysis showed a consistently significant association between airborne DEHP concentration and urinary DEHP metabolite levels in the high-exposure group. Calculating daily DEHP intake based on total urinary metabolite levels showed that the geometric means of total daily urinary metabolite levels of DEHP were 9.2 μg/kg/day (low-exposure group) and 15.5 μg/kg/day (high-exposure group) (P < 0.01). A quartile analysis of all workers showed a significant trend toward an association between the individual contribution of inhalation exposure to DEHP and urinary DEHP metabolite levels, for which the mean inhalation contribution was 46.7% in the highest quartile. We conclude that inhalation-absorbed airborne DEHP significantly increased the total body burden of DEHP in these occupationally exposed workers.     

Studies of Uptake,Elimination, and Late Effects in Atlantic Salmon (<Emphasis Type="Italic">Salmo salar</Emphasis>) Dietary Exposed to Di-2-Ethylhexyl Phthalate (DEHP) During Early Life

The phthalate esters are a group of industrial chemicals considered to have endocrine-disrupting properties. The most common tonnage product among these, di-2-ethylhexyl phthalate (DEHP), is widely spread in the environment. The objectives with the present work were to study uptake and metabolism of orally administered DEHP and its major metabolite mono-2-ethyl hexyl phthalate (MEHP) and to evaluate the impact of early life exposure on sex differentiation in Atlantic salmon. The feeding with contaminated diet started immediately after yolk sac resorption and continued for 4 weeks. Nominal concentrations of DEHP in the diet were 400 (measured 359), 800 (measured 827), and 1500 (measured 1648) mg DEHP/kg and a control group was fed food mixed with solvent. After the exposure period, fish were fed non-contaminated diet until final sampling 4 months post-exposure. There were no effects on growth or survival of the fish and no late effects on hepatosomatic index or sex ratio. However, the histological examination of gonads from fish exposed to 1500 mg DEHP/kg revealed a small but significant incidence (3%) of intersex fish (ovo-testis). Chemical residues of DEHP and MEHP were analyzed weekly during the first 3 months of the post-exposure period. Both DEHP and MEHP were rapidly eliminated to near background levels within one week post exposure. The study indicates that exposure of Atlantic salmon to relatively high concentrations of DEHP during a sensitive part of the life cycle may interfere with gonad differentiation.     

Levels of seven urinary phthalate metabolites in a human reference population

Using a novel and highly selective technique, we measured monoester metabolites of seven commonly used phthalates in urine samples from a reference population of 289 adult humans. This analytical approach allowed us to directly measure the individual phthalate metabolites responsible for the animal reproductive and developmental toxicity while avoiding contamination from the ubiquitous parent compounds. The monoesters with the highest urinary levels found were monoethyl phthalate (95th percentile, 3,750 ppb, 2,610 microg/g creatinine), monobutyl phthalate (95th percentile, 294 ppb, 162 microg/g creatinine), and monobenzyl phthalate (95th percentile, 137 ppb, 92 microg/g creatinine), reflecting exposure to diethyl phthalate, dibutyl phthalate, and benzyl butyl phthalate. Women of reproductive age (20-40 years) were found to have significantly higher levels of monobutyl phthalate, a reproductive and developmental toxicant in rodents, than other age/gender groups (p < 0.005). Current scientific and regulatory attention on phthalates has focused almost exclusively on health risks from exposure to only two phthalates, di-(2-ethylhexyl) phthalate and di-isononyl phthalate. Our findings strongly suggest that health-risk assessments for phthalate exposure in humans should include diethyl, dibutyl, and benzyl butyl phthalates.     

Di(2-ethylhexyl)phthalate (DEHP) exposure of voluntary plasma and platelet donors

Each year thousands of healthy volunteers undergo apheresis procedures to donate blood components and safe lives. However, many disposables used in apheresis contain di(2-ethylhexyl)phthalate (DEHP). This way, donors are exposed to DEHP, which is a reproductive and developmental toxicant in animals and a suspected endocrine modulator in humans. We quantified the DEHP exposure of six plasma donors, six discontinuous-flow platelet donors and six continuous-flow platelet donors by determining three specific metabolites in urine (5OH-MEHP: mono(2-ethyl-5-hydroxyhexyl)phthalate; 5oxo-MEHP: mono(2-ethyl-5-oxo-hexyl)phthalate and MEHP: mono(2-ethylhexyl)phthalate). We found maximum concentrations in urine samples after the discontinuous-flow plateletpheresis procedure with 826 microg/l for 5OH-MEHP, 774 microg/l for 5oxo-MEHP and 266 microg/l for MEHP (mean of the six volunteers). Metabolite excretions were found to be significantly (p<0.0001) higher for both plateletpheresis techniques compared to plasmapheresis and controls. Continuous-flow plateletpheresis led to significantly higher (p<0.0001) excretions than discontinuous-flow plateletpheresis. Mean absolute DEHP exposures were 1.2 mg for discontinuous- and 2.1 mg for continuous-flow plateletpheresis. Exposure for plasmapheresis (0.37 mg) was in the range of the controls (0.41 mg). Mean DEHP doses for both plateletpheresis techniques (18.1 and 32.3 microg/kg/day) were close to or exceeded the reference dose (RfD) of the US EPA and tolerable daily intake (TDI) value of the EU on the day of the apheresis. Therefore, margins of safety might be insufficient to protect especially young men and women in their reproductive age from effects on reproductivity. At present, discontinuous-flow devices should be preferred to avert conceivable health risks from plateletpheresis donors. Strategies to avoid DEHP exposure of donors during apheresis need to be developed.     

Identification of Trace Organic Pollutants in Drinking Water and the Associated Human Health Risks in Jiangsu Province,China

Organochlorine pesticides (OCPs), polycyclic aromatic hydrocarbons (PAHs), dibutyl phthalate (DNBP) and di-2-ethylhexyl phthalate (DEHP) were all detectable in surface water in Jiangsu Province, China. Concentrations of OCPs ranged from 5.13 to 8.15 ng/L. PAHs were found ranging from 14.7 to 24.5 ng/L. Concentrations of DNBP and DEHP ranged from 16 to 5,857.5 ng/L and 556 to 15,670.7 ng/L, respectively. Greater than 70 % of chemicals were removed in water treatment processes. The carcinogenic risks posed by trace organic pollutants through tap water ingestion were lower than 10(-6), and the noncarcinogenic risks were less than 10(-5).     

Metabolites of the plasticizer di (2-ethylhexyl) phthalate in urine samples of workers in polyvinylchloride processing industries

Summary Little is known about occupational exposure to the plasticizer di(2-ethylhexyl)phthalate (CAS number 117-81-7), a compound widely used in polyvinylchloride (PVC) plastics. We have studied the uptake of DEHP in workers by determining the concentrations of four metabolites of DEHP in urine samples, i.e., mono(2-ethylhexyl)phthalate (MEHP), mono (5-carboxy-2-ethylpentyl)phthalate, mono(2-ethyl-5-oxohexyl)phthalate, and mono(2-ethyl-5-hydroxyhexyl)phthalate. In addition DEHP concentrations in the air were determined by personal air sampling. Nine workers in a PVC boot factory exposed to a maximum of 1.2 mg/m³ DEHP showed an increase in the urinary concentrations of all four metabolites over the workshift. These results were obtained on both the first and the last day of the workweek. With the exception of MEHP, the increases in the concentrations of the metabolites during a workday were statistically significant. Six workers from a PVC cable factory exposed to a maximum of 1.2 mg/m³ DEHP showed a one-to fourfold increase in the concentrations of the four metabolites over the workshift, but these increases were not statistically significant. These results indicate that measurement of DEHP metabolites in urine samples may be of use for monitoring the occupational exposure to DEHP.     

Phthalate Excretion Pattern and Testicular Function: A Study of 881 Healthy Danish Men

Background: In animals, some phthalates impair male reproductive development and function. Epidemiological studies have reported inconsistent evidence of associations between phthalates and markers of human testicular function.Objectives: We aimed to provide estimates of the effects of phthalate exposure on reproductive hormone levels and semen quality in healthy men.Methods: A total of 881 men gave urine, serum, and semen samples. Serum levels of testosterone, estradiol (E₂), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and inhibin-B; semen quality; and urinary concentrations of 14 phthalate metabolites, including metabolites of di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP), were assessed. The proportions of DEHP and DiNP excreted as their respective primary metabolites [mono(2-ethylhexyl) phthalate (MEHP) and mono-isononyl phthalate (MiNP)] were calculated and expressed as percentages (%MEHP and %MiNP, respectively).Results: The free androgen index was 15% lower [95% confidence interval (CI): –23, –8%] for men in the highest %MiNP quartile compared to the lowest quartile (p < 0.001) after adjusting for confounders, and 9% lower (95% CI: –16, –1%) in the highest %MEHP quartile (p = 0.02). %MEHP and %MiNP were negatively associated with the ratio of testosterone/LH and testosterone/FSH. %MEHP was negatively associated with total testosterone, free testosterone, and ratio of testosterone/E₂. %MiNP was positively associated with SHBG. There was little evidence of associations between urinary phthalate metabolites or sums of phthalates with reproductive hormones or semen qualityConclusion: Our data suggest that both testosterone production and pituitary–hypothalamic feedback may be compromised in individuals excreting a high proportion of primary metabolites of long-chained phthalates relative to the proportion of secondary metabolites.     

Toxicity of mono- and diesters of o-phthalic esters to a crustacean, a green alga, and a bacterium

The degradation of phthalic acid diesters may lead to formation of o-phthalic acid and phthalic acid monoesters. The ecotoxic properties of the monoesters have never been systematically investigated, and concern has been raised that these degradation products may be more toxic than the diesters. Therefore, the aquatic toxicity of phthalic acid, six monoesters, and five diesters of o-phthalic acid was tested in three standardized toxicity tests using the bacteria Vibrio fischeri, the green algae Pseudokirchneriella subcapitata, and the crustacean Daphnia magna. The monoesters tested were monomethyl, monoethyl, monobutyl, monobenzyl, mono(2-ethylhexyl), and monodecyl phthalate, while the diesters tested were dimethyl, diethyl, dibutyl, butylbentyl, and di(2-ethylhexyl)phthalate, which were assumed to be below their water solubility. The median effective concentration (EC50) values for the three organisms ranged from 103 mg/L to >4.710 mg/L for phthalic acid, and corresponding values for the monoesters ranged from 2.3 mg/L (monodecyl phthalate in bacteria test) to 4,130 mg/L (monomethyl phthalate in bacteria test). Dimethyl and diethyl phthalate were found to be the least toxic of the diesters (EC50 26.2-377 mg/L), and the toxicity of the other diesters (butylbenzyl and dibutyl phthalate) ranged from 0.96 to 7.74 mg/L. In general, the phthalate monoesters (degradation products) were less toxic than the corresponding diesters (mother compounds).     

Effect of di-2-ethylhexyl phthalate (DEHP) on rat gonads.

Activity of succinic dehydrogenase and adenosine triphosphatase was significantly reduced and that of β-glucuronidase was increased in rat gonads after treatment with di-2-ethylhexyl phthalate (DEHP). Histopathological studies revealed focal degeneration of seminiferous tubules and edema of interstitium in testis but no detectable alterations in ovary of treated animals as compared to controls.Such alterations may perhaps be responsible for the reported reproductive dysfunction in experimental animals after exposure to this and other phthalate plasticizers.     

人体生物样品中邻苯二甲酸酯类的含量

目的　研究和探讨环境内分泌干扰物邻苯二甲酸酯类在人体生物样品中的含量水平。方法　运用反相高效液相色谱分析法测定了人体生物样品 (6 0份血清、36份精液、11份脂肪 )中 3种邻苯二甲酸酯类物质 (phthalates) [邻苯二甲酸二乙酯 (DEP)、邻苯二甲酸二丁酯 (DBP)和邻苯二甲酸 2 乙基己酯 (DEHP) ]的含量水平 ,同时测定了血清中有关激素水平和精液常规指标 ,并运用SPSS分析软件中的非参数统计方法对测定结果进行了相关性分析。结果　上述 3种人体生物样品中均可检测到 phthalates,脂肪中的phthalates含量范围在ND～ 2 19mg/kg ,血清中为ND～ 37 91mg/L ,精液中为 0 0 8～ 1 32mg/L ;Spearman相关分析显示 ,女性血清中DBP与E2 呈正相关 (r =0 4 4 2 ) ,DEP与T呈负相关 (r =- 0 4 86 ) ;精液中phthalates与液化时间呈显著正相关关系 (P <0 0 1) ,DBP与精液量、活力分级中的c级精子活力呈显著负相关 ,与b级精子活力呈显著正相关 (P <0 0 5 ) ,DEHP与精液量、活力分级中的c级精子活力呈显著负相关 ,与精子畸形率、b级精子活力呈显著正相关 (P <0 0 5 )。结论　邻苯二甲酸酯类物质存在于人体组织中 ,并可影响人类的精液质量.     

低出生体重儿脐血及其母血中几种环境内分泌干扰物含量水平测定

目的 研究邻苯二甲酸酯类和表面活性剂类环境内分泌干扰物(EDs)在低出生体重儿脐血及其母血中的含量水平.方法 运用反相高效液相色谱分析法测定了21份母血和30份脐血中邻苯二甲酸酯类[邻苯二甲酸-2-乙基己基酯(DEP)、邻苯二甲酸二丁酯(DBP)、邻苯二甲酸-2-乙基己酯(DEHP)及其代谢物邻苯二甲酸单乙基己酯(MEHP)]和2种表面活性剂[辛基酚(OP)和壬基酚(4-NP)]的含量水平.结果 低出生体重儿的平均体重为(2158.48±125.06)g,出生身长为(45.36±2.52)cm.母血中DEP、MEHP、DBP、DEHP、4-NP和OP的浓度分别为18.90、11.8、7.67、8.84、1.51和2.86 mg/L;检出率分别为81.0%、81.0%、71.4%、81.0%、71.4%和57.1%.脐血中,DEP、MEHP、DBP、DEHP、4-NP和OP的浓度分别为11.92、9.94、5.71、5.20、1.12和1.19 mg/L;检出率分别为86.7%、63.3%、60.0%、63.3%、56.7%和66.7%.无论是在母血还是在脐血中,邻苯二甲酸酯类的含量和检出率均高于表面活性剂.代谢物MEHP含量高于原型DEHP.脐血中游离的各EDs含量分别占母血含量的47.82%～84.05%.结论 人从胚胎时期就暴露于环境内分泌干扰物.     

Urinary metabolite concentrations of organophosphorous pesticides, bisphenol A, and phthalates among pregnant women in Rotterdam, the Netherlands: the Generation R study

Concern about potential health impacts of low-level exposures to organophosphorus (OP) pesticides, bisphenol A (BPA), and phthalates among the general population is increasing. We measured levels of six dialkyl phosphate (DAP) metabolites of OP pesticides, a chlorpyrifos-specific metabolite (3,5,6-trichloro-2-pyridinol, TCPy), BPA, and 14 phthalate metabolites in urine samples of 100 pregnant women from the Generation R study, the Netherlands. The unadjusted and creatinine-adjusted concentrations were reported, and compared to National Health and Nutrition Examination Survey and other studies. In general, these metabolites were detectable in the urine of the women from the Generation R study and compared with other groups, they had relatively high-level exposures to OP pesticides and several phthalates but similar exposure to BPA. The median concentrations of total dimethyl (DM) metabolites was 264.0 nmol/g creatinine (Cr) and of total DAP was 316.0 nmol/g Cr. The median concentration of mono-ethyl phthalate (MEP) was 222.0 μg/g Cr; the median concentrations of mono-isobutyl phthalate (MiBP) and mono-n-butyl phthalate (MnBP) were above 50 μg/g Cr. The median concentrations of the three secondary metabolites of di-2-ethylhexyl phthalate (DEHP) were greater than 20 μg/g Cr. The data indicate that the Generation R study population provides a wide distribution of selected environmental exposures. Reasons for the relatively high levels and possible health effects need investigation.     

Sub-acute and sub-chronic toxicity ofmono-2-ethylhexyl phthalate in the rat

Groups of six male Sprague-Dawley rats were administered single oral doses of mono-2-ethylhexyl phthalate (MEHP) at 50, 100 or 200 mg/kg or di-2-ethylhexyl phthalate (DEHP) at 2,000 mg/kg in 2% gum acacia and were observed clinically for seven days. Body weight and food consumption were not affected by treatment. The liver weight increased in the groups receiving 100 mg or 200 mg mono-2-ethylhexyl phthalate and 2,000 mg diethylhexyl phthalate. Hepatic microsomal aniline hydroxylase activity was not altered by treatment.In a subsequent 28-day experiment, groups of ten weanling Sprague Dawley rats were fed diets containing 0, 25, 100, 400, 1,600 or 6,400 ppm of mono-2-ethylhexyl phthalate. Decreased growth rate occurred in the group receiving the highest dose level. Increased heart and liver weights were observed in animals from the 1,600 and 6,400 ppm groups. Minor alterations in serum biochemical values included decreased SDH and calcium levels, and elevated alkaline phosphatase activity in some treated groups. A mild reduction in red cells saturation and hematocrit was noted in some groups.In 3-month and 6-month feeding studies, groups of ten male and female weanling Sprague-Dawley rats were fed diets containing 1, 5, 25, 125 or 625 ppm of mono-2-ethylhexyl phthalate. Growth rate and food consumption were not affected at any dose level or time interval. Relative organ weights of rats of both sexes were not altered in the 3-month period, but the liver weights of female rats in the 6-month experiment were increased. Changes in clinical chemistry and hematological values were mild. These included lower LDH, SGOT, hemoglobin, and hematocrit values in male rats at the 3-month period and reduced potassium content at the 6-month period. Histological changes were mild in both male and female rats at both time intervals. Treatment-related lesions were found in the liver, heart, and adrenals. Alteration in the liver consisted of midzonal and periportal eosinophilic cytoplasmic inclusions and vacuolations with isolated binucleated and necrotic hepatocytes. There was a mild enlargement of myocardial nuclei and segmental deregistration of myocardial striations in test animals. The adrenal glands exhibited vacuolation of the zona fasciculata which was less severe in the 6-month period than the 3-month counterpart. In conclusion, mono-2-ethylhexyl phthalate is similar to its parent compound diethylhexyl phthalate in that it possesses a low order of oral toxicity in rats.     

Estimated daily phthalate exposures in a population of mothers of male infants exhibiting reduced anogenital distance

Phthalate diesters have been shown to be developmental and reproductive toxicants in animal studies. A recent epidemiologic study showed certain phthalates to be significantly associated with reduced anogenital distance in human male infants, the first evidence of subtle developmental effects in human male infants exposed prenatally to phthalates. We used two previously published methods to estimate the daily phthalate exposures for the four phthalates whose urinary metabolites were statistically significantly associated with developmental effects in the 214 mother-infant pairs [di-n-butyl phthalate (DnBP) , diethyl phthalate (DEP) , butylbenzyl phthalate (BBzP) , diisobutyl phthalate (DiBP) ] and for another important phthalate [di-2-ethylhexyl phthalate (DEHP) ]. We estimated the median and 95th percentile of daily exposures to DBP to be 0.99 and 2.68 microg/kg/day, respectively ; for DEP, 6.64 and 112.3 microg/kg/day ; for BBzP, 0.50 and 2.47 microg/kg/day ; and for DEHP, 1.32 and 9.32 microg/kg/day. The U.S. Environmental Protection Agency (EPA) reference doses for these chemicals are 100 (DBP) , 800 (DEP) , 200 (BBzP) , and 20 (DEHP) microg/kg/day. The median and 95th percentile exposure estimates for the phthalates associated with reduced anogenital distance in the study population are substantially lower than current U.S. EPA reference doses for these chemicals and could be informative to any updates of the hazard assessments and risk assessments for these chemicals.