Biomonitoring Summary

Phthalates Overview

Di-2-ethylhexyl Phthalate

CAS No. 117-81-7

General Information

Di-2-ethylhexyl phthalate (DEHP) is primarily used to produce flexibility in plastics, mainly polyvinyl chloride, which is used for many consumer products, toys, packaging film, and blood product storage and intravenous delivery systems. Concentrations in plastic materials may reach 40% by weight. DEHP has been removed from or replaced in most toys and food packaging in the United States.

Following ingestion, DEHP is metabolized to more than 30 metabolites which are rapidly eliminated in urine, and in humans, as glucuronide conjugates (Albro et al., 1982; Albro and Lavenhar, 1989; ATSDR, 2002; Peck and Albro, 1982). Four metabolites have been measured in the National Report on Human Exposure to Environmental Chemicals:mono-(2-ethyl-5-hexyl) phthalate (MEHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP).

MEHP is primarily formed by the hydrolysis of DEHP in the gastrointestinal tract and then absorbed. DEHP present in medical devices and parenteral delivery systems results in the diester rather than the monoester form being directly introduced into the blood. After parenteral administration, hydrolysis of DEHP most likely also occurs in the blood, and subsequent metabolism is similar to that following ingestion (Koch et al., 2005a, 2005b, 2005c). MEOHP, MEHHP, and MECPP are produced by the oxidative metabolism of MEHP and are present at roughly three- to five-fold higher concentrations than MEHP in urine (Barr et al., 2003; Fromme et al., 2007; Koch et al., 2003).

MEHP is the putative toxic metabolite of DEHP. Liver toxicity, decreased testicular weight, and testicular atrophy have been observed in rodents fed high doses over a short term or with chronic dosing (McKee et al., 2004; NTP-CERHR, 2006). In contrast, marmoset monkeys fed high dose DEHP for longer than a year did not demonstrate testicular or liver toxicity (NTP-CERHR, 2006). Very high doses of DEHP have suppressed estradiol production in female rats (Lovecamp-Swan and Davis, 2003). The Food and Drug Administration determined that in adults, the amounts of DEHP or MEHP received from intravenous delivery systems or blood transfusions (DEHP is hydrolyzed to MEHP in stored blood) would result in short-term elevations similar to background levels (FDA, 2001). However, critically ill neonates and infants receiving selected or multiple intensive procedures, such as exchange transfusions, extracorporeal membrane oxygenation, and parenteral nutrition, could receive higher exposures than the general population (Calafat et al., 2004; FDA, 2001; Loff et al., 2000; Weuve et al., 2006).

OSHA has established a workplace air standard for external exposure to DEHP; NIOSH and ACGIH have established guidelines for workplace air exposure to DEHP. IARC considers DEHP to be unclassifiable with respect to human carcinogenicity. NTP determined that DEHP is reasonably anticipated to be a human carcinogen.

Biomonitoring Information

The levels of MEHP reported in NHANES 1999-2000, 2001-2002, and 2003-2004 appear roughly comparable to those reported previously in several small U.S. studies involving adults (Blount et al., 2000), pregnant women in New York City (Adibi et al., 2003), and low income African-American women in Washington, DC (Hoppin et al., 2002). In contrast, a sample of South Korean women had higher urine MEHP levels: the geometric mean was about ten times higher than for females in each of the NHANES survey periods (CDC, 2012; Koo and Lee, 2005). Median urine MEHP levels in a small group of Japanese adults, in a group of Swedish male military recruits, and in samples of men attending an infertility clinic were similar to median values for adults and males, respectively, in NHANES 1999-2000 and 2001-2002 subsamples (Duty et al., 2004, 2005; Itoh et al., 2005).

In another sample of men attending an infertility clinic, the median and 95th percentile values of urinary MEHP were similar, but MEHHP and MEOHP were about three to five times higherthan comparable values found in males in two NHANES survey periods (1999-2000, 2001-2002) (CDC, 2012; Hauser et al., 2007). Compared with the U.S. population in the National Report on Human Exposure to Environmental Chemicals (the Report), urinary MEHP, MEOHP, and MEHHP levels were similar or up to twofold higher in a sample of German residents (Koch et al., 2003; Preuss et al., 2005) and German children (Becker et al., 2004; Koch et al., 2004). During 2001-2003, median levels of urinary MEOHP and MEHHP appeared to be similar in samples of German university students and the adults in the Report (CDC, 2013; Wittasek et al., 2007).

In separate analyses of NHANES 1999-2000 and NHANES 2001-2002, the adjusted geometric mean levels of urinary MEHP were significantly higher in children compared with adolescents and adults, and in females compared with males (Silva et al., 2004). South Korean children had geometric mean urine MEHP levels that were about three times higher than the U.S. children in the Report (CDC, 2013; Koo and Lee, 2005). Younger children eliminate higher proportions of urinary MEHHP and MEOHP relative to MEHP, with the difference increasing as age decreases; this may be the result of differences in metabolism and/or excretion (NTP-CERHR, 2006). Studies of hospitalized neonates have reported urinary geometric mean levels of MEHP, MEOHP, and MEHHP that were two to five times higher, or more (depending on the intensity of DEHP-product exposure), than the geometric means of children in the NHANES subsamples for all three survey periods (Calafat et al., 2004; Weuve et al., 2006). Small studies of plasma and platelet donors have reported very high levels of MEHP, MEOHP, MEHHP and MECPP in urine collected shortly after these procedures (Koch et al., 2005b, 2005c).

Finding a measurable amount of one or more DEHP metabolites in urine does not imply that the levels of the metabolites or the parent compound cause an adverse health effect. Biomonitoring studies on levels of urinary DEHP metabolites provide physicians and public health officials with reference values so that they can determine whether people have been exposed to higher levels of DEHP than are found in the general population. Biomonitoring data can also help scientists plan and conduct research on exposure and health effects.


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