Biomonitoring Summary

Phthalates Overview

Phthalates are industrial chemicals that are added to plastics to impart flexibility and resilience and are often referred to as plasticizers. Phthalates also are used as solubilizing or stabilizing agents in other applications. There are numerous products that may contain phthalates: adhesives; automotive plastics; detergents; lubricating oils; some medical devices and pharmaceuticals; plastic raincoats; solvents; vinyl tiles and flooring; and personal-care products, such as soap, shampoo, deodorants, lotions, fragrances, hair spray, and nail polish. Phthalates are often used in polyvinyl chloride type plastics, such as plastic packaging film and sheet, garden hoses, inflatable recreational toys, blood product storage bags, intravenous medical tubing, and toys (ATSDR, 2001, 2002). Because they are not chemically bound to the plastics to which they are added, phthalates can be released into the environment during use or disposal of the product. Various phthalate esters have been measured in specific foods, indoor and ambient air, indoor dust, water sources, and sediments (Clark et al., 2003).

People are exposed through ingestion, inhalation, and, to a lesser extent, dermal contact with products that contain phthalates. For the general population, dietary sources have been considered as the major exposure route, followed by inhaling indoor air. Infants may have relatively greater exposures from ingesting indoor dust containing some phthalates (Clark et al., 2003). Human milk can be a source of phthalate exposure for nursing infants (Calafat et al., 2004; Mortensen et al., 2005). The intravenous or parenteral exposure route can be important in patients undergoing medical procedures involving devices or materials containing phthalates. In settings where workers may be exposed to higher air phthalate concentrations than the general population, urinary metabolite and air phthalate concentrations are roughly correlated (Liss et al., 1985; Nielsen et al., 1985; Pan et al., 2006).

Phthalates are metabolized and excreted quickly and do not accumulate in the body (Anderson et al., 2001). Ingested phthalate diesters are initially hydrolyzed in the intestine to the corresponding monoesters, which are then absorbed (Albro et al., 1982; Albro and Lavenhar, 1989). Absorbed monoester metabolites are usually oxidized in the body and, in humans, excreted in urine largely as glucuronide conjugates (Albro et al., 1982; Dirven et al,. 1993). The table shows the phthalate diesters, corresponding monoester metabolites, and other oxidized metabolites included in the National Report on Human Exposure to Environmental Chemicals (CDC, 2013).

Human health effects from phthalates at low environmental doses or at biomonitored levels from low environmental exposures are unknown. Phthalates have low acute animal toxicity. In chronic rodent studies, several of the phthalates produced testicular injury, liver injury, liver cancer, and teratogenicity, but these effects either have not been demonstrated when tested in non-human primates or are yet to be studied. In vitro studies showed that certain phthalates can bind to estrogen receptors and may have weak estrogenic or anti-estrogenic activity (Coldham et al., 1997; Harris et al., 1997; Jobling et al., 1995), but in vivo studies did not support phthalates having estrogenic effects (Milligan et al., 1998; Okubo et al., 2003; Parks et al., 2000; Zacharewski et al., 1998); however, not all phthalates and metabolites have been tested. In animals, phthalates produced anti-androgenic effects by reducing testosterone production and, at very high levels, reducing estrogen production, effects that may be mediated by inhibiting testicular and ovarian steroidogenesis. High doses of di-2-ethylhexyl phthalate (DEHP), dibutyl phthalate (DBP), and benzylbutyl phthalate (BzBP) during the fetal period produced lowered testosterone levels, testicular atrophy, and Sertoli cell abnormalities in the male animals and, at higher doses, ovarian abnormalities in the female animals (Jarfelt et al., 2005; Lovekamp-Swan and Davis, 2003; McKee et al., 2004; NTP-CERHR, 2003a, 2003b, 2006). Phthalate urinary metabolite levels in men evaluated at an infertility clinic were associated with several measures of sperm function and morphology (Duty et al., 2004; Hauser et al., 2007), but similar findings were not present in young Swedish men with comparable or higher median levels of urinary metabolites (Jonsson et al., 2005).

The monoester metabolites are thought to mediate toxic effects for some of the phthalates, but there are known species-related differences in the hydrolysis of diester phthalates, efficiency of intestinal absorption, and extent of metabolite conjugation to glucuronide (Albro et al., 1982; Kessler et al., 2004; Rhodes et al., 1986). These differences may contribute to species-specific differences in toxicity (ATSDR, 2001, 2002). Also, phthalates have been shown to induce peroxisomal proliferation in rodents, which may be a pathway to the development of liver toxicity and cancers in these animals. However, peroxisomal proliferation may not be a relevant pathway in humans (Rusyn et al., 2006).

The National Toxicology Program's Office of Health Assessment and Translation, formerly Center for the Evaluation of Risks to Human Reproduction (NTP-CERHR) has reviewed the developmental and reproductive effects of specific phthalates (https://www.niehs.nih.gov/research/atniehs/dntp/ohat/index.cfmexternal icon). Information about external exposure (i.e., environmental levels) and health effects is also available for some phthalates from ATSDR at https://www.atsdr.cdc.gov/toxprofiles/index.asp.

Phthalates and Urinary Metabolites Measured in the National Biomonitoring Program

Table of Phthalates and Urinary Metabolites Measured in the National Biomonitoring Program
Phthalate name (CAS number)	Abbreviation	Urinary metabolite (CAS number)	Abbreviation
Benzylbutyl phthalate (85-68-7)	BzBP	Mono-benzyl phthalate (2528-16-7) (some mono-n-butyl phthalate)	MBzP
Dibutyl phthalates (84-74-2)	DBP	Mono-n-butyl phthalate (131-70-4) Mono-isobutyl phthalate	MnBP MiBP
Dicyclohexyl phthalate (84-61-7)	DCHP	Mono-cyclohexyl phthalate (7517-36-4)	MCHP
Diethyl phthalate (84-66-2)	DEP	Mono-ethyl phthalate (2306-33-4)	MEP
Di-2-ethylhexyl phthalate (117-81-7)	DEHP	Mono-2-ethylhexyl phthalate (4376-20-9) Mono-(2-ethyl-5-hydroxyhexyl) phthalate Mono-(2-ethyl-5-oxohexyl) phthalate Mono-(2-ethyl-5-carboxypentyl) phthalate (40809-41-4)	MEHP MEHHP MEOHP MECPP
Di-isononyl phthalate (28553-12-0)	DiNP	Mono-isononyl phthalate	MiNP
Di-isodecyl phthalate	DiDP	Mono-(carboxynonyl) phthalate	MCNP
Dimethyl phthalate (131-11-3)	DMP	Mono-methyl phthalate (4376-18-5)	MMP
Di-n-octyl phthalate (117-84-0)	DOP	Mono-(3-carboxypropyl) phthalate Mono-n-octyl phthalate (5393-19-1)	MCPP MOP

Urinary levels of phthalate metabolites reflect recent exposure to the parent phthalate diester. The proportions of each metabolite for a given phthalate may vary by differing routes of exposure (Liss et al., 1985; Peck and Albro, 1982). Variation occurs from person to person in the proportions or amounts of a metabolite excreted after similar doses (Anderson et al., 2001); variation also occurs in the same person during repetitive monitoring (Fromme et al., 2007; Hauser et al., 2004; Hoppin et al., 2002). Population estimates of concentrations of specific phthalate metabolites may differ by age, gender, and race/ethnicity (Silva et al., 2004).

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

Di-isononyl Phthalate

CAS No. 28553-12-0

General Information

Di-isononyl phthalate (DiNP) is a mixture of phthalates with branched alkyl side chains of varying length (C8, C9, and C10). DiNP is primarily used to produce flexible plastics and has replaced di-2-ethylhexyl phthalate (DEHP) in some plastics, though not in medical products. DiNP is widely used in such products as toys, flooring, gloves, drinking straws, garden hoses, and in sealants used for food packaging. People exposed to DiNP will excrete small amounts of mono-isononyl phthalate (MiNP) and other secondary oxidative metabolites. Urinary MiNP represents only about 2% of a dose (Koch and Angerer, 2007; Silva et al., 2006a, 2006b). Because DiNP is a complex mixture, MiNP may not reflect exposure to all the chemical components.

DiNP administered to rodents produced liver and kidney toxicity, and may cause liver tumors by a mechanism involving peroxisomal proliferation. High dose DiNP was a developmental toxicant in rodents (NTP-CERHR, 2003c). Although DiNP is considered an animal carcinogen, neither IARC nor NTP has evaluated DiNP with respect to human carcinogenicity.

Biomonitoring Information

MiNP was detected mainly at the 95th percentiles in the National Report on Human Exposure to Environmental Chemicals (CDC, 2012). A low detection rate was also reported in a small sample of African-American women in Washington, DC (Hoppin et al., 2002).

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

References

Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for di-n-butyl phthalate update [online]. September 2001. Available at URL: https://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=859&tid=167. 6/21/13

Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for di(2-ethylhexyl)phthalate update [online]. September 2002. Available at URL: https://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=684&tid=65. 6/21/13

Albro PW, Corbett JT, Schroeder JL, Jordan S, Matthews HB. Pharmacokinetics, interactions with macromolecules and species differences in metabolism of DEHP. Environ Health Perspect 1982;45:19-25.

Albro PW and Lavenhar SR. Metabolism of di(2-ethylhexyl) phthalate. Drug Metab Rev 1989;21:13-34.

Anderson WA, Castle L, Scotter MJ, Massey RC, Springall C. A biomarker approach to measuring human dietary exposure to certain phthalate diesters. Food Addit Contam 2001;18(12):1068-1074.

Calafat AM, Slakman AR, Silva MJ, Herbert AR, Needham LL. Automated solid phase extraction and quantitative analysis of human milk for 13 phthalate metabolites. J Chromatogr B 2004;805:49-56.

Centers for Disease Control and Prevention (CDC). Fourth National Report on Human Exposure to Environmental Chemicals. Updated Tables, 2013. [online] Available at URL: https://www.cdc.gov/exposurereport/. 6/21/13

Clark K, Cousins IT, Mackay D. Assessment of critical exposure pathways. In Staples CA (ed), The Handbook of Environmental Chemistry, Vol, 3, Part Q: Phthalate Esters. 2003;New York, Springer, pp. 227-262.

Coldham NG, Dave M, Silvapathasundaram S, McDonnell DP, Connor C, Sauer MJ. Evaluation of a recombinant yeast cell estrogen screening assay. Environ Health Perspect 1997; 105:734-742.

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Duty SM, Calafat AM, Silva MJ, Brock JW, Ryan L, Chen Z, et al. The relationship between environmental exposure to phthalates and computer-aided sperm analysis motion parameters. J Androl 2004;25(2):293-302.

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Lovekamp-Swan T, Davis BJ. Mechanisms of phthalate ester toxicity in the female reproductive system. Environ Health Perspect 2003;111(2):139-145.

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Milligan SR, Balasubramanian AV, Kalita JC. Relative potency of xenobiotic estrogens in an acute in vivo mammalian assay. Environ Health Perspect 1998;106(1):23-26.

Mortensen GK, Main KM, Andersson A-M, Leffers H, Skakkebaek NE. Determination of phthalate monoesters in human milk, consumer milk, and infant formula by tandem mass spectrometry (LC-MS-MS). Anal Bioanal Chem 2005;382:1084-1092.

Nielsen J, Akesson B, Skerfving S. Phthalate ester exposure—air levels and health of workers processing polyvinylchloride. Am Ind Hyg Assoc J 1985;46(11):643-647.

NTP-CERHR. National Toxicology Program-Health Assessment and Translation (formerly CERHR). Monograph on the Potential Human Reproductive and Developmental Effects of Butyl Benzyl Phthalate (BBP). Research Triangle Park (NC). 2003a [online]. Available at URL: https://ntp.niehs.nih.gov/ntp/ohat/phthalates/bb-phthalate/BBP_Monograph_Final.pdfpdf iconexternal icon. 11/14/12

NTP-CERHR. National Toxicology Program-Health Assessment and Translation (formerly CERHR). Monograph on the Potential Human Reproductive and Developmental Effects of Di-n-Butyl Phthalate (DBP). Research Triangle Park (NC). 2003b [online]. Available at URL: https://ntp.niehs.nih.gov/ntp/ohat/phthalates/dbp/DBP_Monograph_Final.pdfpdf iconexternal icon.11/14/12

NTP-CERHR. National Toxicology Program-Health Assessment and Translation (formerly CERHR). Monograph on the Potential Human Reproductive and Developmental Effects of Di(2-ethylhexyl) Phthalate (DEHP). Research Triangle Park (NC). 2006 [online]. Available at URL: https://ntp.niehs.nih.gov/ntp/ohat/phthalates/dehp/DEHP-Monograph.pdfpdf iconexternal icon. 11/14/12

NTP-CERHR. National Toxicology Program- Health Assessment and Translation (formerly CERHR). Monograph on the Potential Human Reproductive and Developmental Effects of Di-isononyl Phthalate (DINP). Research Triangle Park (NC). 2003c [online]. Available at URL: . https://ntp.niehs.nih.gov/ntp/ohat/phthalates/dinp/DiNP_Monograph_Final.pdfpdf iconexternal icon.11/14/12

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Silva MJ, Kato K, Wolf C, Samandar El, Silva SS, Gray EL, et al. Urinary biomarkers of di-isononyl phthalate in rats. Toxicol 2006a;223:101-112.

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Zacharewski TR, Meek MD, Clemons JH, Wu ZF, Fielden MR, Matthews JB. Examination of the in vitro and in vivo estrogenic activities of eight commercial phthalate esters. Toxicol Sci 1998;46:282-293.

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