Page 5 - Fifth Report on Human Biomonitoring of Environmental Chemicals in Canada

• Previous Page
• Table of Contents
• Next Page

14 Summaries and results for plasticizers

14.1 Phthalates

Diesters of phthalic acid, commonly called phthalates, are a class of high-production volume industrial chemicals that are used in the manufacture of a variety of consumer products. Table 14.1.1 lists phthalates commonly found in commerce and their major metabolites measured in cycle 5 of the Canadian Health Measures Survey (CHMS).

Phthalates are primarily used as plasticizers to impart flexibility and resilience to plastics (Frederiksen et al., 2007; Graham, 1973; Health Canada, 2019). They are also used as solvents in household products, including self-care products, construction and renovation products, and textiles (Health Canada, 2019). In particular, BBP, DnBP, DMP, and DEP are found in self-care products, such as cosmetics (e.g., hair-care products and fragrance) and non-prescription drugs (Cosmetic Ingredient Review Expert Panel, 2005; Environment and Climate Change Canada and Health Canada, 2017; Environment Canada and Health Canada, 2000; Environment Canada and Health Canada, 2015e). DiNP, DiBP, DCHP, DnBP, BBP, and DEHP are used in construction and renovation products, such as lubricants and greases, adhesives and sealants, paints and coatings, and building materials (Environment and Climate Change Canada and Health Canada, 2017; Environment Canada and Health Canada, 2000; Environment Canada and Health Canada, 2015b; Environment Canada and Health Canada, 2015d; Health Canada, 2019). DOP, BBP, DMP, DnBP, DiDP, DiBP, and DiNP are used in electrical items and electronics (Environment and Climate Change Canada and Health Canada, 2017; Environment Canada and Health Canada, 2015b; Environment Canada and Health Canada, 2015c; Environment Canada and Health Canada, 2015d; Environment Canada and Health Canada, 2015e; Health Canada, 2019). Phthalates can also be used in the automotive sector (e.g., BBP, DEHP, DiBP, and DCHP), in printing ink (e.g., DiNP and BBP), and in the formulation of pesticides (e.g., BBP) (Environment and Climate Change Canada and Health Canada, 2017; Environment Canada and Health Canada, 2015d; Health Canada, 2019). Finally, certain phthalates, including BBP, DEHP, DiDP, and DMP, can be found in food-packaging materials (Environment and Climate Change Canada and Health Canada, 2017; Environment Canada and Health Canada, 2015c; Environment Canada and Health Canada, 2015e; Health Canada, 2019). Prior to restrictions enacted in 2010 (see below), phthalates, namely BBP, DnBP, DiNP, and DEHP, were used in Canada as plasticizers in soft vinyl toys and child-care articles.

There are no known major natural sources of phthalates. Releases to the environment are associated with anthropogenic activities (Environment and Climate Change Canada and Health Canada, 2017). Releases may occur during the manufacture and processing of phthalates, including transportation and storage, as well as during the production, use, and disposal of products that contain phthalates (Environment and Climate Change Canada and Health Canada, 2017). Although release into air may occur, water is expected to be the primary receiving medium for phthalates, and occurs through wastewater effluents from industrial sources and disperse releases from consumer products (Environment and Climate Change Canada and Health Canada, 2017; Environment Canada and Health Canada 2015d).

Phthalates have been detected in food, water, air, soil and dust (Clark, 2003; Environment and Climate Change Canada and Health Canada, 2017). The general population can be exposed to phthalates through the inhalation of indoor air; through the ingestion of water, food, beverages, soil, and dust; and through the use of consumer products (Health Canada, 2019). Other potential sources of exposure are breast milk and the mouthing of children's toys and articles (Environment and Climate Change Canada and Health Canada, 2017).

In laboratory animals, phthalates have been observed to undergo rapid absorption following oral exposure and generally slow absorption following dermal exposure (ATSDR, 1995; ATSDR, 1997; ATSDR, 2001; ATSDR, 2002). Phthalate diesters are converted to their corresponding monoesters in the gastrointestinal tract or saliva prior to absorption (ATSDR, 1995; ATSDR, 1997; ATSDR, 2001; ATSDR, 2002; NRC, 2008). Phthalates are rapidly metabolized in the body to form hydrolytic and oxidative monoesters, which can either be excreted in the urine and feces unchanged, or can undergo phase II biotransformation to produce glucuronide conjugates with increased water solubility and, therefore, increased urinary excretion (Hauser and Calafat, 2005; Samandar et al., 2009). Although the metabolism and excretion of monoester phthalates varies based on a number of factors, they are generally characterized by rapid metabolism and short biological half-lives (ATSDR, 1995; ATSDR, 1997; ATSDR, 2001; ATSDR, 2002; Hauser and Calafat, 2005). Phthalates do not bioaccumulate in humans (CDC, 2009). Measurement of phthalate metabolites in urine has become the most common approach to assessing phthalate exposure in humans, and reflects relatively recent exposure (Blount et al., 2000; Calafat and McKee, 2006).

In laboratory animals, exposure to some phthalates adversely affects the male reproductive system. In particular, prenatal exposure to phthalates, such as DnBP, BBP, DEHP, DCHP, and DiNP, has been shown to disrupt the androgen-mediated development of the male reproductive tract (David, 2006; Environment Canada and Health Canada, 2015b; Environment Canada and Health Canada, 2015d; Foster, 2005; Gray et al., 2000; Howdeshell et al., 2007; Main et al., 2006; Mariana et al., 2016; Wine et al., 1997). This response is termed rat phthalate syndrome and is characterized by malformations of the epididymis, vas deferens, seminal vesicles, prostate and external genitalia, among other effects (Lioy et al., 2015). Adverse effects on the testes have also been observed in mature laboratory animals, although these effects occurred at higher doses (David, 2006; Foster, 2005). There is also evidence from animal studies that phthalates exert adverse effects on the ovaries (Environment Canada and Health Canada, 2015b; Hannon and Flaws, 2015; Mariana et al., 2016). Other target organs identified in animal studies include the liver and kidneys, where phthalate exposure may lead to increased organ weights and peroxisome proliferation in the liver (David and Gans, 2003; Environment Canada and Health Canada, 2015b; Environment Canada and Health Canada, 2015c; Environment Canada and Health Canada, 2015d; Environment Canada and Health Canada, 2015e; Howdeshell et al., 2007; Main et al., 2006; Wine et al., 1997).

Numerous studies demonstrate exposure to phthalates in the human population, including prenatal exposure (Becker et al., 2009; Blount et al., 2000; Health Canada, 2016; Lioy et al., 2015; Marsee et al., 2006; NTP-CERHR, 2003a; NTP-CERHR, 2003b; NTP-CERHR, 2003c; NTP-CERHR, 2003d; NTP-CERHR, 2003e; NTP-CERHR, 2003f; NTP-CERHR, 2006; Praveena et al., 2018; Silva et al., 2003; Wittassek et al., 2011). An evaluation by Health Canada of 95 epidemiologic studies of phthalates and health outcomes — including endocrine system effects, reproductive parameters, and growth and development — determined that no health outcome had sufficient evidence of an association with any assessed phthalate (or its metabolite) based on the evaluation approach (Health Canada, 2016). There was only limited evidence of an association between exposure to DiNP/DEHP and sex hormone levels and semen parameters, and between DEHP exposure and birth measures. For effects detected in animal studies related to male reproductive development, the human data on relevant health outcomes were very limited and the quality of the studies was variable (Health Canada, 2016). The International Agency for Research on Cancer (IARC) has classified DEHP as possibly carcinogenic to humans (Group 2B) and BBP as not classifiable as to its carcinogenicity to humans (Group 3) (IARC, 1999; IARC, 2013).

Environment Canada and Health Canada assessed four phthalates (DBP, BBP, DEHP, and DOP) on an individual basis for the First or Second Priority Substances Lists (PSL1 and PSL2) (Environment Canada and Health Canada 1993, 1994a,b, 2000). DBP and BBP were determined not to present a risk to the environment or to human health. DOP was found not to present a risk to the environment; however, at the time of the assessment, the available information was not sufficient to allow a conclusion in terms of human health. A subsequent report concluded that DOP did not pose a risk to human health (Environment Canada and Health Canada, 2003). DEHP was determined to present a risk to human health in Canada; however, there was insufficient information to conclude on the potential for risk to the environment. State of the Science reports were published in 2015 for the short-chain phthalate DMP, medium-chain phthalates (including DCHP and DiBP), long-chain phthalates (including DiDP), and DiNP (Environment Canada and Health Canada, 2015b; Environment Canada and Health Canada, 2015c; Environment Canada and Health Canada, 2015d; Environment Canada and Health Canada, 2015e). In 2017, a draft screening assessment was released that proposed to conclude that 13 of the 14 substances in the Phthalate Substance Grouping (including DMP, DiBP, DiNP, and DiDP) are not harmful to the environment or to human health as set out in section 64 of the Canadian Environmental Protection Act, 1999 (CEPA 1999), but that the remaining substance in the Grouping (B79P), along with DEHP, is harmful to the environment as set out in section 64(a) of CEPA 1999 (Environment and Climate Change Canada and Health Canada, 2017). In addition, a cumulative risk assessment using a conservative, lower-tiered hazard index approach indicated no concern for potential cumulative risk of medium-chain phthalates for the general Canadian population, specifically the more sensitive subpopulations (pregnant women and women of childbearing age, infants, and children) at current exposure levels (Environment Canada and Health Canada, 2015a; Environment and Climate Change Canada and Health Canada, 2017).

DEHP is identified as being prohibited on the List of Prohibited and Restricted Cosmetic Ingredients (more commonly referred to as the Cosmetic Ingredient Hotlist or simply the Hotlist), an administrative tool that Health Canada uses to communicate to manufacturers and others that certain substances, when present in a cosmetic, may not be compliant with requirements of the Food and Drugs Act or the Cosmetic Regulations (Health Canada, 2018). Health Canada has developed and implemented the Phthalates Regulations concerning the use of six phthalates (DEHP, DnBP, BBP, DiNP, DiDP, and DOP) in soft vinyl children's toys and child-care articles (Canada, 2010). Phthalates used in children's toys and child-care articles are also regulated in the United States and the European Union.

In the Maternal–Infant Research on Environmental Chemicals (MIREC) study of approximately 2,000 women from 10 sites across Canada, the following maximum-likelihood estimated geometric mean (GM) concentration (μg/L) of phthalate metabolites from first-trimester urine samples were reported (standardized for specific gravity): MnBP, 13.69; MEP, 37.73; MBzP, 6.14; MCPP, 1.02; MEHP, 2.63; MEOHP, 7.54; and MEHHP, 10.81, with non-detects reported for MMP, MCHP, MiNP, and MOP (Arbuckle et al., 2014).

Eleven monoester phthalate metabolites (MnBP, MEP, MBzP, MCHP, MEHP, MOP, MiNP, MMP, MCPP, MEHHP, and MEOHP) were measured in the urine of CHMS participants aged 6–49 years in cycle 1 (2007–2009), and aged 3–79 years in cycle 2 (2009–2011) and cycle 5 (2016–2017). MiBP was measured in the urine of CHMS cycle 2 (2009–2011) and cycle 5 (2016–2017) participants aged 3–79 years. MCMHP, MECPP, MCiNP, MHiDP, MiDP, MOiDP, MCiOP, MHiNP, MOiNP, 3OH-MBP, and MCHpP were measured in the urine of cycle 5 (2016–2017) participants aged 3–79 years. Data from these monoester phthalate metabolites are presented as both µg/L and µg/g creatinine (Tables 14.1.2 to 14.1.47). Finding a measurable amount of monoester phthalate metabolites in urine is an indicator of exposure to diester phthalates and does not necessarily mean that an adverse health effect will occur.

References

• Albert, O. and Jégou, B. (2014). A critical assessment of the endocrine susceptibility of the human testis to phthalates from fetal life to adulthood. Human Reproduction Update, 20 (2), 231-49.
• Arbuckle, T.E., Davis, K., Marro, L., Fisher, M., Legrand, M., LeBlanc, A., Gaudreau, E., Foster, W.G., Choeurng, V., Fraser, W.D., and the MIREC Study Group (2014). Phthalate and bisphenol A exposure among pregnant women in Canada — Results from the MIREC study. Environment International, 68, 55-65.
• ATSDR (Agency for Toxic Substances and Disease Registry) (1995). Toxicological Profile for Diethyl Phthalate (DEP). U.S. Department of Health and Human Services, Atlanta, GA. Retrieved June 5, 2018.
• ATSDR (Agency for Toxic Substances and Disease Registry) (1997). Toxicological Profile for Di-n-octylphthalate (DNOP). U.S. Department of Health and Human Services, Atlanta, GA. Retrieved June 5, 2018.
• ATSDR (Agency for Toxic Substances and Disease Registry) (2001). Toxicological Profile for Di-n-butyl Phthalate (DBP). U.S. Department of Health and Human Services, Atlanta, GA. Retrieved June 5, 2018.
• ATSDR (Agency for Toxic Substances and Disease Registry) (2002). Toxicological Profile for Di(2-ethylhexyl)phthalate (DEHP). U.S. Department of Health and Human Services, Atlanta, GA. Retrieved June 5, 2018.
• Becker, K., Güen, T., Seiwert, M., Conrad, A., Pick-Fuß, H., Müller, J., Wittassek, M., Schulz, C., and Kolossa-Gehring, M. (2009). GerES IV: Phthalate metabolites and bisphenol A in urine of German children. International Journal of Hygiene and Environmental Health, 212 (6), 685-692.
• Blount, B.C., Silva, M.J., Caudill, S.P., Needham, L.L., Pirkle, J.L., Sampson, E.J., Lucier, G.W., Jackson, R.J., and Brock, J.W. (2000). Levels of seven urinary phthalate metabolites in a human reference population. Environmental Health Perspectives, 108 (10), 979-982.
• Calafat, A.M. and McKee, R.H. (2006). Integrating biomonitoring exposure data into the risk assessment process: Phthalates (diethyl phthalate and di(2-ethylhexyl) phthalate) as a case study. Environmental Health Perspectives, 114 (11), 1783-1789.
• Canada (1999). Canadian Environmental Protection Act, 1999. SC 1999, c. 33. Retrieved June 5, 2018.
• Canada (2010). Phthalates Regulations. SOR/2010-298 December 10, 2010. Retrieved June 5, 2018.
• CDC (Centers for Disease Control and Prevention) (2009). Fourth national report on human exposure to environmental chemicals. Department of Health and Human Services, Atlanta, GA. Retrieved June 5, 2018.
• Clark, K. (2003). Assessment of critical exposure pathways. Phthalate Esters: Series Anthropogenic Compounds. Springer, Berlin.
• Cosmetic Ingredient Review Expert Panel (2005). Annual review of cosmetic ingredient safety assessment – 2002/2003. International Journal of Toxicology, 24 (Supplement 1) (1-2), 1-102.
• David, R.M. (2006). Proposed mode of action for in utero effects of some phthalate esters on the developing male reproductive tract. Toxicologic Pathology, 34 (3), 209-219.
• David, R.M. and Gans, G. (2003). Summary of mammalian toxicology and health effects of phthalate esters. Phthalate Esters: Series Anthropogenic Compounds. Springer, Berlin.
• Duty, S.M., Calafat, A.M., Silva, M.J., Ryan, L., and Hauser, R. (2005). Phthalate exposure and reproductive hormones in adult men. Human Reproduction, 20 (3), 604-610.
• Environment Canada and Health Canada (1993). Priority Substances List Assessment report for Di-n-Octyl Phthalate. Minister of Supply and Services Canada. Ottawa, ON. Retrieved June 5, 2018.
• Environment Canada and Health Canada (1994a). Priority Substances List Assessment Report: Dibutyl Phthalate. Minister of Supply and Services Canada, Ottawa, ON. Retrieved June 5, 2018.
• Environment Canada and Health Canada (1994b). Priority Substances List Assessment Report: Bis(2-ethylhexyl) Phthalate. Minister of Supply and Services Canada, Ottawa, ON. Retrieved June 5, 2018.
• Environment Canada and Health Canada (2000). Priority Substances List Assessment Report for Butylbenzylphthalate. Minister of Supply and Services Canada, Ottawa, ON. Retrieved June 5, 2018.
• Environment Canada and Health Canada (2003). Follow-Up Report on a PSL1 Substance for Which Data Were Insufficient to Conclude Whether the Substance Was "Toxic" to Human Health: Di-n-Octyl Phthalate. Minister of Supply and Services Canada, Ottawa, ON. Retrieved June 5, 2018.
• Environment Canada and Health Canada (2015a). Proposed Approach for Cumulative Risk Assessment of Certain Phthalates under the Chemicals Management Plan. Minister of the Environment, Ottawa, ON. Retrieved June 8, 2018.
• Environment Canada and Health Canada (2015b). State of the Science Report: Phthalate Substance Grouping ‒ 1,2-Benzenedicarboxylic acid, diisononyl ester, 1,2-Benzenedicarboxylic acid, di-C8-10-branched alkyl esters, C9-rich (Diisononyl Phthalate; DINP), Chemical Abstracts Service Registry Numbers 28553-12-0 and 68515-48-0. Minister of the Environment, Ottawa, ON. Retrieved June 8, 2018.
• Environment Canada and Health Canada (2015c). State of the Science Report: Phthalates Substance Grouping ‒ Long-chain Phthalate Esters: 1,2-Benzenedicarboxylic acid, diisodecyl ester (diisodecyl phthalate; DIDP) and 1,2-Benzenedicarboxylic acid, diundecyl ester (diundecyl phthalate; DUP), Chemical Abstracts Service Registry Numbers 26761-40-0, 68515-49-1; 3648-20-2. Minister of the Environment, Ottawa, ON. Retrieved June 6, 2018.
• Environment Canada and Health Canada (2015d). State of the Science Report: Phthalate Substance Grouping ‒ Medium-Chain Phthalate Esters: Chemical Abstracts Service Registry Numbers 84-61-7; 84-64-0; 84-69-5; 523-31-9; 5334-09-8; 16883-83-3; 27215-22-1; 27987-25-3; 68515-40-2; 71888-89-6. Minister of the Environment, Ottawa, ON. Retrieved June 6, 2018.
• Environment Canada and Health Canada (2015e). State of the Science Report: Phthalate Substance Grouping ‒ Short-Chain Phthalate Esters: 1,2-Benzenedicarboxylic acid, dimethyl ester [Dimethyl phthalate (DMP)], Chemical Abstracts Service Registry Number 131-11-3. Minister of the Environment, Ottawa, ON. Retrieved June 6, 2018.
• Environment and Climate Change Canada and Health Canada (2017). Chemicals Management Plan Draft Screening Assessment: Phthalate Substance Grouping. Minister of the Environment, Ottawa, ON. Retrieved June 11, 2018.
• Foster, P.M. (2005). Mode of action: Impaired fetal leydig cell function – Effects on male reproductive development produced by certain phthalate esters. Critical Reviews in Toxicology, 35 (8-9), 713-719.
• Frederiksen, H., Skakkebaek, N.E., and Andersson, A.M. (2007). Metabolism of phthalates in humans. Molecular Nutrition and Food Research, 51, 899-911.
• Graham, P.R. (1973). Phthalate ester plasticizers: Why and how they are used. Environmental Health Perspectives, 3, 3-12.
• Gray, L.E. Jr, Ostby, J., Furr, J., Price, M., Veeramachaneni, D.N., and Parks, L. (2000). Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. Toxicological Sciences, 58 (2), 350-365.
• Hannon, P.R. and Flaws, J.A. (2015). The Effects of Phthalates on the Ovary. Frontiers in Endocrinology, 6, 8.
• Hauser, R. and Calafat, A.M. (2005). Phthalates and human health. Occupational and Environmental Medicine, 62 (11), 806-818.
• Health Canada (2016). Supporting Documentation: Evaluation of Epidemiologic Studies on Phthalate Compounds and Their Metabolites. Minister of Health, Ottawa, ON. Available upon request.
• Health Canada (2018). List of Ingredients that are Prohibited for Use in Cosmetic Products (Hotlist). Minister of Health, Ottawa, ON. Retrieved November 28, 2018.
• Health Canada (2019). Phthalates. Minister of Health, Ottawa, ON, Canada. Retrieved March 20, 2019.
• Howdeshell, K.L., Furr, J., Lambright, C.R., Rider, C.V., Wilson, V.S., and Gray, L.E. Jr (2007). Cumulative effects of dibutyl phthalate and diethylhexyl phthalate on male rat reproductive tract development: Altered fetal steroid hormones and genes. Toxicological Sciences, 99 (1), 190-202.
• IARC (International Agency for Research on Cancer) (1999). IARC monographs on the evaluation of carcinogenic risks to humans – Volume 73: Some chemicals that cause tumours of the kidney or urinary bladder in rodents and some other substances. World Health Organization, Geneva. Retrieved June 7, 2018.
• IARC (International Agency for Research on Cancer) (2013). IARC monographs on the evaluation of carcinogenic risks to humans – Volume 101: Some chemicals present in industrial and consumer products, food and drinking-water. World Health Organization, Geneva. Retrieved June 7, 2018.
• Jensen, M.S., Nörgaard-Pedersen, B., Toft, G., Hougaard, D.M., Bonde, J.P., Cohen, A., Thulstrup, A.M., Ivell, R., Anand-Ivell, R., Lindh, C.H., and Jönsson, B.A.G. (2012). Phthalates and perfluorooctanesulfonic acid in human amniotic fluid: Temporal trends and timing of amniocentesis in pregnancy. Environmental Health Perspectives, 120 (6), 897-903.
• Lioy, P.J., Hauser, R., Gennings, C., Koch, H.M., Mirkes, P.E., Schwetz, B.A. and Kortenkamp, A. (2015). Assessment of phthalates/phthalate alternatives in children's toys and childcare articles: Review of the report including conclusions and recommendation of the Chronic Hazard Advisory Panel of the Consumer Product Safety Commission. Journal of Exposure Science and Environmental Epidemiology, 25 (4), 343–53.
• Liu, S.-B., Ma, Z., Sun, W.-L., Sun, X.-W., Hong, Y., Ma, L., Qin, C., Stratton, H.J., Liu, Q., and Jiang, J.-T. (2012). The role of androgen-induced growth factor (FGF8) on genital tubercle development in a hypospadiac male rat model of prenatal exposure to di-n-butyl phthalate. Toxicology, 293 (1-3), 53–58.
• Main, K.M., Mortensen, G.K., Kaleva, M.M., Boisen, K.A., Damgaard, I.N., Chellakooty, M., Schmidt, I.M., Suomi, A.M., Virtanen, H.E., Petersen, D.V., Andersson, A.M., Toppari, J., and Skakkebaek, N.E. (2006). Human breast milk contamination with phthalates and alterations of endogenous reproductive hormones in infants three months of age. Environmental Health Perspectives, 114 (2), 270-276.
• Mariana, M., Feiteiro, J., Verde, I. and Cairrao, E. (2016). The effects of phthalates in the cardiovascular and reproductive systems: A review. Environment International 94, 758-776.
• Marie, C., Vendittelli, F., and Sauvant-Rochat, M.P. (2015). Obstetrical outcomes and biomarkers to assess exposure to phthalates: A review. Environment International, 83, 116-136.
• Marsee, K., Woodruff, T.J., Axelrad, D.A., Calafat, A.M., and Swan, S.H. (2006). Estimated daily phthalate exposures in a population of mothers of male infants exhibiting reduced anogenital distance. Environmental Health Perspectives, 114 (6), 805-809.
• NRC (National Research Council) (2008). Phthalates and cumulative risk assessment: The tasks ahead. Committee on the Health Risks of Phthalates, The National Academies Press, Washington, DC.
• NTP-CERHR (National Toxicology Program – Center for the Evaluation of Risks to Human Reproduction) (2003a). NTP-CERHR monograph on the potential human reproductive and developmental effects of di-isononyl phthalate (DINP). National Institutes of Health, Research Triangle Park, NC.
• NTP-CERHR (National Toxicology Program – Center for the Evaluation of Risks to Human Reproduction) (2003b). NTP-CERHR monograph on the potential human reproductive and developmental effects of di-isodecyl phthalate (DIDP). National Institutes of Health, Research Triangle Park, NC.
• NTP-CERHR (National Toxicology Program – Center for the Evaluation of Risks to Human Reproduction) (2003c). NTP-CERHR monograph on the potential human reproductive and developmental effects of di-n-butyl phthalate (DBP). National Institutes of Health, Research Triangle Park, NC.
• NTP-CERHR (National Toxicology Program – Center for the Evaluation of Risks to Human Reproduction) (2003d). NTP-CERHR monograph on the potential human reproductive and developmental effects of butyl benzyl phthalate (BBP). National Institutes of Health, Research Triangle Park, NC.
• NTP-CERHR (National Toxicology Program – Center for the Evaluation of Risks to Human Reproduction) (2003e). NTP-CERHR monograph on the potential human reproductive and developmental effects of di-n-octyl phthalate (DnOP). National Institutes of Health, Research Triangle Park, NC.
• NTP-CERHR (National Toxicology Program – Center for the Evaluation of Risks to Human Reproduction) (2003f). NTP-CERHR monograph on the potential human reproductive and developmental effects of di-n-hexyl phthalate (DnHP). National Institutes of Health, Research Triangle Park, NC.
• NTP-CERHR (National Toxicology Program – Center for the Evaluation of Risks to Human Reproduction) (2006). NTP-CERHR monograph on the potential human reproductive and developmental effects of di(2-ethylhexyl) phthalate (DEHP). National Institutes of Health, Research Triangle Park, NC.
• Philippat, C., Mortamais, M., Chevrier, C., Petit, C., Calafat, A.M., Ye, X., Silva, M.J., Brambilla, C., Pin, I., Charles, M.-A., Cordier, S., and Slama, R. (2011). Exposure to phthalates and phenols during pregnancy and offspring size at birth. Environmental Health Perspectives, 120 (3), 464-470.
• Praveena, S.M., Teh, S.W., Rajendran, R.K., Kannan, N., Lin, C., Abdullah, R. and Kumar, S. (2018). Recent updates on phthalate exposure and human health: a special focus on liver toxicity and stem cell regeneration. Environmental Science and Pollution Research, 25 (12), 11333–11342.
• Samandar, E., Silva, M.J., Reidy, J.A., Needham, L.L., and Calafat, A.M. (2009). Temporal stability of eight phthalate metabolites and their glucuronide conjugates in human urine. Environmental Research, 109 (5), 641-646.
• Silva, M.J., Barr, D.B., Reidy, J.A., Malek, N.A., Hodge, C.C., Caudill, S.P., Brock, J.W., Needham, L.L., and Calafat, A.M. (2003). Urinary levels of seven phthalate metabolites in the U.S. population from the National Health and Nutrition Examination Survey (NHANES) 1999-2000. Environmental Health Perspectives, 112 (3), 331-338.
• Snijder, C.A., Roeleveld, N., te Velde, E., Steegers, E.A.P., Raat, H., Hofman, A., Jaddoe, V.W.V., and Burdorf, A. (2012). Occupational exposure to chemicals and fetal growth: The Generation R Study. Human Reproduction, 27(3), 910-920.
• Swan, S.H., Main, K.M., Liu, F., Stewart, S.L., Kruse, R.L., Calafat, A.M., Mao, C.S., Redmon, J.B., Ternand, C.L., Sullivan, S., and Teague, J.L. (2005). Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environmental Health Perspectives, 113 (8), 1056-1061.
• Wine, R.N., Li, L.H., Barnes, L.H., Gulati, D.K., and Chapin, R.E. (1997). Reproductive toxicity of di-n-butylphthalate in a continuous breeding protocol in Sprague-Dawley rats. Environmental Health Perspectives, 105 (1), 102-107.
• Wittassek, M., Koch, H.M., Angerer, J., and Bruning, T. (2011). Assessing exposure to phthalates – The human biomonitoring approach. Molecular Nutrition and Food Research, 55, 7–31.

14.2 Di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH)

Di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH) (CASRN 166412-78-8) is an aliphatic ester compound with the appearance of a colourless liquid at room temperature. This substance may also be referred to as diisononyl hexahydrophthalate, among other synonyms. Produced commercially, DINCH is commonly synthesized by catalytic hydrogenation of the aromatic ring of diisononyl phthalate (DiNP), and consists mostly of cis-isomers (~90%) with a much smaller proportion of trans-isomers (Bhat et al., 2014; Koch et al., 2013; SCENIHR, 2016). DINCH is used as a substitute for high molecular-weight medium-chain phthalate plasticizers such as DiNP and di(2-ethylhexyl) phthalate (DEHP), primarily in polyvinyl chloride (PVC) materials used in beverage and food contact applications (Bhat et al., 2014; NICNAS, 2012). DINCH is also used as a plasticizer and impact modifier in polystyrene for sensitive applications such as toys, food contact materials, and medical devices (Bhat et al., 2014; Koch et al., 2013; NICNAS, 2012).

DINCH does not occur naturally. It is only released to the environment from anthropogenic sources. Release of this substance into the environment can occur during PVC product manufacture and from degradation of consumer products. DINCH has very low volatility and water solubility; therefore, it is expected to occur minimally in air and water (NICNAS, 2012). Given that DINCH can leach out of the polymer matrix when used as a plasticizer, the general population may be exposed to it dermally from contact with consumer products such as plastic toys and car upholstery, orally from materials that contact food or beverages, orally or intravenously through medical applications, or via the inhalation or ingestion of house dust (Bhat et al., 2014; NICNAS, 2012; SCENIHR, 2016). However, due to the limited use of DINCH in products available to consumers and the low leaching of the compound out of the polymer matrix when used as a plasticizer, exposure via use of consumer products is expected to be low (NICNAS, 2012; SCENIHR, 2016). Given the very low vapour pressure of DINCH, exposure via inhalation is of minimal concern (NICNAS, 2012).

The toxicokinetics of DINCH in humans are not well studied. Experimental animal studies have reported rapid absorption of DINCH following ingestion, while no data were identified concerning dermal absorption (Bhat et al., 2014; SCENIHR, 2016). The oral bioavailability of DINCH is inversely proportional to the dose due to saturation of gastrointestinal absorption, with one study demonstrating that a higher oral dose led to a lower absorbed fraction in laboratory animals. Studies of orally exposed animals indicate that DINCH is distributed throughout the body following absorption (Bhat et al., 2014; ECHA, 2016; SCENIHR, 2016). In animals exposed by ingestion, DINCH was found to undergo hydrolysis to cyclohexane-1,2-dicarboxylic mono isononyl ester (MINCH) before being further hydrolyzed to cyclohexane-1,2-dicarboxylic acid (CHDA), the main urinary metabolite; unmetabolized DINCH was the main compound identified in feces (Bhat et al., 2014; Koch et al., 2013). In studies with laboratory animals, total excretion of radiolabelled DINCH and its metabolites represented ~90% of the administered dose. DINCH is mainly excreted in feces within 48 hours, whereas a smaller fraction is eliminated via urinary metabolites over the same period (Bhat et al., 2014).

Acute dermal and ocular exposure to DINCH was found to be non-irritating in laboratory animals, and no skin sensitization was observed. Experimental animal studies have reported that DINCH has low toxicity following acute, short-term, or sub-chronic ingestion exposure. However, chronic ingestion of high doses of this substance was found to result in increased liver, kidney, and thyroid weights (Bhat et al., 2014; SCENIHR, 2016). One study of laboratory animals exposed in utero to DINCH from gestational day 14 until parturition reported a long-term effect on Leydig cells of the testis, indicated by reduced circulating testosterone levels and altered testicular morphology (Campioli et al., 2017). However, this finding has not been repeated in other studies. In a two-generation animal study, DINCH had no adverse reproductive or developmental effects (Bhat et al., 2014). DINCH is not considered genotoxic or carcinogenic (Bhat et al., 2014; ECHA, 2016; SCENIHR, 2016).

Six metabolites of DINCH (trans-cyclohexane-1,2-dicarboxylic mono isononyl ester [trans-MINCH]; cyclohexane-1,2-dicarboxylic mono oxoisononyl ester [oxo-MINCH]; cyclohexane-1,2-dicarboxylic mono hydroxyisononyl ester [OH-MINCH]; cis-cyclohexane-1,2-dicarboxylic mono carboxyisononyl ester [cis-cx-MINCH]; trans-cyclohexane-1,2-dicarboxylic mono carboxyisononyl ester [trans-cx-MINCH]; and CHDA) were analyzed in the urine of Canadian Health Measures Survey participants aged 3–79 years in cycle 5 (2016–2017). Data from the metabolites are presented both as μg/L and μg/g creatinine. Finding a measurable amount of these metabolites in urine can be an indicator of recent exposure to DINCH and does not necessarily mean that an adverse effect will occur.

References

• Bhat, V.S., Durham, J.L., Ball, G.L., and English, J.C. (2014). Derivation of an oral reference dose (RfD) for the nonphthalate alternative plasticizer 1,2-cyclohexane dicarboxylic acid, di-isononyl ester (DINCH). Journal of Toxicology and Environmental Health, Part B, 17(2), 63–94.
• Campioli, E., Lee, S., Lau, M., Marques, L., and Papadopoulos, V. (2017). Effect of prenatal DINCH plasticizer exposure on rat offspring testicular function and metabolism. Scientific Reports, 7, 11072.
• ECHA (European Chemicals Agengy) (2016). Analysis of the most appropriate risk management option (RMOA): 1,2-cyclohexanedicarboxylic acid, diisononyl ester (DINCH®). Retrieved November 9, 2018.
• Health Canada (2018). Licensed natural health products database. Minister of Health, Ottawa, ON. Retrieved November 1, 2018.
• Koch, H.M., Schütze, A., Pälmke, C., Angerer, J., and Brüning, T. (2013). Metabolism of the plasticizer and phthalate substitute diisononyl-cyclohexane-1,2-dicarboxylate (DINCH®) in humans after single oral doses. Archives of Toxicology, 87(5), 799–806.
• NICNAS (National Industrial Chemicals Notification and Assessment Scheme) (2012). Public Report: 1,2-Cyclohexanedicarboxylic acid, 1,2-diisononyl ester ('Hexamoll DINCH'). Sydney, Australia. Retrieved November 1, 2018.
• SCENIHR (Scientific Committee on Emerging and Newly-Identified Health Risks) (2016). Opinion on the safety of medical devices containing DEHP-plasticized PVC or other plasticizers on neonates and other groups possibly at risk (2015 update). Published February 2016. Retrieved February 14, 2019.

14.3 2,2,4-Trimethyl-1,3-pentanediol diisobutyrate (TXIB)

2,2,4-Trimethyl-1,3-pentanediol diisobutyrate (TXIB) (CASRN 6846-50-0) is an ester compound with the appearance of a clear liquid at room temperature. This substance may also be referred to as propanoic acid, 2-methyl-, 2,2-dimethyl-1-(1-methylethyl)-1,3-propanediyl ester, among other synonyms. It is produced commercially, and is commonly synthesized by the esterification of isobutyraldehyde with 2,2,4-trimethyl-1,3-pentanediol (Törmäkangas and Koskinen, 2001). TXIB is a secondary plasticizer, used in combination with other plasticizers, and is used in products like weather stripping, furniture, wallpaper, vinyl flooring, sporting goods, traffic cones, vinyl gloves, inks, water-based paints, and toys (CIR, 2017).

TXIB does not occur naturally. It is only released to the environment from anthropogenic sources. TXIB has moderate volatility and water solubility; therefore, it can be expected to occur in air and water, although it will likely volatilize from water surfaces (CIR, 2017). Given that TXIB can leach out of the polymer matrix when used as a plasticizer, the general population may be exposed to it dermally from the use of products available to consumers such as cosmetics. Exposure may also occur through the inhalation of indoor air or dust.

The toxicokinetics of TXIB in humans are not well studied. Experimental animal studies have reported a high level of absorption of TXIB following ingestion; however, no dermal absorption data were identified. Animal studies indicate that TXIB is not significantly distributed throughout the body following absorption. In animals exposed by ingestion, TXIB was found to undergo metabolic hydrolysis to the monoisobutyrate of 2,2,4-trimethyl-1,3-pentanediol (TMPD). Total excretion of TXIB following metabolism represented 95% to 99% of the administered dose. It is mainly excreted in urine within 72 hours; a smaller fraction is eliminated in feces over approximately one week (CIR, 2017). Animal studies report that TXIB is predominantly excreted as the O-glucuronide of TMPD in urine, and to a much lesser extent as 2,2,4-trimethyl-3-hydroxyvaleric acid (HTMV) and its glucuronides, 2-methylmalonic acid, and unchanged TXIB (CIR, 2017). In feces, TXIB is excreted unchanged and as the metabolite TMPD and its monoester (CIR, 2017; ECHA, 2018).

Experimental animal studies have reported that TXIB has low toxicity following acute ingestion exposure (producing moderate weakness and some vasodilation), while chronic ingestion of this substance has been associated with increased liver and kidney weights (CIR, 2017; OECD, 1995). Histopathological investigation of chronically exposed animals revealed necrosis of the proximal tubules, dilatation of distal tubules, fibrosis in the kidneys, and centrilobular swelling of hepatocytes in the liver (CIR, 2017; OECD, 1995). TXIB has been associated with reproductive toxicity in animal studies on the basis of a reduction in the number of implantation sites in females (ECHA, 2001). TXIB is not considered genotoxic and is not expected to be carcinogenic (OECD, 1995).

A Chemicals Management Plan screening-level risk assessment is currently underway to determine whether TXIB presents or may present a risk to the environment or human health as per the criteria set out in section 64 of the Canadian Environmental Protection Act, 1999 (Canada, 1999; Environment and Climate Change Canada, 2019). TXIB is also found in cosmetic products notified under the Cosmetic Regulations of the Food and Drugs Act (Canada, 1985).

Two metabolites of TXIB (TMPD and HTMV) were analyzed in the urine of Canadian Health Measures Survey (CHMS) participants aged 3–79 years in cycle 5 (2016–2017). Data from the metabolites are presented as μg/L and µg/g creatinine. Finding a measurable amount of these metabolites in urine can be an indicator of recent exposure to TXIB and does not necessarily mean that an adverse effect will occur.

References

• Canada (1985). Food and Drugs Act. RSC 1985, c. F-27. Retrieved February 22, 2018.
• Canada (1999). Canadian Environmental Protection Act, 1999. S.C. 1999, c. 33. Retrieved September 13, 2018.
• CIR (Cosmetic Ingredient Review) (2017). Safety Assessment of Monoalkylglycol Dialkyl Acid Esters as Used in Cosmetics. Washington, D.C. Retrieved February 27, 2019.
• David, R.M., Lockhart, L.K. and Ruble, K.M. (2003). Lack of sensitization for trimellitate, phthalate, terephthalate and isobutyrate plasticizers in a human repeated insult patch test. Food and Chemical Toxicology 41(4), 589–593.
• ECHA (European Chemicals Agency) (2001). 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate, CAS RN 6846-50-0. Industry Submission to ECHA. Retrieved October 18, 2018.
• ECHA (European Chemicals Agency) (2018). Registration dossier for isobutyric acid, monoester with 2,2,4-trimethylpentane-1,3-diol. Retrieved October 31, 2018.
• Environment and Climate Change Canada (2019). List of substances in the third phase of CMP (2016–2021): July 2019 update. Minister of Environment and Climate Change, Ottawa, ON. Retrieved September 6, 2019.
• OECD (Organisation for Economic Co-operation and Development) (1995). (SIDS) Initial Assessment Report on 2,2,4-Trimethyl-1,3-pentanediol diisobutyrate, CAS N°:6846-50-0. Williamsburg, VA, USA.
• Törmäkangas, O.P. and Koskinen, A.M.P. (2001). Fast Aldol-Tishchenko reaction utilizing 1,3-diol monoalcoholates as the catalysts. Organic Process Research and Development 5(4), 421–425.

14.4 Tri-(2-ethylhexyl) trimellitate (TEHT)

Tri-(2-ethylhexyl) trimellitate (TEHT) (CASRN 3319-31-1) is an ester compound with the appearance of a yellow oily liquid at room temperature. This substance may also be referred to as trioctyl trimellitate (TOTM) or triethylhexyl trimellitate, among other synonyms. It is most commonly manufactured through the esterification of trimellitic anhydride with 2-ethylhexyl alcohol (CIR, 2015). TEHT is primarily used as a plasticizer in floor coverings, building and construction materials, plastic and rubber materials, medical devices, and in cosmetics as an emollient and skin-conditioning agent. It may also be used as a fuel additive, in adhesives and sealants used in the transportation sector, and as a lubricant and lubricant additive (CIR, 2015; Environment and Climate Change Canada and Health Canada, 2019).

TEHT does not occur naturally and is only released to the environment from anthropogenic sources (Environment and Climate Change Canada and Health Canada, 2019). TEHT has very low volatility and water solubility, and is therefore expected to minimally occur in air and water (Environment and Climate Change Canada and Health Canada, 2019). The general population may be exposed to TEHT dermally from the use of products available to consumers, including cosmetics, and through the ingestion of dust (CIR, 2015; Environment and Climate Change Canada and Health Canada, 2019). Since only low levels leach out of the polymer matrix when TEHT is used as a plasticizer, exposure via the use of consumer products is expected to be low (SCENIHR, 2016). The mouthing of plastic toys is not expected to result in exposure to TEHT (Environment and Climate Change Canada and Health Canada, 2019). Given the very low volatility of TEHT, exposure via inhalation is of minimal concern (Environment and Climate Change Canada and Health Canada, 2019).

The toxicokinetics of TEHT in humans are not well studied. Experimental animal studies have shown that the absorption of TEHT following ingestion or dermal exposure is low (<1%). TEHT was mainly distributed to the liver, lungs, and spleen in animals following an intravenous dose. In animals exposed through ingestion, TEHT was found to undergo hydrolysis, and its elimination was biphasic, with half-lives of 3.1 and 42 hours in urine, and 4.3 and 31 hours in expired CO2 (CIR, 2015). TEHT is mostly excreted in feces; a small fraction is excreted in urine. An animal study reported that orally administered TEHT was excreted in feces predominantly in an unchanged form and to a much lesser extent as mono-(2-ethylhexyl) trimellitate, di-(2-ethylhexyl) trimellitate, and unidentified polar metabolites; in urine, the metabolites were identified as mono-(2-ethylhexyl) trimellitate, 2-ethylhexanol, 2-ethylhexanoic acid, and 2-heptanone (CIR, 2015).

Experimental animal studies have reported that TEHT has low toxicity following acute ingestion exposure; chronic ingestion was found to result in enlarged liver and spleen (CIR, 2015; OECD, 2002). Animals acutely exposed to high concentrations of TEHT via inhalation showed lung irritation, but no other signs of toxicity (CIR, 2015; OECD, 2002). TEHT has been associated with male reproductive toxicity based on reduced testes weight and decreased numbers of spermatocytes and spermatids in laboratory animals (Environment and Climate Change Canada and Health Canada, 2019; OECD, 2002). TEHT is not considered genotoxic and is not expected to be carcinogenic (Environment and Climate Change Canada and Health Canada, 2019).

The Government of Canada has conducted a science-based screening assessment under the Chemicals Management Plan to determine whether TEHTpresents or may present a risk to the environment or human health as per the criteria set out in section 64 of the Canadian Environmental Protection Act, 1999 (CEPA 1999) (Canada, 1999; Environment and Climate Change Canada and Health Canada, 2019). The assessment concluded that TEHT does not meet any of the criteria for being considered toxic under CEPA 1999. TEHT is found in cosmetic products notified under the Cosmetic Regulations of the Food and Drugs Act (Canada, 1985).

Three metabolites of TEHT — 1-mono(2-ethylhexyl) trimellitate (1-MEHTM), 2-mono(2-ethylhexyl) trimellitate (2-MEHTM), and 4-mono(2-ethylhexyl) trimellitate (4-MEHTM) — were analyzed in the urine of Canadian Health Measures Survey participants aged 3–79 years in cycle 5 (2016–2017). Data for the metabolites are presented as both µg/L and μg/g creatinine. Finding a measurable amount of these metabolites in urine can be an indicator of recent exposure to TEHT and does not necessarily mean that an adverse effect will occur.

References

• Canada (1985). Food and Drugs Act. RSC 1985, c. F-27. Retrieved February 22, 2018.
• Canada (1999). Canadian Environmental Protection Act, 1999. S.C. 1999, c. 33. Retrieved September 13, 2018.
• CIR (Cosmetic Ingredient Review) (2015). Safety Assessment of Trialkyl Trimellitates as Used in Cosmetics. Final report. Washington, D.C. Retrieved September 5, 2018.
• Environment and Climate Change Canada and Health Canada (2019). Screening assessment trimellitates group. Government of Canada, Ottawa, ON. Retrieved March 6, 2019.
• OECD (Organisation for Economic Co-operation and Development) (2002). (SIDS) Initial Assessment Report for Tris(2-ethylhexyl)benzene-1,2,4-tricarboxylate (CAS No. 3319-31-1). Retrieved September 21, 2018.
• SCENIHR (Scientific Committee on Emerging and Newly-Identified Health Risks) (2016). Opinion on the safety of medical devices containing DEHP-plasticized PVC or other plasticizers on neonates and other groups possibly at risk (2015 update) . Retrieved September 27, 2018.

• Previous Page
• Table of Contents
• Next Page