Page 5: Sixth Report on Human Biomonitoring of Environmental Chemicals in Canada

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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 products available to consumers and industrial products. Table 14.1.1 lists phthalates commonly found in commerce and their major metabolites measured in 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; HC, 2020). They are also used as solvents in household products, including self-care products, construction and renovation products, and textiles (HC, 2020). 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; ECCC and HC, 2020; EC and HC, 2000; 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 (ECCC and HC, 2020; EC and HC, 2000; 2015b; 2015d; HC, 2020). DOP, BBP, DMP, DnBP, DIDP, DiBP and DINP are used in electrical items and electronics (ECCC and HC, 2020; EC and HC, 2015b; 2015c; 2015d; 2015e; HC, 2020). Phthalates are also 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) (ECCC and HC, 2020; EC and HC, 2015d; HC, 2020). Finally, certain phthalates, including BBP, DEHP, DIDP and DMP, can be found in food-packaging materials (ECCC and HC, 2020; EC and HC, 2015c; 2015e; HC, 2020). 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 childcare articles.

There are no known natural sources of phthalates. Releases to the environment are associated with anthropogenic activities (ECCC and HC, 2020). Releases may occur during the manufacture, processing, transportation and storage of phthalates as well as during the production, use and disposal of products that contain phthalates (ECCC and HC, 2020). Although release into air may occur, water is expected to be the primary receiving medium for phthalates through wastewater effluents from industrial sources and disperse releases from products available to consumers (ECCC and HC, 2020; EC and HC, 2015d).

Phthalates have been detected in food, water, air, soil and dust (Clark, 2003; ECCC and HC, 2020). The general population can be exposed through the inhalation of indoor air; through the ingestion of water, food, beverages, soil and dust; and through the use of products available to consumers (HC, 2020). Other potential sources of exposure are breast milk and the mouthing of children's toys and articles (ECCC and HC, 2020).

In laboratory animals, phthalates have been observed to undergo rapid absorption following oral exposure and generally slow absorption following dermal exposure (ATSDR, 1995; 1997; 2001). Phthalate diesters are converted to their corresponding monoesters in the gastrointestinal tract or saliva prior to absorption (ATSDR, 1995; 1997; 2001; 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, as a result, 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; 1997; 2001; 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; EC and HC, 2015b; 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, termed "rat phthalate syndrome," 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 (EC and HC, 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; EC and HC, 2015b; 2015c; 2015d; 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; HC, 2018a; 2018b; Lioy et al., 2015; Marsee et al., 2006; NTP-CERHR, 2003a; 2003b; 2003c; 2003d; 2003e; 2003f; 2006; Praveena et al., 2018; Silva et al., 2003; Wittassek et al., 2011). An evaluation by Health Canada of 134 epidemiologic studies of phthalates and health outcomes in categories including hormonal effects, growth and development, and reproductive parameters (HC, 2018a) — as well as a Health Canada evaluation of 125 epidemiologic studies of phthalates and health outcomes in categories including behaviour and neurodevelopment, cardiovascular function, oxidative stress, breast cancer, obesity, allergy (inflammation of the airways and skin) and metabolic disorders (HC, 2018b) — determined that no health outcome had sufficient evidence of an association with any assessed phthalate or its metabolite (HC, 2018a; 2018b). The International Agency for Research on Cancer has classified DEHP as possibly carcinogenic to humans (Group 2B) and has determined that BBP's carcinogenicity to humans is not classifiable (Group 3) (IARC, 1999; 2013).

Environment Canada and Health Canada assessed 4 phthalates (DBP, BBP, DEHP and DOP) on an individual basis as part of the First and Second Priority Substances Lists (PSL1 and PSL2) (EC and HC, 1993; 1994a; 1994b; 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 (EC and HC, 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 at the time of the assessment. 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 (EC and HC, 2015b; 2015c; 2015d; 2015e). A screening assessment concluded that 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 DEHP, previously assessed under the Priority Substances Assessment Program, is harmful to the environment as set out in section 64(a) of CEPA 1999 (Canada, 1999; ECCC and HC, 2020). 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, women of child-bearing age, infants and children) at current exposure levels (EC and HC, 2015a; ECCC and HC, 2020).

Health Canada has developed and implemented the Phthalates Regulations under the Canada Consumer Product Safety Act concerning the use of 6 phthalates (DEHP, DnBP, BBP, DINP, DIDP and DOP) in soft vinyl children's toys and childcare articles (Canada, 2010). Phthalates used in children's toys and childcare articles are also regulated in the United States and the European Union. DEHP is on the List of Ingredients that are Prohibited for Use in Cosmetic Products (HC, 2019).

Phthalate metabolite concentrations in urine have been measured in a number of biomonitoring studies conducted in Canada, including the Maternal–Infant Research on Environmental Chemicals study (Arbuckle et al., 2014), the First Nations Biomonitoring Initiative (AFN, 2013), and the Canadian Healthy Infant Longitudinal Development (CHILD) study (Navaranjan et al., 2020).

Eleven 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 in cycle 1 (2007–2009) and aged 3–79 in cycle 2 (2009–2011), cycle 5 (2016–2017) and cycle 6 (2018–2019). MiBP was measured in the urine of CHMS participants aged 3–79 in cycles 2, 5 and 6. MCMHP, MECPP, MCiNP, MHiDP, MiDP, MOiDP, MCiOP, MHiNP, MOiNP, 3OH-MBP and MCHpP were measured in the urine of CHMS participants aged 3–79 in cycles 5 and 6. Data from these cycles are presented as both µg/L and µg/g creatinine (Tables 14.1.2 to 14.1.47). Finding a measurable amount of phthalate metabolites in urine is an indicator of exposure to parent phthalates and does not necessarily mean that an adverse health effect will occur.

References

• AFN (Assembly of First Nations) (2013). First Nations Biomonitoring Initiative: National results (2011). Assembly of First Nations, Ottawa, ON. Retrieved May 18, 2021.
• 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. U.S. Department of Health and Human Services, Atlanta, GA. Retrieved March 4, 2021.
• ATSDR (Agency for Toxic Substances and Disease Registry) (1997). Toxicological Profile for Di-n-octylphthalate. U.S. Department of Health and Human Services, Atlanta, GA. Retrieved March 4, 2021.
• ATSDR (Agency for Toxic Substances and Disease Registry) (2001). Toxicological Profile for Di-n-butyl Phthalate. U.S. Department of Health and Human Services, Atlanta, GA. Retrieved March 4, 2021.
• 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 March 5, 2021.
• Canada (2010). Phthalates Regulations. SOR/2010-298 December 10, 2010. Retrieved March 5, 2021.
• 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 March 5, 2021.
• 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.
• EC and HC (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 March 5, 2021.
• EC and HC (Environment Canada and Health Canada) (1994a). Priority Substances List Assessment Report: Dibutyl Phthalate. Minister of Supply and Services Canada, Ottawa, ON. Retrieved March 5, 2021.
• EC and HC (Environment Canada and Health Canada) (1994b). Priority Substances List Assessment Report: Bis(2-ethylhexyl) Phthalate. Minister of Supply and Services Canada, Ottawa, ON. Retrieved March 5, 2021.
• EC and HC (Environment Canada and Health Canada) (2000). Priority Substances List Assessment Report for Butylbenzylphthalate. Minister of Supply and Services Canada, Ottawa, ON. Retrieved March 5, 2021.
• EC and HC (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 March 5, 2021.
• EC and HC (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 March 5, 2021.
• EC and HC (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 March 5, 2021.
• EC and HC (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 March 5, 2021.
• EC and HC (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 March 5, 2021.
• EC and HC (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 March 5, 2021.
• ECCC and HC (Environment and Climate Change Canada and Health Canada) (2020). Screening assessment - Phthalate substance grouping. Minister of Environment and Climate Change, Ottawa, ON. Retrieved March 26, 2021.
• 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.
• HC (Health Canada) (2018a) Supporting Documentation: Evaluation of Epidemiologic Studies on Phthalate Compounds and Their Metabolites for Hormonal Effects, Growth and Development and Reproductive Parameters. Minister of Health, Ottawa, ON. Available on request from: substances@ec.gc.ca.
• HC (Health Canada) (2018b) Supporting Documentation: Evaluation of Epidemiologic Studies on Phthalate Compounds and Their Metabolites for Effects on Behaviour and Neurodevelopment, Allergies, Cardiovascular Function, Oxidative Stress, Breast Cancer, Obesity, and Metabolic Disorders. Minister of Health, Ottawa, ON. Available on request from: substances@ec.gc.ca.
• HC (Health Canada) (2019). List of Ingredients that are Prohibited for Use in Cosmetic Products (Hotlist). Minister of Health, Ottawa, ON. Retrieved March 5, 2021.
• HC (Health Canada) (2020). Phthalates. Minister of Health, Ottawa, ON, Canada. Retrieved March 5, 2021.
• 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 March 5, 2021.
• 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 March 5, 2021.
• 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.
• 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.
• 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.
• Navaranjan, G., Takaro, T.K., Wheeler, A.J., Diamond, M.L., Shu, H., Azad, M.B., Becker, A.B., Dai, R., Harris, S.A., Lefebvre, D.L. and Lu, Z. (2020). Early life exposure to phthalates in the Canadian Healthy Infant Longitudinal Development (CHILD) study: a multi-city birth cohort. Journal of Exposure Science and Environmental Epidemiology, 30 (1), 70-85.
• 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. Retrieved March 5, 2021.
• 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. Retrieved March 5, 2021.
• 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. Retrieved March 5, 2021.
• 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. Retrieved March 5, 2021.
• 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. Retrieved March 5, 2021.
• 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. Retrieved March 5, 2021.
• 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. Retrieved March 5, 2021.
• 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.
• 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 Brüning, 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 that is a colourless liquid at room temperature. This substance may also be referred to as diisononyl hexahydrophthalate, among other synonyms. Commercial production of DINCH uses catalytic hydrogenation of the aromatic ring of diisononyl phthalate (DINP), and results in a mixture of cis-isomers (~90%) and 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 for beverage and food contact applications (Bhat et al., 2014; NICNAS, 2012). DINCH is also used as a plasticizer and impact modifier in polystyrene in toys, food contact materials and medical devices (Bhat et al., 2014; Koch et al., 2013; NICNAS, 2012).

DINCH does not occur naturally and is released to the environment from anthropogenic sources. It may be released during product manufacture and from degradation of products and packaging. DINCH has very low vapour pressure (volatility) and water solubility, and is therefore expected to occur minimally in air and water (NICNAS, 2012). The general population may be exposed to DINCH dermally from contact with 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). Because the use of DINCH in products available to consumers is limited — and given that it leaches only minimally from the polymer matrix when used as a plasticizer — exposure via product use 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).

Rapid absorption of DINCH has been reported in experimental animal studies following ingestion, while no data were identified concerning dermal absorption (Bhat et al., 2014; SCENIHR, 2016). In 1 study, DINCH showed rapid but saturable absorption following oral exposure, with oral bioavailability estimated to be higher after a lower dose than a higher dose (SCENIHR, 2016). Studies of orally exposed animals indicate that DINCH is distributed throughout the body following absorption (Bhat et al., 2014; ECHA, 2016; SCENIHR, 2016). In a study of human volunteers administered DINCH orally, more than 85% of the administered dose was excreted as cyclohexane-1,2-dicarboxylic acid (CHDA) within 70 hours following hydrolysis; OH-MINCH was the main secondary metabolite, with about 14% of the administered dose (Völkel et al., 2016). In orally exposed animals, DINCH was hydrolyzed to cyclohexane-1,2-dicarboxylic mono isononyl ester (MINCH) before being further hydrolyzed to CHDA, the main urinary metabolite (Bhat et al., 2014; Koch et al., 2013). Minor urinary metabolites include the oxidized monoesters hydroxy-MINCH, oxo-MINCH and carboxy-MINCH (Bhat et al., 2014; Völkel et al., 2016). In studies with laboratory animals, unmetabolized DINCH was mainly excreted in feces within 48 hours, whereas a smaller fraction was eliminated via urinary metabolites over the same period. The total excretion of radiolabelled DINCH and its metabolites represented ~90% of the administered dose (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 subchronic 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). In a 2-generation animal study, DINCH had no adverse reproductive or developmental effects (Bhat et al., 2014). One study of laboratory animals exposed to DINCH in utero from gestational day 14 until parturition reported a long-term effect on Leydig cells of the testes, indicated by reduced circulating testosterone levels and altered testicular morphology (Campioli et al., 2017). 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 in cycle 5 (2016–2017) and cycle 6 (2018–2019). Data from these cycles 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 DINCH and does not necessarily mean that an adverse health 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 Agency) (2016). Analysis of the most appropriate risk management option (RMOA): 1,2-cyclohexanedicarboxylic acid, diisononyl ester (DINCH®). Retrieved March 5, 2021.
• 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 July 16, 2021.
• 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 March 5, 2021.
• Völkel, W., Kiranoglu, M., Dettbarn, G., John, A., Jessel, S., Seidel, A., and Fromme, H. (2016). Urinary toxicokinetics of di-(isononyl)-cyclohexane-1,2-dicarboxylate (DINCH®) in humans following single oral administration. Toxicology Letters, 248, 16–24.

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 and is 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. Research suggests that oral exposure may occur as a result of migration from baby bottles (Onghena et al., 2016; Simoneau et al., 2012).

The toxicokinetics and health effects of TXIB are not well studied in humans. Experimental animal studies have reported a high level of absorption of TXIB following ingestion; however, no dermal absorption data were identified (CIR, 2017). 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) (CIR, 2017). 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 1 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, 2021).

Experimental animal studies have reported that TXIB has low toxicity following acute ingestion exposure (producing moderate weakness and some vasodilation), while subchronic oral exposure has been associated with increased liver and kidney weights (CIR, 2017; OECD, 1995). Histopathological investigation of subchronically exposed animals revealed necrosis of the proximal tubules, dilatation of distal tubules and 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 has not been found to be genotoxic in bacterial assays or in mammalian cells, while no carcinogenicity or chronic studies have been identified (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; ECCC, 2019). TXIB is 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 participants aged 3–79 in cycle 5 (2016–2017) and cycle 6 (2018–2019). Data from these cycles 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 TXIB and does not necessarily mean that an adverse health effect will occur.

References

• Canada (1985). Food and Drugs Act. RSC 1985, c. F-27. Retrieved March 5, 2021.
• Canada (1999). Canadian Environmental Protection Act, 1999. S.C. 1999, c. 33. Retrieved March 5, 2021.
• CIR (Cosmetic Ingredient Review) (2017). Safety Assessment of Monoalkylglycol Dialkyl Acid Esters as Used in Cosmetics. Washington, D.C. Retrieved March 5, 2021.
• ECHA (European Chemicals Agency) (2001). 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate, CAS RN 6846-50-0. Industry Submission to ECHA. Retrieved March 5, 2021.
• ECHA (European Chemicals Agency) (2021). Isobutyric acid, monoester with 2,2,4-trimethylpentane-1,3-diol. Retrieved March 5, 2021.
• ECCC (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 March 5, 2021.
• 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.
• Onghena, M., Negreira, N., Van Hoeck, E., Quirynen, L., Van Loco, J., and Covaci, A. (2016). Quantitative Determination of Migrating compounds from Plastic Baby Bottles by Validated GC-QqQ-MS and LC-QqQ-MS Methods. Food Analytical Methods 9, 2600–2612.
• Simoneau, C., Van den Eede, L., and Valzacchi, S. (2012) Identification and quantification of the migration of chemicals from plastic baby bottles used as substitutes for polycarbonate, Food Additives & Contaminants: Part A, 29 (3), 469-480.
• 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; ECCC and HC, 2019).

TEHT does not occur naturally and is released to the environment from anthropogenic sources (ECCC and HC, 2019). TEHT has very low vapour pressure (volatility) and water solubility; therefore, it is expected to occur minimally in air and water (ECCC and HC, 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; ECCC and HC, 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 (ECCC and HC, 2019). Given the very low volatility of TEHT, exposure via inhalation is of minimal concern (ECCC and HC, 2019).

The toxicokinetics and health effects of TEHT have not been well studied in humans. Experimental animal studies have shown that the absorption of TEHT following dermal exposure is low (<1%) (CPSC, 2018). TEHT was mainly distributed to the liver, lungs and spleen in animals following an intravenous dose (OECD, 2002). In animals exposed through ingestion TEHT was found to undergo hydrolysis; elimination of TEHT metabolites 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 was mainly excreted in feces (75%), with 16% excreted in urine as hydrolysis products of TEHT and approximately 2% excreted as expired CO₂. The hydrolysis products in feces were mono-(2-ethylhexyl) trimellitate, di-(2-ethylhexyl) trimellitate and unidentified polar metabolites; in urine, the metabolites were 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 is associated with male reproductive toxicity in laboratory animals, based on dose-related reduction in testes weight and decreased numbers of spermatocytes and spermatids (CPSC, 2018; ECCC and HC, 2019; OECD, 2002). TEHT is not considered genotoxic, and is not expected to be carcinogenic (ECCC and HC, 2019).

The Government of Canada has conducted a science-based screening assessment under the Chemicals Management Plan to determine whether TEHT 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 (CEPA 1999) (Canada, 1999; ECCC and HC, 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 in cycle 5 (2016–2017) and cycle 6 (2018–2019). Data from these cycles 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 health effect will occur.

References

• Canada (1985). Food and Drugs Act. RSC 1985, c. F-27. Retrieved March 4, 2021.
• Canada (1999). Canadian Environmental Protection Act, 1999. S.C. 1999, c. 33. Retrieved March 4, 2021.
• CIR (Cosmetic Ingredient Review) (2015). Safety Assessment of Trialkyl Trimellitates as Used in Cosmetics. Final report. Washington, D.C. Retrieved March 4, 2021.
• CPSC (U.S. Consumer Product Safety Commission) (2018). Toxicity Review for Trioctyltrimellitate (TOTM). University of Cincinnati. Retrieved March 16, 2021.
• ECCC and HC (Environment and Climate Change Canada and Health Canada) (2019). Screening assessment trimellitates group. Minister of Environment and Climate Change, Ottawa, ON. Retrieved March 4, 2021.
• 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 March 4, 2021.
• 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 March 4, 2021.

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