Di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH)
CAS No. 166412-78-8
Di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH) is a clear, colorless, liquid high molecular weight plasticizer. It was developed for use in polyvinyl chloride plastics (PVC) and in products with human contact, including toys, medical devices, and food packaging, largely as an alternative to di-(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP) (Crespo et al., 2007; EFSA, 2006). DINCH is also used in the production of cosmetic products, shoes, exercise mats and cushions, textile coatings, printing inks, as well as floorings and wall coverings (Bui et al., 2016). Use of DINCH has been increasing since its market introduction in 2002, and in 2014, production capacity was doubled from 100,000 to 200,000 metric tons (BASF, 2014). Because it is not chemically bound to the plastics to which it is added, DINCH can be released into the environment during use or disposal of the product, where it is generally persistent, having a half-life of about one year in water and two to three years in soil. DINCH can also migrate into foods wrapped in plastic films or other food-contact materials.
People are exposed through ingestion and possibly, dermal contact with products that contain DINCH. For the general population, dietary sources have been considered the major exposure route, although DINCH has been measured in indoor air and dust (Fromme et al., 2016; Nagorka et al., 2011). Children also may ingest DINCH when they mouth toys or other DINCH-containing plastics. Intravenous or parenteral exposure can occur in persons undergoing medical procedures involving devices or materials containing DINCH.
DINCH was rapidly but incompletely absorbed from the intestinal tract after ingestion and did not accumulate in tissues. In animal studies, the absorption was related to the dose administered, ranging from about 50% at low doses to 5-6% at high doses (SCENIHR, 2008). Human metabolism was rapid, first to the monoester, cyclohexane-1,2-dicarboxylic monoisononyl ester (MINCH) which undergoes further oxidative modifications. The more abundant of these metabolites include cyclohexane-1,2-dicarboxylic acid (CHDA), cyclohexane-1,2-dicarboxylic mono hydroxyisononyl ester (MHNCH or OH-MINCH), cyclohexane-1,2-dicarboxylic mono oxoisononyl ester (MONCH or oxo-MINCH), and cyclohexane-1,2-dicarboxylic mono carboxyisononyl ester (MCHOH or cx-MINCH) (Koch et al., 2013). In animals, metabolites were eliminated mainly in the feces but also in urine (SCEINHR, 2008; Silva et al., 2012).
DINCH was not acutely toxic following high dose oral and dermal exposure in single large doses administered to animals (EFSA, 2006). Short-term and chronic oral administration to laboratory animals produced liver enzyme induction and slightly increased thyroid weight and serum thyroxine stimulating hormone concentrations; at the mid-dose of 300 mg/kg/day, male animals developed hematuria and signs of renal toxicity (REACH, 2010; EFSA, 2006). In vitro studies showed no evidence of genotoxicity or mutagenicity (SCENIHR, 2007). In animal studies, DINCH did not result in developmental or reproductive toxicity, and chronic dosing did not result in treatment related mortality or malignant tumors (Bui, et al., 2016; EFSA, 2006). DINCH has not been evaluated for human carcinogenicity by the International Agency for Research on Cancer (IARC), National Toxicology Program (NTP), or the U.S. Environmental Protection Agency (U.S. EPA). The European Union has established a tolerable daily intake for DINCH at 1 mg/kg body weight per day (EFSA, 2006)
Urinary levels of DINCH metabolites reflect recent exposure to DINCH. In the NHANES 2011-2012 survey period, MHNCH was detectable above 0.4 µg/L at the 90th percentile in the total U.S. population, although children ages 6-19 years had detectable concentrations at the 75th percentile. In a small study of healthy adults, oxidized DINCH metabolites (OH-MINCH, oxo-MINCH and cx-MINCH) were found in more than 80% of urine samples. The most abundant metabolite was OH-MINCH, followed by cx-MINCH and oxo-MINCH, respectively. MINCH was seldom detected and thus, was considered to be a weak marker of exposure, while the other metabolites were more frequently detected and considered to be strong biological markers of DINCH exposure (Schutze, et al., 2012). A random sample of spot urines collected from a convenience group of U.S. adults, beginning in 2000, reported an increasing detection rate (above a detection limit of 0.4 µg/L) of MHNCH (OH-MINCH) beginning in 2007 and reaching 19% in 2012 (Silva et al., 2013). Banked 24-hour urine samples collected from German adults between 1999 and 2012 also found increasing detection rates of DINCH metabolites over time. The highest detection rates were in 2012: OH-MINCH (MHNCH) 98%; cx-MINCH (MCOCH) 88%; oxo-MINCH (MONCH) 85%; and MINCH 5% (Schutze et al., 2014). Detection limits in this study were quite low, 0.05 µg/L for each metabolite except MINCH (0.01 µg/L). In a sample of young children (27-66 months old) attending German daycare centers, three DINCH metabolites were detected in virtually all of the spot urine samples. The highest median concentration was OH-MINCH (MHNCH) 1.68 µg/L, followed by oxo-MINCH (MONCH) 1.54 µg/L, and cx-MINCH (MCHOH) 1.14 µg/L (Fromme et al., 2016). In Australia, residual urine samples collected between 2012 and 2013 were pooled by age and sex. MHNCH was detectable in all pools at concentrations above the detection limit of 0.4 µg/L (LOD). Results ranged from 1.2 to 14.4 µg/L and were not associated with age (Gomez Ramos et al., 2016)
Finding a measurable amount of one or more DINCH metabolites in urine does not imply that the levels of the metabolites or DINCH cause an adverse health effect. Biomonitoring studies on levels of DINCH metabolites provide physicians and public health officials with reference values so that they can determine whether people have been exposed to higher levels of DINCH than are found in the general population. Biomonitoring data can also help scientists plan and conduct research on exposure and health effects.
Common Urinary Metabolites of DINCH
|Cyclohexane-1,2-dicarboxylic mono hydroxyisononyl ester||MHNCH, or OH-MINCH|
|Cyclohexane-1,2-dicarboxylic mono oxoisononyl ester||MONCH, or oxo-MINCH|
|Cyclohexane-1,2-dicarboxylic mono carboxyisononyl ester||MCHOH, or cx-MINCH|
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