Derivation of an Oral Reference Dose (RfD) for the Nonphthalate Alternative Plasticizer 1,2-Cyclohexane Dicarboxylic Acid, Di-Isononyl Ester (DINCH)

Abstract

1,2-Cyclohexanedicarboxylic acid, 1,2-diisononylester (DINCH), a polyvinyl chloride plasticizer, has food, beverage, and medical device applications that may result in general population exposure. Although no apparent toxicity information in humans was identified, there is a substantial data set in lab animals to serve as the basis of hazard identification for DINCH. Target tissues associated with repeated dietary DINCH exposure in lab animals included liver, kidney, and thyroid and mammary glands. In contrast to some phthalate ester plasticizers, DINCH did not show evidence of hepatic peroxisomal proliferation, testicular toxicity, or liver tumors in rats. Liver and thyroid effects associated with DINCH exposure were attributed to compensatory thyroid stimulation secondary to prolonged metabolic enzyme induction. The toxicological significance of mammary fibroadenomas in female rats is unclear, given that this common benign and spontaneously occurring tumor type is unique to rats. The weight of evidence suggests DINCH is not genotoxic and the proposed mode of action (MOA) for thyroid gland lesions was considered to have a threshold. No adverse reproductive effects were seen in a two-generation study. An oral reference dose (RfD) of 0.7 mg/kg-d was derived from a human equivalent BMDL₁₀ of 21 mg/kg-d for thyroid hypertrophy/hyperplasia seen in adult F₁ rats also exposed in utero. The total uncertainty factor of 30x was comprised of intraspecies (10×) and database (3×) factors. An interspecies extrapolation factor was not applied since rodents are more sensitive than humans with respect to the proposed indirect MOA for thyroid gland lesions.

Toxicity of Hexamoll® DINCH® following intravenous administration

“…Rubin (1975) and Schulz et al (1975). Bhat et al (2014) reported what had been reviewed by the independent National Sanitation Foundation (NSF) Health advisory board and by regulatory bodies such as EFSA and NICNAS on the toxicology of Hexamoll ® DINCH ® . They all concluded that target organs from oral administration were the thyroid gland and the kidneys.…”

“…The issues for substitution range from ease of "drop-in" to efficacy for blood storage. Hexamoll ® DINCH ® was developed as a substitute plasticizer for "sensitive" applications: it has a low toxicity; is not considered to be an endocrine-active substance (Furr et al, 2014); and has a low migration from PVC (Bhat et al, 2014). Oral exposure was associated in rats with induction of liver enzymes that are believed to have altered circulating thyroid gland hormones, resulting in an enlarged thyroid gland; this effect is a secondary mechanism that is not considered to be relevant for humans (European Food Safety Authority, 2006).…”

Stoffmonographie für 1,2-Cyclohexandicarbonsäure-di-isononylester (Hexamoll® DINCH®) – HBM-Werte für die Summe der Metabolite Cyclohexan-1,2-dicarbonsäure-mono-hydroxyisononylester (OH-MINCH) und Cyclohexan-1,2-dicarbonsäure-mono-carboxy­isooctylester (cx-MINCH) im Urin von Erwachsenen und Kindern

“…Zusammenfassende Darstellungen der relevanten toxikologischen Untersuchungen und ihre Bewertungen finden sich in dem Bericht der europäischen Behör-de für Lebensmittelsicherheit [16], in der Dokumentation der australischen Chemikalienbehörde (NICNAS) [19] sowie in der Publikation von Bath et al [20]. Die Verwendung von DINCH in Medizinprodukten wurde durch ein wissenschaftliches Expertengremium der EU Kommission bewertet [4].…”

“…Die 2-Generationen-Studie wurde sowohl von der EFSA [16] wie auch von Bhat et al [20] einer Neubewertung unterworfen (s. Kap. 5).…”

“…Gemeinsam haben beide Ableitungen, dass jeweils ein Sicherheitsfaktor von 100 verwendet wurde. Ferner liegt eine aktuelle und ausführliche Ableitung für eine RfD von Bath et al [20] vor. Bewertungen der toxikologischen Daten durch weitere Gremien liegen vor, die Ableitungen von NOAEL-Werten werden nachfolgend dargestellt, TDI-Werte wurden jedoch nicht abgeleitet.…”