Toxicity of Hexamoll® DINCH® following intravenous administration

Abstract

Alternative plasticizers to di(2-ethylhexyl) phthalate (DEHP) for blood bags have been sought for many years. Cyclohexane-1,2-dicarboxylic acid, diisononylester (Hexamoll(®) DINCH(®)) is an alternative that has been evaluated in preliminary studies for compatibility and efficacy to preserve whole blood. While Hexamoll(®) DINCH(®) has an extensive database for mammalian toxicity via oral administration, data were needed to evaluate toxicity from intravenous (IV) administration to support the use of the plasticizer Hexamoll(®) DINCH(®) in blood bags. A series of studies was performed by slow IV injection or IV infusion of Hexamoll(®) DINCH(®), a highly viscous, hydrophobic substance, suspended in Intralipid(®) 20% (20% intravenous fat emulsion). Rats were injected once, followed by 14 days of recovery; injected daily for 5 days followed by 5 days of recovery, or infused for 29 days (4h/day) followed by 14 days of recovery. Dose levels were 0, 62, 125, and 250-300mg/kg body weight/day. These dose levels represent the limits of suspension and far exceed any anticipated exposures from migration out of plasticized blood bags. Animals were observed for signs of toxicity; body weight and feed consumption were measured; blood collected for clinical chemistry and hematology; and tissues collected and processed for histopathology. Special emphasis was placed on evaluating endpoints and tissues that are commonly associated with plasticizer exposure in rodents. Urine was collected during the 4-week study to quantify urinary metabolites of Hexamoll(®) DINCH(®). The results of the studies indicate that no substance-related toxicity occurred: no effects on behavior, no effects on organ weight, no effect on serum chemistry including thyroid hormones; and no effect on major organs, especially no testicular toxicity and no indication for peroxisome proliferation in the liver. The only effects seen were petechia and granulomas related to dissipation of suspended Hexamoll(®) DINCH(®) in the aqueous environment of the blood. However, the results of metabolite analyses demonstrate that Hexamoll(®) DINCH(®) was bioavailable. Therefore, based on the lack of Hexamoll(®) DINCH(®)-related systemic toxicity with the exception of the physical limitations, the no-observed-adverse-effect level for parenterally administered Hexamoll(®) DINCH(®) is considered to be 300mg/kg bw/day.

In Utero and Lactational Exposure Study in Rats to Identify Replacements for Di(2-ethylhexyl) Phthalate

“…Recent in vitro studies suggest that DINCH is a bioactive compound 29 , a potent metabolic disruptor 49 , and an endocrine disruptor 30 . The increase in hemorrhaging testes that we observed after DINCH exposure occurred at doses that were below or equal to the no observed adverse effect level (NOAEL) for parenteral exposure 50 . Together, these data suggest a need for a deeper exploration of the possible endocrine disruptive properties of DINCH.…”

In Vitro Inhalation Bioaccessibility of Phthalate Esters and Alternative Plasticizers Present in Indoor Dust Using Artificial Lung Fluids

“…Franken et al (2017) reported the high occurrence of asthma in Belgian teenagers (especially girls) associated with high DEHP and DnBP exposure 32 . DEHT and DINCH administration to rodents revealed no signs of DEHP-like toxicity [33][34][35] . However, DINCH in utero exposure has been associated with signs of impaired liver metabolism and premature testicular aging such as decreased testosterone secretion, physical changes in seminal glands and testicular atrophy in rats and their young offspring 36 .…”

Exposure of Portuguese children to the novel non-phthalate plasticizer di-(iso-nonyl)-cyclohexane-1,2-dicarboxylate (DINCH)

“…In 2002, the plasticizer DINCH was introduced into the market, intended for the use in sensitive products such as toys, food contact materials and medical devices (Bhat et al, 2014;Biedermann-Brem et al, 2008;David et al, 2015;EFSA, 2006). DINCH is produced by catalytic hydrogenation of the aromatic ring of DINP, and commercialized as Hexamoll® DINCH® (Koch et al, 2013a).…”