title: 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.
authors.affiliation: Ecology and Safety, BASF Corporation, 100 Park Avenue, Florham Park, NJ 07932, USA.
authors.forename: Raymond M
authors.initials: RM
authors.lastname: David
authors.affiliation: WuXi App Tec, 2540 Executive Drive, St. Paul, MN 55120, USA.
authors.forename: Randy D
authors.initials: RD
authors.lastname: White
authors.affiliation: Ibex Preclinical Research, 1072 West RSI Drive, Logan, UT 84321, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Larson
authors.affiliation: Covance Laboratories Inc., 3301 Kinsman Boulevard, Madison, WI 53704, USA.
authors.forename: Jay K
authors.initials: JK
authors.lastname: Herman
authors.affiliation: BASF SE, Carl-Bosch-Strasse 38, 67056 Ludwigshafen, Germany. Electronic address: rainer.otter@basf.com.
authors.forename: Rainer
authors.initials: R
authors.lastname: Otter
mesh_terms: D000818:Animals; D001682:Biological Availability; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001711:Biotransformation; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D003998:Dicarboxylic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D010968:Plasticizers / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment
chemical_list: D015415:Biomarkers; D003509:Cyclohexanecarboxylic Acids; D003998:Dicarboxylic Acids; D010968:Plasticizers; C558012:diisononyl 1,2-cyclohexanedicarboxylic acid
keywords: Cyclohexane-1,2-dicarboxylic acid, diisononylester (Hexamoll(®) DINCH(®)); Intravenous infusion; Intravenous injection