Cis-1,1,1,4,4,4-hexafluoro-2-butene (HFO-1336mzz-Z) (2018)

Abstract

Cis-1,1,1,4,4,4-hexafluoro-2-butene (HFO-1336mzz-Z) is a clear, colorless liquid that finds uses as a foam-blowing agent, refrigerant, fire extinguishing agent, and solvent. HFO-1336mzz-Z is not an acute dermal or eye irritant and has very low acute toxicity via inhalation exposure (4-h lethal concentration (LC50) > 102,000 ppm). The no-observed adverse effect level (NOAEL) and lowest-observed adverse effect level (LOAEL) for cardiac sensitization (in epinephrine-challenged dogs) were 12,500 ppm and 25,000 ppm, respectively. In a GLP, subacute (4-week) repeat-dose inhalation study in Crl: CD(SD) male and female rats at exposure concentrations of 0, 2500, 5000, or 10,000 ppm, the only significant observations attributed to exposure were reduced body weight, reduced body weight gain, and reduced food consumption. The study NOAEL was determined to be 2500 ppm. Two separate GLP, 13-week repeat-dose inhalation studies (Organisation for Economic Cooperation and Development (OECD) 413) have been conducted on HFO-1336mzz-Z using male and female Crl: CD (SD) rats. In the first study, exposure concentrations were 0, 500, 1500, or 10,000 ppm, and in the second study, 0, 3000, 4000, 5000, or 7500 ppm. The only significant exposure-related observations in the first study were reductions in body weights, food consumption, and food efficiency in males and females at 10,000 ppm (study NOAEL = 1500 ppm). In the second study, done in part to better define the NOAEL, reductions in body weight and food consumption were observed in males at 7500 ppm; there were no exposure-related observations on these end points in females. Therefore, the study NOAEL was established at 5000 ppm for males and 7500 ppm for females. HFO-1336mzz-Z has also been examined for its potential to produce developmental toxicity in both Crl: CD(SD) rats (0, 500, 1500, or 10,000 ppm) and New Zealand White rabbits (0, 2500, 5000, 7500, or 15,000 ppm) according to GLP and OECD 414. The NOAEL for both maternal and fetal effects in rats was 1500 ppm and the NOAELs for maternal effects and fetal effects in rabbits were 5000 ppm and 7500 ppm, respectively. A non-GLP, two-generation reproductive pilot study, for a planned multigenerational study noted reduced body weight and body weight gain in males at 1500 ppm and above; the NOAEL for this pilot study was set at 500 ppm. There are no chronic toxicity/carcinogenicity studies available, and HFO-1336mzz-Z was not genotoxic/mutagenic in in vitro and in vivo studies. The NOAEL for male rats of 5000 ppm (based on reductions in body weight and food consumption) from the 13-week inhalation study was selected as the point of departure for the derivation of the 8-h time-weighted average (TWA), health-based workplace environmental exposure level (WEEL) value. This subchronic inhalation NOAEL was adjusted to account for duration of exposure, inter-individual variability, and intra-individual variability. The resulting 8-h TWA WEEL value of 500 ppm is fully expected to provide a significant margin of safety against the production of any potential adverse health effects in workers following long-term inhalation exposure to HFO-1336mzz-Z vapor.