Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Two-generation study with Rat exposure via the inhalation route, performed according to OECD Guideline 416 and the EPA Guideline OPPTS 870.3800 and following GLP principles, the parental NOAEL for HFO-1336mzz-E was found to be at least 7500 ppm based on clinical signs observed at the highest dose tested (12500 ppm), whereas the NOAEL for reproduction was found to be at least 12500 ppm. Reliability - K1;

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
83 750 mg/m³
Study duration:
chronic
Species:
rat
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

A Prenatal development toxicity study performed according to OECD 414 on female rats, exposed via whole body inhalation, was assessed as K1 study and used as supportive study.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
50 322 mg/m³
Study duration:
subchronic
Species:
rat
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Reproductive toxicity includes adverse effects on sexual function and fertility in adult males and females, as well as developmental toxicity in the offspring.

A GLP two-generation reproduction study was conducted in Crl:WI(Han) rats (30/sex/concentration) at exposure levels of 0, 5000, 7500, or 12500 ppm (0, 33500, 50250, or 83750 mg/m3) of the substance in air according to OECD test guideline 416. Exposures were via whole-body inhalation for 6 hours per day, 7 days per week for at least 70 consecutive days prior to mating and continuing through the day prior to euthanasia. Exposure was suspended from Gestation Day 21 through Lactation Day 4 for gravid and presumed gravid females. Exposure for the offspring selected to constitute the P1 parental generation began on the day of weaning, PND 28.

In the 12500 ppm group, 1 male was euthanized in extremis and 1 male was found dead in the F0 generation. Test substance-related clinical findings included tremors for F0 and F1 males and females in the 12500 ppm group and clonic convulsions for F0 females in the 12500 ppm group at the midpoint of exposure; these findings were considered adverse. No adverse test substance-related effects were noted on F0 or F1 parental body weights, body weight gains, food consumption, or food efficiency at any exposure concentration. No test substance-related effects were noted on F0 or F1 reproductive performance (mating, fertility, copulation, or conception), estrous cyclicity, gestation lengths, the process of parturition, precoital intervals, or spermatogenesis at any exposure concentration. There were no test substance-related effects on attainment of balanopreputial separation and vaginal patency or body weights at attainment of these developmental landmarks in the F1 pups at any exposure level. There were no test substance-related effects noted on F1 and F2 mean numbers of pups born, live litter size on PND 0, percentage of males, or postnatal survival. Mean F1 and F2 male and female pup body weights and body weight changes in the 5000, 7500, and 12500 ppm groups were unaffected by test substance exposure throughout the postnatal period. There were no test substance-related macroscopic findings noted at any dosage level in the F1 and F2 pups that were found dead or pups that were euthanized at the scheduled necropsy on PND 28. No test substance-related effects on organ weights were observed for F1 and F2 pups on PND 28. No test substance-related adverse macroscopic or microscopic findings or organ weight alterations were noted for F0 and F1 males or females at any exposure level. Based on the effects on survival for F0 males at 12500 ppm and adverse clinical findings of tremors noted for F0 and F1 males and females at 12500 ppm at the midpoint of exposure, an exposure level of 7500 ppm (50250 mg/m3) was considered to be the NOAEC for systemic toxicity. Due to the lack of effects on reproductive parameters or survival and growth of the offspring during the pre-weaning period, the NOAEC for parental reproductive toxicity and neonatal toxicity was 12500 ppm (83750 mg/m3), the highest exposure concentration evaluated.

A GLP prenatal developmental toxicity study was conducted according to OECD test guideline 414 wherein five groups of 24 time-mated nulliparous female Wistar rats were exposed to 0, 1000, 5000, 7500 or 15000 ppm (0, 6700, 33500, 50250, or 100500 mg/m3) of the substance via whole-body inhalation for 6 hours per day beginning on gestation day (GD) 6 up to and including GD 19.  No maternal, embryo, or fetal lethality or fetal structural malformations were observed at any exposure concentration.  A lower maternal body weight gain during gestation was observed and a reduced food intake after the start of exposure from GD 6-12 was noted in the 15000ppm exposure group.  Mean fetus weight and mean placenta weight were decreased in the 15000 ppm exposure group for both male and female fetuses.  Skeletal examination showed reduced ossification in the fetuses in the 15000 ppm exposure group, which was indicative of growth retardation and considered to be related to the lower fetus weight in this group.  Under the conditions of this study, the NOAEC for maternal and fetal effects was 7500 ppm (50250 mg/m3).

In conclusion, no test substance-related adverse effects on reproductive outcomes or unique pre- or postnatal developmental toxicity were observed after exposure to the test substance. These assessments were made in GLP guideline studies carried out in rats. The substance does not need to be classified for reproductive or developmental toxicity according the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.