Cyclohexane, 1,4-bis(ethoxymethyl)-

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Toxicity to reproduction

oral

- Dose selection rationale: In order to obtain information on the effect of the test substance Cyclohexane, 1,4-bis(ethoxymethyl)- on male sexual organs after repeated oral administration (gavage) a Screening Study on Testes Toxicity in Male Wistar Rats was (BASF SE, 2015, 00R0804/11N025) was performed. The test substances were administered at dosis of 1000 mg/kg bw once per day to groups of 5 male Wistar rats via gavage for a maximum of 14 days. During the study, all animals were observed for any clinically abnormal signs. One day after the last administration the animals were sacrificed and assessed by gross pathology, special attention was given to the reproductive organs. A decreased food consumption (-33%) and body weight loss (-13%) were observed. No test substance-related relevant findings were noted concerning sperm parameters. The following effects were noted on male sexual organs: decreased absolute weights (i.e. -10%) of epididymides, decreased absolute weights (i.e. -35%) of seminal vesicles, decreased absolute weights (i.e. -12%; not statistically significant) of testes and degeneration of pachytene spermatocytes with single multinucleated cells in 5/5 animals in the left testicle. Because of severe body weight loss the study cannot be used for assessment, as the observed effects may be secondary to the treatment and not substance specific. To avoid secondary effects resulting from peak exposure a feeding study with Cyclohexane, 1,4-bis(ethoxymethyl)- in male Wistar rats was perfomed (BASF SE, 2014, 00R0652/13N073). The encapsulated test substance (w: 46.65% 1,4-bis(ethoxymethyl)-Cyclohexane and w: 46.57% corn oil) was administered in concentrations of 6000 and 12000 ppm (active ingredient) via the diet for 14 days. Because of the continuing body weight loss (19% in the low dose group and 14% in the high dose group from study day 0 to 10), the reduced food consumption (down to 67% in the low-dose and high-dose group in comparison to the control) and the poor general state of all test substance treated animals, e.g. piloerection and hunched posture, these animals were sacrificed moribund. The vehicle control groups have been sacrificed unscheduled for reasons of humanity. The study was terminated before the experimental completion date and cannot be used therefore for assessment. A range finder study was performed to select the appropriate dose levels for a One-Generation Reproduction Toxicity Study in Wistar Rats. Therefore, 5 male and female Wistar rats/group were dosed with 200 and 600 mg/kg bw/day. As food consumption was reduced and a body weight loss in male and female animals was observed, the animals were scarified on study day 25. Another 28-day range finder study was performed administering 10 and 50 mg/kg bw/day to investigate toxicological effects at or below the maximal tolerable dose. No test substance-related findings with regard to body weight, hematology, clinical chemistry in males and females were observed. Sperm analysis did not show any abnormalities. The histopathological investigation of the testis revealed a minimal tubular degeneration and a minimal luminal debris in the corresponding epididymidal tubules in 2 (out of 5) animals (for further details please refer to IUCLID section 7.5.1).

An oral toxicity to reproduction study was conducted according to OECD 415 with extended parameter examinations (BASF SE, 2016, 70R0261/14R090). 1,4-bis(ethoxymethyl)-Cyclohexane 97% given daily throughout the entire study as an oily solution to groups of 25 male and 25 female healthy young Wistar rats (F0 parental generation) by stomach tube at doses of 5, 15 and 50 mg/kg body weight/day. Control animals were dosed daily with the vehicle only (corn oil). At least 69 days after the beginning of treatment, F0 animals were mated to produce a litter (F1 rearing animals). Mating pairs were from the same dose group. The female F0 animals were allowed to deliver and rear their pups (F1 generation pups) until postnatal days (PND) 4 or 21, when the offspring was necropsied. The male F0 generation parental animals were sacrificed during rearing of the F1 generation pups. The female F0 generation parental animals were sacrificed after weaning of the F1 generation pups.

The parents' and the pups' state of health was checked each day, and parental animals were examined for their mating and reproductive performances. Food consumption of the F0 parental animals was determined regularly once weekly and weekly during gestation (days 0 - 7, 7 - 14, 14 - 20) and lactation periods (days 1 - 4, 4 - 7, 7 - 14 and 14 - 21). In general, body weights of F0 parental animals were determined once weekly. However, during gestation and lactation F0 females were weighed on gestation days (GD) 0, 7, 14 and 20 and on postnatal days (PND) 0, 4, 7, 14 and 21. Estrous cycle data were evaluated for F0 generation females over a three week period prior to mating until evidence of mating occurred. Moreover, the estrous stage of each female was determined on the day of scheduled sacrifice. The F1 pups were sexed on the day of birth (PND 0) and were weighed on the first day after birth (PND 1) as well as on PND 4, 7, 14 and 21. Their viability was recorded. At necropsy, all pups were examined macroscopically (including weight determinations of brain, spleen and thymus in one pup/sex/litter). All surviving pups were examined for the presence or absence of nipple/areola anlagen on PND 13. If nipple/areola anlagen were recorded, all surviving male pups were carefully reexamined on PND 21 before necropsy. Anogenital distance measurements were conducted in a blind randomized fashion on all live male and female pups on PND 1. Blood samples were withdrawn from 12 selected F0 and F1 parental animals per sex and group shortly before scheduled sacrifice. Various sperm parameters were assessed in the F0 and F1 generation males at scheduled sacrifice or after appropriate staining. All F0 parental animals were assessed by gross pathology and subjected to an extensive histopathological examination, including the organs of the reproductive system. In female F0 animals treated with 50 mg/kg bw/day a decreased food consumption during PND 1 - 14 and 1 - 21 (up to 24 % and 15 % below control) and a decreased body weight on GD 20 (about 7 % below control) and during PND 4 - 14 (up to 8 % below control) were observed. In addition they showed a decreased body weight gain during GD 14 - 20 (about 22 % below control). Pups treated with 50 mg/kg bw/day showed a body weight decrease up to 17 % below the control group during PND 7 – 21 and a decreased body weight gain between PND 4 and 21. Pups treated with 15 and 5 mg/kg bw/day showed no test substance related effects. In female parental animals during GD 7 – 20 and PND 0 - 4 a decrease in body weight up to 6 % and 5 % below the control group was detected. In addition the body weight gain was decreased during GD 14 – 20 (approx. 11 %). For F0 generation treated with 5 mg/kg bw/day no test substance related effects were observed.

Under the conditions of the present modified one-generation reproduction toxicity study the NOAEL for general, systemic toxicity is 5 mg/kg bw/day for the F0 parental rats, based on reduced food consumption and/or reduced body weight gain towards the end of gestation and 14 days into lactation, observed at the LOAEL of 15 mg/kg bw/day in the F0 parental animals. The NOAEL for fertility and reproductive performance for the F0 parental rats is 50 mg/kg bw/day, the highest dose tested. The NOAEL for developmental toxicity in the F1 progeny is 15 mg/kg bw/day, based on slightly decreased pre-weaning pup body weights/pup weight gain, at the LOAEL of 50 mg/kg bw/day in the F1 offspring, secondary to decreased food consumption/body weight gain in the corresponding F0 parental females. Developmental effects did not occur in the absence of parental toxicity.

Short description of key information:
A oral toxicity to reproduction study was conducted according to OECD 415 with extended parameter examinations.
The NOAEL for fertility and reproductive performance for the F0 parental rats is 50 mg/kg bw/day.
The NOAEL for general, systemic toxicity is 5 mg/kg bw/day for the F0 parental rats.

Effects on developmental toxicity

Description of key information

The NOAEL for developmental toxicity in the F1 progeny is 15 mg/kg bw/day.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Please refer to the discussion section "Effects on fertility".

Justification for classification or non-classification

Reproductive toxicity

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available experimental test data is reliable and suitable for classification purposes under Regulation (EC) No 1272/2008, as amended for the seventh time in Regulation (EU) No 2015/1221. As a result the substance is considered not to be classified for reproductive toxicity.