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Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
25 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Additional information

No reproductive toxicity data are available for the test substance. A 1-generation reproductive toxicity study in rats with 6:2 FTOH was used as a read across to fulfill the data gap for the test substance. The underlying hypothesis for the read-across between the test substance and 6:2 FTOH is that the test substance is transformed metabolically to 6:2 FTOH. The available in vitro data show that this transformation occurs extremely rapidly (half-life less than 3 minutes). While no actual in vivo rate data are available (aside from one study that demonstrates disappearance of the test substance), the transformation is still expected to occur rapidly. Additionally, based on the consistency in effects seen in the repeated dose studies coupled with the knowledge of the metabolism, it is reasonable to read-across the information from the 1-generation reproduction toxicity study on 6:2 FTOH to address the data gap for the test substance.

Male and female rats were administered the 6:2 FTOH via gavage at doses of 0, 5, 25, 125, or 250 mg/kg in a 1-generation reproduction toxicity study according to OECD Guideline 415. The no-observable-effect level (NOEL) for general toxicity, as well as reproductive and offspring effects is 25 mg/kg/day. At ≥125 mg/kg/day, mortality was increased in the male rats only, adverse clinical signs (primarily dental problems) were increased in both sexes, feed consumption values were significantly reduced in the lactating female rats, organ weights (uterus with the cervix) were significantly reduced in the female rats, and there was a significant reduction in pup body weights and a significant increase in pup mortality. At 250 mg/kg/day, mortality was increased in the female rats, both sexes had significantly reduced body weights and body weight changes during the study, and the increased pup mortality resulted in a significant decrease in the litter size, as well as the indices for viability and lactation. There was also an increase in the number of pups that appeared dehydrated, were not nursing, were not nesting, or were cold to touch at 250 mg/kg/day.

Male and female mice were administered 6:2 FTOH via gavage at doses of 0, 1, 5, 25, or 100 mg/kg in a 1-generation reproduction toxicity study according to OECD Guideline 415. The no-observed-adverse-effect level (NOAEL) for systemic toxicity was 25 mg/kg/day (males) and 5 mg/kg/day (females). Observations of systemic toxicity in P1 males and females at 100 mg/kg/day included mortality, clinical abnormalities, and differences in body weight, nutritional parameters, haematology (red and white blood cell), clinical chemistry (liver-related), liver weights, and histopathology (liver, teeth, reproductive tract, and mammary gland). Observations of systemic toxicity in P1 females at 25 mg/kg/day included differences in clinical chemistry and histopathology, both of which pertained to the liver and were consistent with observations at 100 mg/kg/day. The NOAEL for reproductive toxicity was > 100 mg/kg/day; no effects on reproductive outcome were observed at any dosage. The NOAEL for viability and growth of the offspring was 25 mg/kg/day, based on clinical observations of delayed development in pups, and reductions in pup survival and pup body weight during lactation at 100 mg/kg/day.


Short description of key information:
The general toxicity, reproductive, and offspring NOEL for 6:2 FTOH is 25 mg/kg/day.

Justification for selection of Effect on fertility via oral route:
NOAEL is based on read across to rat 1-generation reproduction study with 6:2 FTOH (OECD Guideline, GLP study).

Effects on developmental toxicity

Description of key information
The maternal and developmental NOAEL for the test substance is 320 mg/kg/day.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
320 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Additional information

A developmental toxicity study was conducted to detect adverse effects on pregnant female rats and on the development of their conceptuses consequent to exposure of the female with the test substance by oral gavage administration from gestation day 5 to 19.

None of the pregnant females died before scheduled necropsy and there were no treatment related clinical signs of systemic toxicity observed. Lower body weight and body weight gain (including incidences of body weight loss) as well as reduced food consumption were noted in dams of the 1000 mg/kg bw/day dose group, and were attributed to the treatment with the test item (maternal toxicity). Necropsy alterations (macroscopic findings) were found with low incidence in the 1000 mg/kg bw/day dose group and were neither proved nor excluded to have a relationship with the treatment. The treatment resulted in slightly lower fetal body weight (values were within the historical control range) and lower absolute placental weight in the 1000 mg/kg bw/day dose group. With regard to reduced food consumption and reduced body weight/body weight gain noted in pregnant females at this dose level (maternal toxicity), a relation to the treatment with the test item could not be excluded for the fetal body weight and placental weight reduction. The test item caused no fetal malformations and no external or visceral fetal variations. At 1000 mg/kg bw/day, there was an increased incidence of skeletal variations such as markedly incomplete ossification of one or more skull bones, retarded skull bones, unossified hyoid bone, wavy ribs as well as delayed ossification of thoracic, lumbar and sacral vertebrae, which were attributed to the treatment of the dams with the test item. However, it has to be noted that these variations are reversible and that they were seen at the maternally toxic dose level of 1000 mg/kg bw/day only. Based on these observations the No Observed Adverse Effect Levels (NOAEL) were determined as 320 mg/kg bw/day for both maternal and developmental toxicity.

A developmental toxicity study in rats with 6:2 FTOH was used as a read across to support the developmental toxicity endpoint. The underlying hypothesis for the read-across between the test substance and 6:2 FTOH is that the test substance is transformed metabolically to 6:2 FTOH. The available in vitro data show that this transformation occurs extremely rapidly (half-life less than 3 minutes). While no actual in vivo rate data are available (aside from one study that demonstrates disappearance of the test substance), the transformation is still expected to occur rapidly. Additionally, based on the consistency in effects seen in the repeated dose studies coupled with the knowledge of the metabolism, it is reasonable to read-across the information from the developmental toxicity study on 6:2 FTOH to support the findings from the developmental toxicity study with the test substance.

Pregnant female rats were administered the 6:2 FTOH via gavage at doses of 0, 5, 25, 125, or 250 mg/kg on gestation days 6-20 in a prenatal developmental toxicity study according to OECD Guideline 414. The no-observed-adverse-effect level (NOAEL) for both the dam and the foetus was 125 mg/kg/day. Test substance-related effects on maternal and developmental endpoints were observed at 125 and 250 mg/kg/day. The effects seen at 250 mg/kg/day (reduced maternal body weight and food consumption; increased skeletal variations) were generally considered to be adverse; whereas at 125 mg/kg/day, the maternal weight and foetal skeletal effects were sufficiently minimal such that they were considered not adverse. There was no evidence of either maternal or developmental toxicity at 5 or 25 mg/kg/day.

Justification for classification or non-classification

The test substance is not uniquely toxic to the foetus with a maternal and developmental NOAEL of 320 mg/kg. Although no data are available for the test substance for reproductive effects, data are available for the read-across material, 6:2 FTOH. 6:2 FTOH has been evaluated in a developmental toxicity study and one-generation reproduction studies in rats and mice. Effects on offspring were mostly limited to body weight decrements and/or mortality at maternally toxic doses, with no effects on fertility. Although signs of developmental toxicity were observed at higher doses, the substance was not embryolethal or teratogenic in rats and produced no effects at doses that were not maternally toxic. Therefore, 6:2 FTOH was not uniquely toxic to the offspring. Based on these considerations, the test substance does not need to be classified for reproductive/developmental toxicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 (ATP02).