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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information
No data available.
Additional information

Based on the available data for an analog substance, isooctanol will not be a reproductive toxicant. A one-generation study in rats (Hansen, 1992) was performed with the analog substance 1-dodecanol (CAS RN 112-53-8) using the Combined Repeat Dose and Reproductive/Developmental Toxicity Screening Test protocol. Male and female rats were administered 1-dodecanol orally via the feed at doses of 100, 500 and 2000 mg/kg/day for a period of 14 days. No effects were seen on reproductive or developmental parameters up to doses of 2000 mg/kg/day. 1-Dodecanol at the dose administered had no influence on body weight, weight gain, food consumption and reproductive efficiency in the parental generation. Pregnancy rates were not statistically altered and there were no differences in the lengths of the gestation periods. No organ toxicity was observed in the females, and there was no effect on the number of pups per litter, weight, sex ratio, or mortality rate from Days 1 to 5 after birth.

Members of the Exxal group of alcohols are currently undergoing testing as part of an integrated testing strategy (outlined in Chapter 13 assessment report, read across and integrated testing strategy) as agreed upon by ECHA (decision number CCH-D-2114342397-45-01/F) and we are awaiting the results to inform further testing.



Short description of key information:
Low potential for reproductive toxicity.

Effects on developmental toxicity

Description of key information
Low potential for developmental toxicity.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Additional information

A NOAEL of 1000mg/kg/day was observed in developmental toxicity studies on isooctanol. As supporting information, testing of 1-dodecanol in a combined repeated dose developmental / reproductive study showed no effects to parents or offspring. These data support the conclusion that members of the Oxo Alcohols C9 to C13 category are not selective reproductive toxicants.

In the key study, isooctanol (Exxal 8) was administered by gavage to three groups of Crl:CDBR female rats at doses of 100, 500, and 1000 mg/kg. A fourth group (Group 1) served as a control and received the carrier (corn oil) only. Mated females were dosed once daily from Gestation Day (GD) 6 through GD 15. Dosing volumes were 5 ml/kg for all groups and based on the animals' most recent body weight.

 

Males and females were paired and housed overnight until confirmation of mating (sperm/plug = GD 0). Each mated female then was returned to its own cage and new females were placed in the males' cages until the required number of mated females was obtained. Mated females were assigned to dose groups in the order of mating.

 

Clinical observations were made daily during gestation. The animals were examined for viability at least twice daily during the treatment period and at least once daily at other times during the study. Body weight and food consumption measurements were made on GD 0, 6, 9, 12, 15, 18, and 21. On GD 21, animals were euthanized and cesarean sections were performed. Gross necropsies were performed, uterine weights with ovaries attached measured, uterine contents examined, and the required uterine implantation data recorded. All live fetuses were weighed, sexed externally, and examined externally for gross malformations. 

 

Approximately one-half of the fetuses of each litter were decapitated after being euthanized. The heads were preserved in Bouin's solution for at least two weeks, rinsed, and subsequently stored in 70% alcohol. Sections of the fetal heads were prepared with a razor blade, examined for the presence of abnormalities, and then discarded. The viscera of these fetuses were immediately examined for abnormalities by dissection. The remaining live fetuses were eviscerated, processed for skeletal staining, and examined for the presence of malformations and ossification variations.

 

Unscheduled mortality was limited to one high dose female which was euthanized in a moribund condition on GD 9. This animal was observed with extreme abdominal staining just prior to death. There were no significant findings at postmortem examination and therefore, the cause of morbidity could not be established. 

 

Adverse clinical signs were observed primarily in the high dose dams following dose initiation. Approximately eight of the twenty-four surviving dams were observed with a least one of the ensuing signs: emaciation, little sign of food consumption, abdominal/anogenital staining, rales, hypoactivity, no stool, and/or little sign of stool. These signs were transient, occurring for only one day in some animals, and were generally not observed in the animals following the cessation of dosing. The remaining dams in the group were free of observable abnormalities throughout the study, or had incidental findings such as alopecia. The majority of dams in the control, low and mid dose groups were free of observable abnormalities during the entire gestation period. 

 

Statistically significant body weight gain suppression was observed in the high dose females at the GD 6-9 body weight change interval and during the overall treatment period (GD 6-15) when compared with controls. Statistically significant decreases in mean food consumption were observed in the high dose females during the GD 6-9 interval and during the treatment period (GD 6-15) when compared with controls. However, these changes were transient and corrected mean body weight and mean food consumption of all treated group females were essentially equivalent for the overall gestation period (GD 0-21). 

 

There were no maternal findings found postmortem which were judged to be the result of treatment with EXXAL 8N. The majority of uterine implantation parameters were essentially equivalent between treated and control groups. There was an increase in post-implantation loss in the high dose females (17.3%) compared with controls (4.8%), although this difference was not statistically significant. Three dams in the high dose group did not have any viable fetuses at cesarean section, and only had implantation sites or early resorptions. The resorption of these fetuses was considered the result of the poor health of the dams rather than a direct developmental effect.

 

There were no statistically significant differences in mean fetal body weight between treated and control fetuses of either sex. Three low dose, two mid dose, and one high dose fetus were stunted. There were no statistically significant increases in total or individual external, visceral, or skeletal malformations, or external and visceral variations in the treated groups when compared with controls. Additionally, there were no statistically significant differences in the mean skeletal ossification sites between treated and control fetuses. 

 

There were statistically significant increases in total fetuses with skeletal variations and in the incidence of hypoplastic skull bones in the high dose group when compared with controls. However, the incidences of these findings were only slightly higher than the historical control range of this laboratory. Additionally, since the litter is the preferred unit of measure in developmental toxicology, the absence of a statistically significant increase in the litter-based incidence provides additional evidence the observed increase in this parameter was not biologically meaningful.

 

Statistically significant increases in rudimentary and well formed lumbar ribs were observed in the high and/or mid dose groups compared with controls on a per fetus and/or litter basis. On a per litter basis the increase in rudimentary lumbar ribs was statistically significant in the mid dose group when compared with controls. Although these increased incidences were not within the historical range of this laboratory, variations in skeletal structure such as rudimentary ribs are so common, they are regarded as alternative normal patterns and not regarded as harmful developmental toxic effects. Furthermore, rudimentary or well formed ribs are not considered biologically significant in the absence of other conventional signs of embryotoxicity, i.e. malformations, embryolethality, or fetal weight reduction. Rib variations have often been associated with maternal toxicity or stress. Therefore, the developmental significance of rib variations in the high dose fetuses probably relates to the transient maternal toxicity observed in the high dose females during the treatment phase of this study. Thus, this variation was not considered to be an adverse effect on the fetuses.  

 

In conclusion, signs of toxicity were apparent in the maternal animals at a dose level of 1000 mg/kg, as indicated by adverse clinical signs, reductions in body weight gain and food consumption. However, the findings were generally transient. There also was an increase in post-implantation loss in the high dose females, as three dams did not have any viable fetuses at cesarean section, only implantation sites/early resorptions. The resorption of these fetuses was considered the result of the poor health of the dams rather than a direct developmental effect. There were several statistically significant increases in the incidence of fetal skeletal variations both on an individual and litter basis in the treated groups compared with controls. However, most of these incidences were only slightly higher than the historical control range of this laboratory, or regarded as alternative normal patterns, and not regarded as harmful developmental toxic effects (Harris and DeSesso, 1994). Therefore, these common findings in fetal rats were not considered biologically important. Accordingly, the maternal NOAEL (No Observable Adverse Effect Level) was established at 500 mg/kg. The developmental NOAEL was established as 1000 mg/kg under the conditions of this study.

 

Justification for classification or non-classification

No classification for reproductive or developmental toxicity is indicated according to the general classification and labeling requirements for dangerous substances and preparations (Directive 67-548-EEC) or the classification, labeling and packaging (CLP) regulation (EC) No 1272/2008.