Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Additional information

Reproductive effects of the registered substance were examined in a 90 -day oral gavage GLP-study in rats according to OECD test guideline 408 with examinations of reproductive organ weights, the oestrus cycle and the spermatogenesis. The rats were treated daily with 100, 300 or 1000 mg/kg bw/day.

No mortality occured. No influence on the behaviour or external appearance was observed. Body weight and body weight gain, food and drinking water consumption were comparable to control. No effect on reproductive organs, the oestrus cycle and the spermatogenesis was observed. Histopathology did not reveal any test substance related changes.

Therefore, the NOEL for reproductive effects of the registered substance was determined as 1000 mg/kg bw/day (LPT, 2006).


Short description of key information:
In a GLP-study according to OECD test guideline 408 (90-days rat study, oral gavage) with examinations of reproductive organ weigts, the oestrus cycle and the spermatogenesis, the NOEL of the registered substance was determined as 1000 mg/kg bw/day.

Effects on developmental toxicity

Additional information

The target molecule propylheptylcaprylate is an ester based on the educts propylheptanol (CAS 10042-59-8) and octanoic acid (CAS 124-07-2). In a developmental gavage study, it can be expected that the ester propylheptylcaprylate will be cleaved into propylheptanol and octanoic acid due to the acidic milieu. For both substances, developmental toxicity studies are available which do not exhibit any major concern with regard to developmental toxicity.

In addition, the diester of propylheptanol and a carbonate (dipropylheptylcarbonate, CAS 1238449-42-7) was tested for its teratogenic potential. No effects on the fetuses were also observed in this study. For further information please see below.

In summary, it is not expected that propylheptylcaprylate will have a potential to cause teratogenic effects based on data obtained with the educts of this ester and based on data obtained with dipropylheptylcarbonate. As a consequence, a OECD 414 for propylheptylcaprylate is not proposed.

In a developmental toxicity study according to OECD guideline 414, 2-propylheptan-2-ol was administered to 25 female Wistar rats/dose by gavage at dose levels of 0, 50, 200 and 600 mg/kg bw/d from days 6 to 19 of gestation. Animals were sacrificed on gestation day 20. Maternal examinations included detailed clinical observations, body weight, food and water consumption, post mortem examinations (gross pathology, organ weights of liver, kidneys, spleen and unopened uterus) and clinical pathology (hematology, clinical chemistry). The examinations of the uterus included number of corpora lutea, implantations, early and late resorptions. Furthermore, calculations of conception rate and pre- and postimplantation losses were carried out. The fetal examinations included external examination of all fetuses and soft tissue and skeletal examinations of half the respective litters.

There were no substance-related mortalities in any of the groups of maternal animals. At 600 mg/kg bw/d salivation and urine smeared fur was observed. Furthermore significantly reduced food consumption (11 % below control), significantly reduced final body weight (7% below control), and significantly reduced absolute (23% below control) and net (52% below control) body weight gain was observed. The water consumption was significantly increased. Decreased platelets, sodium, chloride, total protein, globulins and cholesterol and increased inorganic phosphate and urea were observed. The absolute and relative liver weight was also increased. At 200 mg/kg bw/d salivation was observed as well as significantly reduced final body weight (6% below control) and significantly reduced absolute (15% below control) and net (19% below control) body weight gain. An increased relative liver weight (5% above control) was also observed (due to peroxisomal proliferation). At 50 mg/ kg bw/d no substance related effects were observed.

Fetal examinations revealed statistically significantly decreased fetal weights (11 % below control) and an increased incidence of skeletal variations, in particular incompletely or non-ossified morphologically unchanged skeletal structures or unspecific variants of ossification (supernumerary thoracic vertebrae, supernumerary and/or wavy ribs) at the highest tested dose. Though slight signs of a retardation of prenatal development (lower fetal weights, delay of ossification) were observed at high dose level (600 mg/kg body weight/day) they were considered to be secondary to the clear disturbance of maternal homeostasis during pregnancy and not relevant in terms of developmental toxicity. No effects were observed at 200 and 50 mg/kg bw/d.

Based on the above results the maternal NOAEL was set to 50 mg/kg bw/d. The NOAEL for developmental toxicity was determined to be 600 mg/kg bw/d.

In a developmental toxicity study according to OECD guideline 414, carbonic acid, bis (2-propylheptyl) esterwas administered to 25 female Wistar rats/dose by gavage at dose levels of 0, 100, 300 and 1000 mg/kg bw/d from days 6 to 19 of gestation. Animals were sacrificed on gestation day 20. Maternal examinations included detailed clinical observations, body weight, food consumption and post mortem examinations (gross pathology, weight of unopened uterus). The examinations of the uterus included number of corpora lutea, number and distribution of implantation sites, early and late resorptions and dead fetuses. Furthermore, calculations of conception rate and pre- and postimplantation losses were carried out. The fetal examinations included external examination soft tissue and skeletal examinations of all fetuses.

There were no substance-related mortalities in any of the groups of maternal animals. In the highest tested dose slightly reduced food consumption (4% below control), statistically significantly reduced mean body weight gain on GD 6-10 (30% below control) and GD 15-17 (17% below) and statistically significantly reduced corrected body weight gain (12% below control) was observed. No test substance-related adverse effects on gestational parameters were seen.

No test substance-related adverse findings at any test concentration were observed for the offspring.

Based on the above results the maternal NOAEL was set to 300 mg/kg bw/d. The NOAEL for developmental toxicity was determined to be1000 mg/kg bw/d.

 

In a publication by Scott et al. (1994) the developmental toxicity of octanoic acid was determined by applying a single dose of 18.75 mmol/kg bw (2704 mg/kg bw) by gavage to 12 female Sprague Dawley rats on day 12 of gestation. Fetuses were analyzed on day 20 of gestation. Maternal examinations included post mortem examination of the uterus and content of octanoic acid in maternal plasma at 0.25, 0.5, 1, 2, 4, 8, and 24 h after dosing (pharmokinetics). The examinations of the uterus included number of implantations, early and late resorptions. The fetal examinations included external examination of 1/3 of each litter. Soft tissue, skeletal and head examinations in 2/3 of each litter. The content of octanoic acid in the embryo was also determined at 0.25, 0.5, 1, 2, 4, 8, and 24 h after dosing.

Severe maternal effects were noted that were not specified in the publication. Octanoic acid was essentially devoid of embryotoxic effects except for a slight reduction of fetal weight, most likely attributable to the severe maternal toxicity that accompanied the administration of this agent.

Toxicity to reproduction: other studies

Additional information

The target molecule propylheptylcaprylate is an ester based on the educts propylheptanol (CAS 10042-59-8) and octanoic acid (CAS 124-07-2). In a developmental gavage study, it can be expected that the ester propylheptylcaprylate will be cleaved into propylheptanol and octanoic acid due to the acidic milieu. For both substances, developmental toxicity studies are available which do not exhibit any major concern with regard to developmental toxicity. In addition, the diester of propylheptanol and a carbonate (dipropylheptylcarbonate, CAS 1238449-42-7) was tested for its teratogenic potential. No effects on the fetuses were also observed in this study.  In summary, it is not expected that propylheptylcaprylate will have a potential to cause teratogenic effects based on data obtained with the educts of this ester and based on data obtained with dipropylheptylcarbonate. As a consequence, a OECD 414 for propylheptylcaprylate is not proposed.

Justification for classification or non-classification