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Effects on fertility

Description of key information

No effects on fertility were observed in a screening study in rats at the highest dose level of 250 mg/kg bw (BASF, 2011). A 90-day study with the oxidation product of the substance did not show adverse effects on reproductive organs (Freudenthal 2001).

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Study duration:
subchronic
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 was investigated in a GLP compliant screening study (OECD 421) (BASF 2011). Four groups of 10 males and 10 females were treated by gavage once daily. Males were treated over a 14-day pre-pairing period and during the pairing period up to one day before necropsy. Females were treated throughout the pre-pairing, pairing, gestation and lactation period up to day 4 post partum. Dose levels were 0, 10, 50 and 250 mg/kg bw. PEG was used as a vehicle. All animals survived until the scheduled necropsy. Signs of discomfort such as salivation at dose level of 50 and 250 mg/kg body weight/day and pushing the head through the bedding material at dose level of 250 mg/kg body weight/day were observed during the course of the study. Mating performance, fertility, conception and gestation indices were not affected by treatment with the test item. The mean duration of gestation was also unaffected by treatment with the test item. The mean number of corpora lutea, the mean number of implantations per dam, and the incidence of post-implantation losses were not affected by treatment with the test item. No test item-related effects were observed in mean values of absolute and relative weight of testes and epididymides. No differences on the completeness of stages or cell populations of the testes were recorded between controls and high dose animals.

Effects on developmental toxicity

Description of key information

A GLP-compliant developmental toxicity study according to OECD guideline 414 is available. In this study, the fetal examinations revealed that there may be an adverse effect of the compound on the development of the shoulder girdle (scapula/humerus) at 500 mg/kg bw/d, as there was a slight but statistically significant increase of scapula/humerus shortenings detected in the respective dose group, exceeding the historical control values. A relation to test substance administration cannot be excluded.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
150 mg/kg bw/day
Species:
rat
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

In a prenatal developmental toxicity study, the test substance Irgalube 232 was administered to pregnant Wistar rats daily by gavage from implantation to one day prior to the expected day of parturition (GD 6-19) to evaluate its potential maternal and prenatal developmental toxicity. Analyses confirmed the correctness of the prepared concentrations, the homogeneous distribution and the stability of the test substance in the vehicle.

All females of the high-dose group (500 mg/kg bw/d) and some females (8 out of 25) of the mid-dose group (150 mg/kg bw/d) showed transient salivation during the treatment period. Salivation persisted in the respective animals only for some time after daily gavage dosing (maximum up to 2 hours) and was initially observed on GD 11. Transient salivation shortly after dosing most likely reflects a reaction of the animals to the taste and smell of the test substance. It is not considered to be a sign of systemic toxicity.

The mean food consumption of the mid- and high-dose dams (150 and 500 mg/kg bw/d) was statistically significantly reduced on GD 6-10 (maximum 10 and 16%, respectively), but recovered afterwards. The high-dose of the test substance temporarily affected the gross body weight gain of the dams in the respective test group on GD 6-8 (approx. 54% below control). These dams recovered from this effect afterwards. There was neither a treatment related effect on body weights nor on carcass weights or corrected (net) body weight gain in any of the test groups. Regarding pathology, the target organ was the liver. The livers showed significantly increased absolute and relative weights in test groups 1 to 3. The liver weights in all test groups lay above the range of historical control data (absolute: 10.808g - 11.455g; relative: 4.549% - 4.729%) and correlated to macroscopically enlarged livers in 4/25 animals in the high-dose group. The increased absolute and relative liver weights in all test groups were regarded as treatment related. However, the weight increase was only slight in the low- and mid-dose groups (test group 1: 8% absolute, 6%relative; test group 2: 14% absolute, 16% relative) and was regarded as non-adverse. Animals of test group 3 showed considerably increased liver weights (35% absolute, 34% relative) which were interpreted as treatment related and adverse. Altogether the temporary reduction of food consumption and body weight gain along with considerably increased liver weights constitute signs of systemic toxicity of the test substance at the high-dose level (500 mg/kg bw/d).

The mean number of implantation sites and consequently the mean live litter size were statistically significantly higher in the mid- and high-dose groups. The preimplantation loss was significantly lower in all treatment groups. However, these apparent increases/decreases came from comparatively low/high control values for these parameters rather than being real treatment-related effects. In addition, these are not at all adverse findings of any toxicological relevance. Thus, no differences of toxicological relevance between the control and the treated groups (50, 150 or 500 mg/kg bw/d) were determined for any reproductive parameters, such as conception rate, mean number of corpora lutea, mean number of implantations, as well as pre- and postimplantation loss. Similarly, no influence of the test substance on placental weight, fetal weight and sex distribution of the fetuses was noted at any dose.

Fetal examinations revealed that there may be an adverse effect of the compound on the development of the shoulder girdle (scapula/humerus) at a dose of 500 mg/kg bw/d, as there was a slight increase of scapula/humerus shortenings detected in the respective dose group, which was above the single case of shortened humerus in the concurrent control as well as above the historical incidence for shortened humerus and/or scapula (in the historical data both findings are usually combined). The single case of shortened scapu-la/humerus at 150 mg/kg bw/d is comparable to both concurrent and historical control and thus considered as an accidental finding. Increased incidences of incomplete ossification of skull and wavy ribs at 500 mg/kg bw/d represent species-specific anatomic variation at the time around birth without any detrimental effects on further development. Thus, the increase of these two variants is considered as a treatment-related but not as an adverse finding.

Under the conditions of this prenatal developmental toxicity study, the oral administration of the test item to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) at a dose of 500 mg/kg bw/d caused evidence of maternal toxicity, such as temporarily reduced food consumption and body weight gain as well as increased absolute and relative liver weights. In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity is 150 mg/kg bw/d. Fetal examinations revealed a slight increase of scapula/humerus shortenings at a dose of 500 mg/kg bw/d. Hence, the no observed adverse effect level (NOAEL) for prenatal developmental toxicity is 150 mg/kg bw/d.

Justification for classification or non-classification

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

In the available developmental toxicity study a slight but statistically significant increase of scapula/humerus shortenings in the high dose group was observed exceeding the historical control values. A relationship to the treatment cannot be excluded. Therefore, the substance is classified for reproductive toxicity under Regulation (EC) No. 1272/2008 with Category 2, H361d: Suspected of damaging the unborn child.

Additional information