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Effects on fertility

Description of key information
No data available
Additional information

For further data on the comprehensive chronic 2-year study (D. Stout, 1992), see chapter repeated dose toxicity.


Short description of key information:
The available information on reproductive parameters for the substance includes a comprehensive chronic 2-year study (D. Stout, 1992), that gives no indication of adverse effects on organs of the male and female reproductive system. Taken together, although studies on fertility were not available for the substance, further testing is considered to be of low priority.

Effects on developmental toxicity

Description of key information
Overall, fetal morphological effects were observed at  high doses in the presence of pronounced maternal toxicity. In a reliable developmental toxicity study in rats a dose of 20 mg/kg was considered the NOEL for maternal toxicity and a dose of 120 mg/kg was considered the NOEL for developmental toxicity.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
120 mg/kg bw/day
Additional information

A reliable developmental toxicity study is available in SD rats. Twenty-five mated rats per dose were orally dosed with 0, 20, 120 and 300 mg/kg/day from gestation day 6 to 15. All animals were euthanized on gestation day 20 and subjected to a cesarean section. Fetuses were individually weighted, sexed and examined for external, visceral and skeletal abnormalities.

Homogeneity and stability of the test material was analyzed and considered to be appropriate. No effect on maternal survival and pregnancy status was observed. Body weight gain was statistically reduced during gestation days 6 -9 in the high dose group and food consumption was reduced at some time points in the mid and high dose group. Clinical signs were observed at the following doses:

120 mg/kg: slight increase in the incidence of dark material around the nose and post-dose salvation; 300 mg/kg: increased incidence of reddish vaginal discharge, soft stool, fecal stain, urine stain, dark material around the nose and/or eye(s) and post-dose observation of salvation, rubbing of chin on cage floor and dried red material around mouth.

Maternal necropsy observations were generally unremarkably. Maternal liver weight was dose related and statistically significantly increased in the 120 and 300 mg/kg groups. Cesarean section showed no effect on any parameter.

Fetal morphological observations: In the high dose group the number of litter with malformations was statistically increased with increased number of litter with kinked tail, rib anomalies and vertebral abnormalities with or without associated rib anomalies. In the same group statistically significant increase in the number of litter with various developmental variations were noted (malalingned sternegra(e), 14th rudimentary rib, 7th cervical rib and 27 presacral vertebrae). Additional, observation in the high dose group, although not statistically significant, were: descendent urethra(s), renal papilla(e) not developed and 14th full rib.

In conclusion: Fetal morphological effects were observed at the high dose group in the presence of pronounced maternal toxicity expressed as reduced maternal body weight, reduced food consumption, clinical signs, and liver toxicity.

Sitarek et al. 1996 investigated the developmental toxicity of TMQ in a prenatal toxicity study with severe limitations. Animals were dosed with 170, 340 and 670 mg/kg/day from GD 6 to 15. Fetuses were investigated on GD20. The authors concluded, that embryo toxic and fetotoxic effects were observed at doses toxic to the dam. The authors selected the TMQ doses based on acute toxicity data and concluded that 170, 340 and 670 mg/kg/day corresponds to 6, 13 and 25% LD50. Mortality was seen in the mid dose group (4/16) and in the high dose group (1/15). Additional systemic effects in the dams at 670 mg/kg included increased liver, adrenal, ovary and spleen weight, decreased body weight gain (controls: 98 g; 670 mg/kg group 60 g).

Developmental effects were reported at 670 mg/kg and included increased post-implantation losses, decreased fetal body weight and fetal crown-rump length, increased number of fetuses with variations in cranium, vertebrae, palatine bones and cleft plate (3 fetuses out of 65), unilateral renal pelvis, congenital defect internal hydrocephalus. At 340 mg/kg and 670 mg/kg an increase in the number of fetuses with delayed ossification and number of fetuses with variations in ribs was reported.

The authors discuss that the disturbances in the prenatal development of the offspring as the result of exposure to 670 mg TMQ/kg/day may result from the toxic damage to the pregnant female organism. Exposure to TMQ at a lower dose (340 mg/kg/day) still results in delayed fetal development. However, the pathophysiological consequences of these findings are not known.

Due to limitations in study design and documentation this study is not reliable for risk assessment because: an in-house strain was used and no historical data concerning the background incidence of external, skeletal or visceral alterations is given, the number of dams is low compared to guideline requirements, the authors used the individual fetus as the base for the statistical evaluation but correct would be to use the litter as statistical unit and the MTD was clearly exceeded in this study because mortality was high in the mid dose group (4/16 dams; 25%) but not dose related since only 1/15 dams died in the high dose group.

Justification for classification or non-classification