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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

For the assessment of fertility, a screening study following OECD guideline 421 is available (BASF 2012b). This study included extra investigations on target organs known to be affected from previous investigations. The substance was administered orally via gavage to groups of 10 male and 10 female Wistar rats (F0 animals) at dose levels of 0 mg/kg body weight/day (mg/kg bw/d; test group 0) 0.5 mg/kg bw/d (test group 1), 2.0 mg/kg bw/d (test group 2) and 10.0 mg/kg bw/d (test group 3). Drinking water containing 1% carboxymethylcellulose and 5 mg/100 mL Cremophor EL served as vehicle.

 

The duration of treatment covered a 2-week pre-mating and mating period in both sexes, approximately 1 week post-mating in males, and the entire gestation period as well as 4 days of lactation in females with continued treatment until one day before sacrifice.

After 2 weeks of premating treatment the F0 animals were mated to produce F1 generation pups. Mating pairs were from the same test group. Mating was discontinued as soon as sperm was detected in the vaginal smear.

A detailed clinical observation (DCO) was performed in all animals before initial test substance administration and as a rule thereafter at weekly intervals. Food consumption of the F0 parents was determined once weekly during premating. In dams food consumption was determined for gestation days (GD) 0-7, 7-14, 14-20 and lactation days 1-4. Body weights of F0 parents were determined once a week, in males throughout the study and in females during premating and mating. During gestation and lactation period, F0 females were weighed on GD 0, 7, 14 and 20, after the day of parturition (postnatal day [PND] 0) and on PND 4. The pups were sexed and examined for macroscopically evident changes on PND 0. They were weighed on PND 1 and on PND 4. Their viability was recorded. At necropsy on PND 4, all pups were sacrificed under isoflurane anesthesia with CO2and examined macroscopically for external and visceral findings. Hematological examinations were performed in all animals per sex and test group towards the end of the administration period.All F0 parental animals were sacrificed by decapitation under isoflurane anesthesia, and were assessed by gross pathology. Sex organ weights were recorded and a histopathological examination was performed for sex organs as well as liver spleen, jejunum and mesenteric lymph nodes.

As a result, reproductive function of parental animals were not affected. Also offspring was not affected.

Adverse effects indicating severe toxicity were observed at the highest dose group of 10 mg/kg bw. These findings are presented below:

Clinical Examinations

  • Body weight loss in 4 male animals during towards the end of the administration period
  • Poor general condition in 2 male animals towards the end of the administration period
  • Swelling of limbs and unsteady gait in 2 male animals towards the end of the administration period
  • Piloerection in 1 male animal towards the end of the administration period

Clinical Pathology

  • Decreased hemoglobin and hematocrit values in both sexes
  • Decreased red blood cell (RBC) counts in females
  • Decreased mean corpuscular volume (MCV) and mean corpuscular hemoglobincontent (MCH) in males
  • Increased platelet counts in females
  • Increased total white blood cell (WBC) counts, absolute and relative neutrophil, absolute monocyte and absolute large unstained (LUC) counts in both sexes
  • Decreased relative lymphocyte counts in both sexes

Pathology

  • Minimal to moderate necrosis of the liver in 5 of 10 male animals
  • Granulomatous inflammation with necrosis of the mesenteric lymph node in 9 of 10 male (graded marked to massive) and 9 of 10 female (graded moderate to marked) animals
  • Granulomatous inflammation with necrosis of the spleen in 2 of 10 male (graded moderate to marked) and 2 of 10 female (graded slight to moderate) animals

 

Further testing of effects on fertility is not considered necessary due to the very specific effet occurring at very low doses in the gastrointestinal tract. The substance is classified as toxic upon repeated exposure (GHS RE TOST Cat 1) with the mesenteric lymph nodes being the most sensitive organ and the toxicity spreading to spleen and liver (granulomatous inflammation). It appears that the substance is taken up by macrophages which then have difficulty in degradation. Due to this mechanism, an effect on fertility or offspring occurring at lower doses than the parental toxicity is not expected. Considering the low effective levels and the very low DNELs, further specific investigation of reproductive toxicity endpoints is not considered necessary.

 


Short description of key information:
No adverse effects on fertility were observed in a screening study in rats (OECD 421, GLP). The highest dose of 10 mg/kg bw caused poor general condition in males and marked granulomatous inflammation in mesenteric lymph nodes. Spleen, liver and intestine were also affected, but to a lesser degree.

Justification for selection of Effect on fertility via oral route:
valid study

Effects on developmental toxicity

Description of key information
No indication of developmental toxicity was observed in a screening gavage study in rats (OECD 421, GLP) at the highest tolerable dose of 10 mg/kg bw (BASF 2012b).
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
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

For the assessment of developmental toxicty, a screening study following OECD guideline 421 is available (BASF 2012b). This study included extra investigations on target organs known to be affected from previous investigations. The substance was administered orally via gavage to groups of 10 male and 10 female Wistar rats (F0 animals) at dose levels of 0 mg/kg body weight/day (mg/kg bw/d; test group 0) 0.5 mg/kg bw/d (test group 1), 2.0 mg/kg bw/d (test group 2) and 10.0 mg/kg bw/d (test group 3). Drinking water containing 1% carboxymethylcellulose and 5 mg/100 mL Cremophor EL served as vehicle.

As described above for the endpoint fertility, significant systemic toxicity was observed at the highest tested dose level of 10 mg/kg bw. 

No test substance-related, adverse findings were noted for the offspring. The mean number of delivered pups per dam and the rate of liveborn and stillborn pups, i.e. each 1 pup of female Nos. 115 and 118 in test group 1 (0.5 mg/kg bw/d) and 1 pup of female No. 121 in test group 2 (2 mg/kg bw/d), reflect the normal range of biological variation inherent in the strain used in this study. The viability index as indicator for pup mortality between PND 0 and 4 was 99% for the control (test group 0; 1 pup of female No. 101 cannibalized), 98% for test group 1 (0.5 mg/kg bw/d; each 1 pup of female Nos. 113 and 115 cannibalized) and 100% for test groups 2 and 3 (2 and 10 mg/kg bw/d). The remaining pups which belonged to female Nos. 101, 113 and 115 did not show any findings until sacrifice. The sex distribution and sex ratios of live F1 pups on the day of birth and on PND 4 did not show biologically relevant differences between test groups. The surviving F1 pups of any test group did not show adverse clinical signs up to scheduled sacrifice on PND 4. Mean pup body weights and pup body weight changes of all pups in all test groups were comparable to the concurrent control values. No runts were seen in any test group. During the necropsy of all F1 pups no test substance-related findings were observed.

 

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available screening study is considered reliable and suitable for classification purposes under 67/548/EEC. As a result the substance is not considered to be classified for fertility or developmental toxicity under Directive 67/548/EEC, as amended for the 31st time in Directive2009/2/EG. 

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

The available screening study is reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified for fertility or developmental toxicity under Regulation (EC) No. 1272/2008, as amended for the third time in Directive (EC 618/2012).

During the four days covered in the screening study, no effects via lactation were observed.

 

Additional information

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