Registration Dossier

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information
No additional data available.
Additional information

Glycerin 3 EOTA was tested in a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test according to OECD TG 422 and in compliance with GLP regulations by BASF SE (2010). The substance was administered orally via gavage to groups of 10 male and 10 female Wistar rats (F0 animals) at doses of 50, 150, and 500 mg/kg body weight/day. Control animals were dosed daily with the vehicle (1% Carboxymethylcellulose suspension in drinking water). 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.

 

After 2 weeks of premating treatment 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. F0 animals were examined for their reproductive performance including determination of the number of implantation sites and the calculation of postimplantation loss for all F0 females. A detailed clinical observation (DCO) was performed in all animals before test substance administration and 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 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. During gestation and lactation period, F0 females were weighed on gestation days (GD) 0, 7, 14 and 20, on the day of parturition (postnatal day [PND] 0) and on PND 4. Pups were sexed on PND 0 and weighed one day after birth and on PND 4. Their viability was recorded twice daily on each workday or only in the morning on Saturday and Sunday. On PND 4 all pups were sacrificed under Isoflurane anesthesia with CO2and were examined macroscopically. Clinicochemical and hematological examinations as well as urinalyses were performed in 5 parental males and females per group towards the end of the administration period. At the end of the administration period a functional observational battery was performed and motor activity was measured in 5 parental males and females per group. All surviving F0 parental animals were sacrificed by decapitation, under Isoflurane anesthesia, and were assessed by gross pathology. Organ weights were recorded and a histopathological examination was performed.

 

Clinically, distinct toxicity was noted in the F0 males and F0 females at 500 mg/kg bw/d. Mortality in 4 high-dose males and 3 high-dose females as well as clinical observations such as respiratory sounds, labored respiration and piloerection were observed during major parts of treatment. These findings were also observed in individual males at 150 mg/kg bw/d, however, they were less severe and no mortality was observed there.

 

Pathology (see below) confirmed that mortality and adverse clinical observations were subsequent to local irritant effects of the test substance in the fore- and glandular stomach. Also, reduced food consumption in males and females during premating and reduced body weights/body weight gain in males are considered to be secondary to these local effects. Thus, these distinct adverse effects, in particular mortality, are not regarded to be due to systemic toxicity of Glycerin 3 EOTA.

 

Clinical pathology revealed a slight anemia in mid- and high-dose females (150 and 500 mg/kg bw/d) indicated by reduced RBC counts, haemoglobin and hematocrit values. Maybe, anemia was due to erosions and ulcers in the forestomach and glandular stomach of rats of both sexes in the mentioned dose groups. Females seemed to be more prone to anemia due to gestation and lactation.

 

Pathology and histopathology revealed fore- and glandular stomach, liver lymph node, duodenum, and liver as target organs in this study.

In the forestomach, erosions or ulcers were noted in 7 males and one female of test group 2 (150 mg/kg bw/day) as well as in all males and females of test group 3 (500 mg/kg bw/day). The erosions or ulcers were associated with inflammation. Their occurrence is regarded to be the primary response to an irritant effect of the test substance. As proliferative response secondary to ulceration, squamous cell hyperplasia was observed in 8 males and one female of test groups 2 (150 mg/kg bw/day) as well as in all males and 9 females of test group 3 (500 mg/kg bw/day). The severity of the squamous cell hyperplasia was dose-related increased. The occurrence of erosions or ulcers and squamous cell hyperplasia is considered to be treatment-related and adverse.

In the glandular stomach, the test substance led to erosions or ulcers that were observed in 5 males and 2 females of test group 3 (500 mg/kg bw/day). In addition, focal hyperemia was noted in 4 males and 2 females of test group 3 (500 mg/kg bw/day). Erosions or ulcers and the focal hyperemia are considered as consequence of irritant effects of the test substance and are regarded to be adverse.

In the liver lymph node, a lympho-reticulocellular hyperplasia was observed in 3 males of test group 2 (150 mg/kg bw/day) as well as in 7 males and 7 females of test group 3 (500 mg/kg bw/day). Furthermore, lymphoid cysts occurred in 5 males and 5 females of test group 3 (500 mg/kg bw/day). These findings are considered to be secondary effects as consequence of the inflammatory processes in the forestomach and regarded to be adaptive and non-adverse.

The increased liver weights in females of test group 2 (150 mg/kg bw/day) as well as in males and females of test group 3 (500 mg/kg bw/day) are related to treatment. They are regarded to be adaptive and non-adverse. In males, the increased liver weights correlated with a minimal central hepatocellular hypertrophy that occurred in the liver of 5 animals in test group 3 (500 mg/kg bw/day). The hepatocellular hypertrophy is assessed treatment-related and adaptive.

 

Under the conditions of this Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in Wistar Rats Glycerin 3 EOTA had no adverse effects on fertility and reproductive performance of the F0 parental animals of both sexes at 50, 150 and 500 mg/kg bw/d. Most of the F0 parental animals proved to be fertile. Failure of pregnancy in one control female and in two test substance-treated females could not be attributed to the treatment by gross and histopathological examinations of the respective animals of both genders. Mating behaviour, conception, implantation and parturition were not influenced.

 

No signs of developmental toxicity were noted in any of the treated groups, numbers of liveborn pups, pup survival and growth were not influenced by the test compound.

 

In conclusion, under the conditions of the present reproduction/developmental toxicity screening test the NOAEL (no observed adverse effect level) for fertility and reproductive performance was 500 mg/kg bw/d for the parental rats, the highest tested dose.

 

The NOAEL for general, systemic toxicity of the test substance was 150 mg/kg bw/d for males and females based on clinical chemistry changes at next higher dose level. Local irritation in fore- and glandular stomach led to mortality at 500 mg/kg bw/d and triggered adverse clinical observations as well as hematological changes at 150 and 500 mg/kg bw/d. Thus, the NOAEL for local irritation effects was 50 mg/kg bw/d.


Short description of key information:
Reproduction:
- oral: NOAEL = 500 mg/kg bw /day (Wistar rat, OECD TG 422, gavage)
- dermal: no data
- inhalation: no data

Effects on developmental toxicity

Description of key information
Development:
- oral: NOAEL = 500 mg/kg bw/d (developmental toxicity), NOAEL (systemic toxicity) = 150 mg/kg bw/d (maternal toxicity), NOAEL (local effects) = 50 mg/kg bw/d (maternal toxicity) (Wistar rat, gavage, OECD TG 422)
- dermal: no data
- inhalation: no data
Additional information

Glycerin 3 EOTA was tested in a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test according to OECD TG 422 and in compliance with GLP regulations by BASF SE (2010). The substance was administered orally via gavage to groups of 10 male and 10 female Wistar rats (F0 animals) at doses of 50, 150, and 500 mg/kg body weight/day. Control animals were dosed daily with the vehicle (1% Carboxymethylcellulose suspension in drinking water).

 

Under the conditions of this Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in Wistar Rats Glycerin 3 EOTA had no adverse effects on fertility and reproductive performance of the F0 parental animals of both sexes at 50, 150 and 500 mg/kg bw/d. Most of the F0 parental animals proved to be fertile. Failure of pregnancy in one control female and in two test substance-treated females could not be attributed to the treatment by gross and histopathological examinations of the respective animals of both genders. Mating behaviour, conception, implantation and parturition were not influenced.

 

No signs of developmental toxicity were noted in any of the treated groups, numbers of liveborn pups, pup survival and growth were not influenced by the test compound. No malformations were observed at any dose level.

 

The NOAEL for general, systemic toxicity of the test substance was 150 mg/kg bw/d for males and females based on clinical chemistry changes at next higher dose level. Local irritation in fore- and glandular stomach led to mortality at 500 mg/kg bw/d and triggered adverse clinical observations as well as hematological changes at 150 and 500 mg/kg bw/d. Thus, the NOAEL for local irritation effects was 50 mg/kg bw/d. (for details see above, Chapters Repeated dose toxicity and Effects on fertility).

 

The NOAEL for developmental toxicity in the F1 progeny of the test substance treated groups was found to be 500 mg/kg bw/d, the highest tested dose.

Justification for classification or non-classification

Based on the available data, no classification of the substance concerning toxicity to reproduction and developmental toxicity is warranted.

  • EU classification according to Annex VI of Directive 67/548/EEC: no classification required
  • GHS classification (REGULATION (EC) No 1272/2008 (CLP)): no classification required

Additional information