Pyrrolidine

Endpoint summary

Description of key information

Under the conditions of an OECD 422 combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in Wistar rats via vapour inhalation the following no observed adverse effect concentration (NOAEC) of pyrrolidine were determined:
- NOAEC general, local toxicity at the respiratory tract = 50 mg/m³
- NOAEC general, systemic toxicity = 150 mg/m³ (highest dose tested)
- NOAEC reproductive performance and fertility = 150 mg/m³ (highest dose tested)
- NOAEC developmental toxicity = 150 mg/m³ (highest dose tested)  

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

150 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

The study was performed according to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test), GLP compliant and has Klimsch score 1.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

50 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

The study was performed according to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test), GLP compliant and has Klimsch score 1.

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Oral: no data available

Inhalation:

The key study was performed according to OECD guideline 422 in compliance with GLP (BASF SE/DSM, 2013).To evaluate the toxicity profile ofPyrrolidine(PYR) after inhalation exposure, groups of ten male and ten female Wistar rats (F0 animals) per test group were exposed nose-only to dynamic atmosphere of PYR for 6 hours per day on each day. The duration of treatment covered a 2-week pre-mating and 2-week mating period in both sexes, 1 day post-mating in males, and the entire gestation period of the females. After the lactation period and after necropsy of the pups total all parental females were exposed to the test substance on 9 consecutive days. The target concentrations were 15, 50 and 150 mg/m³. A concurrent control group was exposed to conditioned air. For adaptation to the experimental conditions all animals were kept in glass restraining tubes identical to those used in the study and were exposed nose-only to fresh air on two days before start of the exposure period. 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. 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 initial test substance exposure and, as a rule, thereafter at weekly intervals. Clinical observation was performed at least three times on exposure days and once a day during the other days. 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. During the 4 exposure days after necropsy of the pups the food consumption was determined also. 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 after parturitionpostnatal day [PND] 1) and on PND 4. After the pups are sacrificed the females that were exposed for 9 consecutive days were weighed on study day 47, 49 and 54. A functional observational battery (FOB) was performed and motor activity was measured in 5 parental males and females per group. The FOB of the female animals was on study day 12. The male animals were performed at the end of the exposure period on study day 26. 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 with CO2, under isoflurane anesthesia, and examined macroscopically for external and visceral findings. Clinico-chemical and hematological examinations were performed in 5 animals per sex and grouptowards the end of the exposure period. A complete necropsy including gross pathological evaluation and weighing of selected organs was performed. Organs and tissues were examined histopathologically as required by the corresponding test guidelines. All F0 parental animals were sacrificed under pentobarbitone anesthesia by exsanguination from the abdominal aorta and vena cava and were assessed by gross pathology. Weights of selected organs were recorded and a histopathological examination was performed. The following test substance-relate adverse effecst were observed: Test group 3 (150 mg/m³):Ulceration of the squamous and/or respiratory epithelium in the nasal cavity (level I) in 2 male and 2 female animals; minimal to severe degeneration/regeneration of squamous and/or respiratory epithelium in the nasal cavity (level I) in 9 male and 9 female animals; minimal to moderate degeneration/regeneration of squamous and/or respiratory epithelium in the nasal cavity (level II) in 6 male and 5 female animals. Test group 2 (50 mg/m³):No adverse test substance-related histopathologic and macroscopic findings or weight changes. Test group 1 (15 mg/m³):No adverse test substance-related histopathologic and macroscopic findings or weight changes. Under the conditions of this OECD 422 combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in Wistar rats the following no observed adverse effect concentration (NOAEC) of pyrrolidine were determined: The NOAEC for general, local toxicity at the respiratory tract was 50 mg/m³ for the F0 females and males based on histological findings in nasal cavity. The NOAEC for general, systemic toxicity was 150 mg/m³ for the F0 females and males. The NOAEC for reproductive performance and fertility was 150 mg/m³ for the F0 parental rats. The NOAEC for developmental toxicity in the F1 offspring was 150 mg/m³. In a non-GLP and non-guideline study of Zaeva (1974, Russian publication (Val 4) cited byGesundheitsschaedliche Arbeitsstoffe, Toxikologisch-arbeitsmedizinische Begruendung von MAK-Werten (Maximale Arbeitsplatz-Konzentrationen), Pyrrolidin, 1977, VCH Weinheim, Germany, 20.Lieferung 1994) 40 male rats were exposed to the test item for 6 months with a daily exposure period of 4 hours at a concentration of 2.6 mg/m³. Effects described were reduced hemoglobin level and decreased daily diuretic volume. With increasing exposure duration, excitation of the nervous system was observed in exposed animals. Furthermore, a decrease in the number of normal spermatogones and a reduction of the spermatogenic index was observed as well as an increase in the number of tubuli seminiferi contorti with desquamation of seminiferous epithelium. The movement of spermatozoa and the fertility of the rats were unchanged. No cytotoxic effect and no increase of chromosomal aberration were observed in bone marrow cells. In the recovery period, an increased permeability of skin capillaries was found. Morphological investigation of the organs exhibited week atrophic and dystrophic changes.

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC) The available experimental test data for repeated dose toxicity are reliable and suitable for the purpose of classification under Directive 67/548/EEC. As a result the substance is not warranted to be classified for repeated dose toxicity under Directive 67/548/EEC.

Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008 The available experimental test data for repeated dose toxicity are reliable and suitable for the purpose of classification under Regulation (EC) No.1272/2008. As a result the substance is not warranted to be classified for repeated dose toxicity, under Regulation (EC) No.1272/2008.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
highest dose tested

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Highest quality study.