γ-valerolactone

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

The results from a 14-day range finding study similar to OECD guideline 414 showed no relevant maternal toxicity up to a dose of 1000 mg/kg bw in rats. Thus, the NOAEL was found to be ≥ 1000 mg/kg bw.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2020-01-24 to 2020-02-17

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Justification for type of information:

A 14-day range-finding test with pregnant animals was conducted previous to an OECD 422 study with gamma-Valerolactone. The combined repeated dose toxicity study with the reprod./develop. tox. screening test, OECD 422, rats (gavage) is ongoing, the results will be submitted as soon as the data are available.

Qualifier:

equivalent or similar to guideline

Guideline:

other: EU Method No. L 142 (Prenatal Developmental Toxicity Study)

Version / remarks:

2008-05-30

Deviations:

yes

Remarks:

Not all parameters indicated in the guideline were investigated.

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)

Version / remarks:

1998-08

Deviations:

yes

Remarks:

Not all parameters indicated in the guideline were investigated.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Version / remarks:

2018-06-25

Deviations:

yes

Remarks:

Not all parameters indicated in the guideline were investigated.

Principles of method if other than guideline:

- Principle of test: 14-day maternal toxicity range-finding test study, not all parameters indicated in the guideline were investigated.
- Short description of test conditions: 14-day range finding study with pregnant female rats (7 animals per dose, 2 doses)
- Parameters analysed / observed: Cage side observations, clinical signs, body weight, haematology, clinical chemistry, organ weights. Only the maternal toxicity was investigated.

GLP compliance:

yes

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Batch number of test material: Zimmerma 00003
- Expiration date of the batch: 12 Aug 2021

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Age at study initiation: (P) about 10-12 weeks
- Housing: Polycarbonate cages type III 2000P with dust-free wooden bedding. Cages were enriched with wooden gnawing blocks and large play tunnels
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: From gestation day 0 to the beginning of administration (gestation day 6)

DETAILS OF FOOD AND WATER QUALITY:
The food used in the study was assayed for chemical and microbial contaminants. Fed. Reg. Vol. 44, No. 91 (09 May 1979), p 27354 (EPA), served as the guideline for maximum tolerable contaminants. Additionally, the levels of
phytoestrogens should not exceed 350 μg of genistein equivalents/gram. According to recommendations of the GVSOLAS, the total amount of bacteria must not exceed 1*10^5 per g food.

The drinking water is regularly assayed for chemical contaminants both by the municipal authorities of Frankenthal and by the Environmental Analytics Water/Steam Monitoring Department of BASF SE as weil as for bacteria by a contract laboratory. The Drinking Water Regulation will serve as the guideline for maximum tolerable contaminants.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 45-65
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From day 0 (gestation day 6) to day 14 (gestation day 19)

Route of administration:

oral: gavage

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
For the test substance preparation, the specific amount of test substance is weighed, topped up with deionized water in a graduated flask and intensely mixed with a magnetic stirrer until it is completely dissolved. Before and during administration, the preparations is kept homogeneous with a magnetic stirrer.

VEHICLE
- Concentration in vehicle: 3 g/100 mL (for 300 mg/kg bw group) and 10 g/100 mL (for 1000 mg/kg bw group)
- Amount of vehicle: 10 mL/kg bw

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

GC analysis: No test substance could be detected in the vehicle control sample with a concentration of ≥ 30 % of the lowest calibration solution. The values of the test item in deionized water were found to be in the range of 90 % – 110 % of the nominal concentrations. These results demonstrated the correctness of the concentrations of the test item in deionized water.

Details on mating procedure:

The animals were paired by the breeder (time-mated animals)

Duration of treatment / exposure:

14 days

Frequency of treatment:

Daily

Duration of test:

14 days

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Dose / conc.:

300 mg/kg bw/day (nominal)

Dose / conc.:

0 mg/kg bw/day (nominal)

No. of animals per sex per dose:

7 females per dose

Control animals:

yes

Details on study design:

- Dose selection rationale: Low and high dose levels as requested by the sponsor
- Rationale for animal assignment: According to their weight

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily (mondays-fridays) or once daily (saturdays, sundays and public holidays) from gestation day 0 to 20 for mortality.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: At least once daily for any signs of morbidity, pertinent behavioral changes and/or signs of overt toxicity. During the administration period (gestation day 6-19), all animals will be checked daily for any abnormal clinical signs before the administration as well as within 2 hours and between 2 and 5 hours after administration.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights are recorded on gestation day 0, 1, 3, 6, 8, 10, 13, 15, 17, 19 and 20

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: Uterus and early resorptions
- The tissues indicated in Table 1 were prepared for microscopic examination and weighed, respectively

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: No
- Number of implantations: No
- Number of early resorptions: Yes
- Number of late resorptions: No

Blood sampling:

On gestation day 20, blood samples were obtained from all surviving animals by retrobular venous puncture. After blood sampling, all dams are sacrificed and examined.

Fetal examinations:

- External examinations: No
- Soft tissue examinations: No
- Skeletal examinations: No
- Head examinations: No

Statistics:

Means and standard deviations are calculated. In addition, water consumption, food consumption, body weight, body weight change, corrected body weight gain and carcass weight are statistically analyzed by Dunnett's test. The weights of the unopened uterus were analyzed by Kruskal-Wallis and Wilcoxon test.

Indices:

Not examined

Historical control data:

Not specified

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

3/7 animals from the 1000 mg/kg bw group showed salivation.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Endocrine findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Slight increase in absolute (+11% )/relative (+10 %) liver weights in the 1000 mg/kg bw test group

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Number of abortions:

not examined

Pre- and post-implantation loss:

not examined

Total litter losses by resorption:

not examined

Early or late resorptions:

no effects observed

Dead fetuses:

not examined

Changes in pregnancy duration:

not examined

Changes in number of pregnant:

not examined

Other effects:

not examined

Key result

Dose descriptor:

LOAEL

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Abnormalities:

no effects observed

Fetal body weight changes:

not examined

Reduction in number of live offspring:

not examined

Changes in sex ratio:

not examined

Changes in litter size and weights:

not examined

Anogenital distance of all rodent fetuses:

not examined

Changes in postnatal survival:

not examined

External malformations:

not examined

Skeletal malformations:

not examined

Visceral malformations:

not examined

Other effects:

not examined

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Comparable to guideline study with acceptable restrictions

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

Maternal toxicity (14 days), rat, RL2

A 14-day prenatal range-finding toxicity study with pregnant animals similar to an OECD 414 study has been conducted previous to an OECD 422 study. The test item was administered orally by repeated gavage to female Wistar rats from gestation day (GD) 6 through GD 19 to facilitate the selection of the dose levels for the subsequent definite study. Doses of 0, 300 and 1000 mg/kg bw in deionized water were given to seven animals per dose. For this purpose, disposable syringes of suitable size and suitable gavage tubes were used. During the study, all animals were observed for any clinically abnormal signs and food and water consumption and body weights were recorded. On GD 20, blood samples were obtained from all surviving animals by retrobular venous puncture. After blood sampling, all dams were sacrificed and assessed by gross pathology. Hematological parameters were examined as well as clinical chemistry and organ weights. The fetuses were not investigated. The administration of the test item by gavage to pregnant female Wistar rats from GD 6-19 caused no substance related findings up to a dose of 1000 mg/kg body weight/day except slightly increased absolute/relative liver weights. Thus, the NOAEL was found to be ≥1000 mg/kg bw (BASF 2020).

 

 

 

 

Justification for classification or non-classification

The available experimental test data are reliable but not sufficient for classification purposes under Regulation (EC) No 1272/2008, as amended for fifteenth time in Regulation (EU) No 2020/217.