γ-valerolactone

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

14-day repeated-dose oral toxicity study

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2019-09-24 to 2019-11-06

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 non-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.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2019

Report date:

2019

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

Not all parameters indicated in the guideline were investigated and a shorter period of time (14 days) was chosen.

Principles of method if other than guideline:

- Principle of test: 14-day range-finding test study to obtain initial information on the effect of the test substance after repeated oral administration (gavage) to non-pregnant, female Wistar rats before the beginning of subsequent maternal and prenatal toxicity studies.
- Short description of test conditions: Not all parameters indicated in the guideline were investigated.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

γ-valerolactone

EC Number:

203-569-5

EC Name:

γ-valerolactone

Cas Number:

108-29-2

Molecular formula:

C5H8O2

IUPAC Name:

5-methyloxolan-2-one

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

Test animals

Species:

rat

Strain:

Wistar

Details on species / strain selection:

The rat is the preferred animal species for repeated dose toxicity studies according to the various test guidelines. This Wistar rat strain (Crl:Wl(Han)) is selected because extensive historical control data is available for these rats.

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Females non-pregnant: Yes
- Age at study initiation: About 15 weeks
- Housing: Polysulfonate cages Typ 2000P (H-Temp) with dust-free wooden bedding. Cages were enriched with wooden gnawing blocks and large play tunnels.
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: 29 days

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 well 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 to day 14

Administration / exposure

Route of administration:

oral: gavage

Details on route of administration:

The oral administration of a test substance has been proven useful worldwide in numerous studies for discovering a potential toxicological profile.

Vehicle:

water

Details on oral 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:

no

Duration of treatment / exposure:

From day 0 to day 14

Frequency of treatment:

Daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

300 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

0 mg/kg bw/day (nominal)

No. of animals per sex per dose:

3 animals per sex 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

Positive control:

No positive control included

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily (mondays-fridays) or once daily (saturdays, sundays and public holidays)


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Within 2 hours and between 2 and 5 hours after the administration, afterwards daily observations

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights are recorded on days 0, 3, 7, 10, and 13.


OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

PLASMA/SERUM HORMONES/LIPIDS: No


URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No

Sacrifice and pathology:

One day after the last administration, the animals were anesthetized with isoflurane, sacrificed by decapitation and assessed by gross pathology.

Optional endpoint(s):

Optional endpoints: No

Statistics:

Body weight and body weight change: DUNNETT-test (two-sided)

Results and discussion

Results of examinations

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

Females of the 300 and 1000 mg/kg bw group, effects not further specified

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

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

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Endocrine findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

female

Remarks on result:

not determinable due to absence of adverse toxic effects

Target system / organ toxicity

Key result

Critical effects observed:

no