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Diss Factsheets

Administrative data

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.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2020
Report date:
2020

Materials and methods

Test guidelineopen allclose all
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

Test material

Constituent 1
Chemical structure
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 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)

Administration / exposure

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
Doses / concentrationsopen allclose all
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

Examinations

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

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

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

Maternal developmental toxicity

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

Effect levels (maternal animals)

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

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

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

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day

Applicant's summary and conclusion