γ-valerolactone

Carcinogenicity

Description of key information

In a chronic carcinogenity study in mice, repeated subcutaneous exposure to approx. 3.4 mg/kg bw of the test item 3 times a week for 4 weeks induced no tumors after 18 months.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity, other

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

Data published in 1970

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: 18 months carcinogenicity study in mice after subcutaneously injections.
- Short description of test conditions: CFW Swiss-Webster mice (2 month of age) were randomly divided into a group of 16 animals after 1 week of quarantine. They were housed in plastic shoe-box type cages in air conditioned quarters, with heat-treated absorbent cedar cubed wood for bedding. The animals were fed Teklad mouse diet pellets and water ad libitum. Water bottles were treated weekly with a germicidal detergent, and the animals were transferred to clean cages twice a week. 16 mice were subcutaneously injected 2 mg of the test material in 0.1 mL tricaprylin to the inguinal region of the rats. Injections were made to approximately the same site, and repeated 2 –3 times each week, for a total of 10 – 114 injections. The control animals were untreated.
- Parameters analysed / observed: All the animals were weighed at the start of the experiments and at regular intervals throughout the observation period of 18 months. They were observed twice weekly for the appearance of subcutaneous tumors. Animals with tumors or those in poor condition were sacrificed and necropsied. Suspected neoplasms and other grossly abnormal tissues were removed, fixed and histologically examined.

GLP compliance:

not specified

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source: Givaudan-Delawanna Inc., New York
- Purity: >98 %

Species:

mouse

Strain:

Swiss Webster

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: H. B. Andervont's (BALB/c mice) and Carworth Inc., New York (CFW mice)
- Females nulliparous and non-pregnant: Yes
- Age at study initiation: 2 month
- Housing: In groups of 8, in plastic shoe-box type cages with heat-treated absorbent cedar cubed wood
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Not indicated, quarters are air conditioned
- Humidity (%): Not indicated
- Air changes (per hr): Not indicated
- Photoperiod: Not indicated

Route of administration:

subcutaneous

Vehicle:

other: tricaprylin

Details on exposure:

VEHICLE
- Concentration in vehicle: 20 mg/mL
- Amount of vehicle: 0.1 mL

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

4 weeks

Frequency of treatment:

3 times/week

Post exposure period:

18 months

Dose / conc.:

34.3 mg/kg bw/day

Remarks:

2 mg in 0.1 mL vehicle was injected 3 times/week. Assuming a mean rat body weight of 250 g, the dose was approx. 8 mg/kg bw and 3.4 mg/kg bw/day.

No. of animals per sex per dose:

16 females per dose

Control animals:

yes, concurrent no treatment

yes, concurrent vehicle

Positive control:

Not specified

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: At the start of the experiment, at regular intervals throughout the ensuing period of observation

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Not specified (animals with tumors or those in poor condition were killed and autopsied)

HISTOPATHOLOGY: Yes (suspected neoplasms and other grossly abnormal tissues were removed and fixed in buffered 10 % formalin. All diagnoses were based on histological examination of sections stained with hematoxylin and eosin)

Other examinations:

Not specified

Statistics:

Not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

effects observed, non-treatment-related

Description (incidence and severity):

In some instances, ulcerations developed at the sites of injection. However, as their number was low, no relation to the administered material could be established.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

3/16 mice died after 18 month of treatment which represents the normal mortality for mice of this age and is comparable to the mortality of conroll mice.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No excessive weight losses or gains were found as compared to the untreated control group.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not specified

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

not examined

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Endocrine findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

No subcutaneous sarcomas, pulmonary tumors, breast cancers, lymphomas or other tumors were found after 18 months of observation.

Other effects:

not specified

Key result

Dose descriptor:

NOAEL

Effect level:

>= 3.4 mg/kg bw/day

Based on:

test mat.

Remarks:

2 mg in 0.1 mL vehicle was injected 3 times/week. Assuming a mean rat body weight of 250 g, the dose was approx. 3.4 mg/kg bw/day.

Sex:

female

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Critical effects observed:

no

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As the test substance showed no carcinogenic potential in any study, it is not considered to be classified for carcinogenity under Regulation (EC) No 1272/2008, as amended for fifteenth time in Regulation (EU) No 2020/217.

Additional information

Carcinogenicity, mouse, RL2

CFW Swiss-Webster mice (2 month of age) were randomly divided into a group of 16 animals after 1 week of quarantine. They were housed in plastic shoe-box type cages in air conditioned quarters, with heat-treated absorbent cedar cubed wood for bedding. The animals were fed Teklad mouse diet pellets and water ad libitum. Water bottles were treated weekly with a germicidal detergent, and the animals were transferred to clean cages twice a week. 16 mice were subcutaneously injected 2 mg of the test material in 0.1 mL tricaprylin to the inguinal region of the rats. Injections were made to approximately the same site, and repeated 2 –3 times each week, for a total of 10 – 114 injections. The control animals were untreated. All the animals were weighed at the start of the experiments and at regular intervals throughout the observation period of 18 months. They were observed twice weekly for the appearance of subcutaneous tumors. Animals with tumors or those in poor condition were sacrificed and necropsied. Suspected neoplasms and other grossly abnormal tissues were removed, fixed and histologically examined. After 18 months, 13/16 mice were alive. None of the mice developed subcutaneous sarcomas, pulmonary tumors, breast cancers, lymphomas or other tumor (Swern et al., 1970).