5-nitrofurfurylidene di(acetate)

Carcinogenicity

Description of key information

Supporting study: Carcinogenity (Morris 1969):

The carcinogenic activity of 5 -nitrofurfurylidene diacetate was evaluted. Female albino rats (5 and 13 rats, of 60 days and 22 days ages, in experiments 1 and 2) were exposed to 0.2% in diet for up to 44.5 weeks (33 and 44.5 weeks in experiments 1 and 2). An unexpectedly large number of animals died early in the experiments. The pathologic findings and the clinical experience that penicillin therapy almost completely controlled these deaths support the opinion that they were usually the result of overwhelming infections superimposed on chronic respiratory disease often seen in rat colonies. 4 mammary tumors were detected in Experiment 2. All mammary tumors were histologically benign. Three rats in the control group for Experiment 2 had mammary lesions too, 2 of which were clearly benign. One lesion was considered to be an atypical fibroadenoma. The atypical lesions always contained small areas suggestive of carcinoma, but the majority of the tumor was too well differentiated to be labeled as malignant. Based on these results, the test item did not show carcinogenic activity when administered to female rats at 0.2% in diet for up to 44.5 weeks.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

significant methodological deficiencies

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

yes

Remarks:

(only females, only one dose tested, 5 or 13 animals (experiment 1 or 2), 60 or 22 days (experiment 1 or 2), duration 36 and 44.5 weeks (experiment 1 or 2); few parameters reported, administration of penicillin)

GLP compliance:

no

Specific details on test material used for the study:

Chemical name: 5-nitro-2-furanmethanediol diacetate
Source: Eastman Organic Chemicals, Rochester, New York (USA)

Species:

rat

Strain:

other: Holtzman albino rats

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Holtzman Rat Company, Madison, Wisconsin (USA)
- Females (if applicable) nulliparous and non-pregnant: [yes/no]
- Age at study initiation: Experiment 1: 60 days age / Experiment 2: 22 days of age
- Weight at study initiation: Experiment 1: 170-175 g / Experiment 2: 55-58 g
- Housing: 3 to 6 animals per cage (screen-bottomed)
- Diet (e.g. ad libitum): Ad libitum (Ground Wayne Lab-Blox (Allied Mills, Inc., Chicago, Illinois))
- Water (e.g. ad libitum): Ad libitum

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): Not specified.
- Mixing appropriate amounts with (Type of food): Test supplements were prepared by grinding the chemical and glucose together in a glass mortar in proportions such that the test diets could be prepared by the addition of 10 g of the triturate/kg of ration. The supplement and stock diet were then mixed thoroughly in an institutional food-mixing machine.
- Storage temperature of food: Diets were prepared in 5-kg quantities and stored at 8-12 C until needed.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Experiment 1: 36 weeks
Experiment 2: 44.5 weeks

Frequency of treatment:

Daily

Dose / conc.:

0.2 other: % in diet

Remarks:

Average (mg/day): Experiment 1 = 29 / Experiment 2 = 31
Total (g): Experiment 1 = 7.20 / Experiment 2 = 8.94

No. of animals per sex per dose:

Experiment 1: 5
Experiment 2: 12

Control animals:

yes, concurrent no treatment

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
The animals were inspected at least once and usually twice a day

DETAILED CLINICAL OBSERVATIONS: Yes
The rats were palpated approximately biweekly at the time of weighings to detect superficial tumors.

BODY WEIGHT: Yes

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
The partially emptied food containers were weighed for 3 days at least once every 3 weeks to permit calculation of the amount of chemical consumed.

FOOD EFFICIENCY: 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: Yes
All animals were subjected to thorough postmortem examinations. The brain and the thoracic and abdominal viscera, including the lumen of the gastrointestinal tract and the lumen of the urinary bladder, were grossly examined.

HISTOPATHOLOGY: Yes
All tissues except the bladders were fixed in 10% formalin, 10% buffered formalin, or formalin acetic acid (2000 ml of distilled water, 1000 ml of 95% ethanol, 300 ml of formalin solution, and 50 ml of glacial acetic acid). All bladders were fixed in Bouin's solution. Specimens of all gross tumors, all bladders, and samples of the livers, kidneys, and spleens were embedded in paraffin, sectioned, and stained with hematoxylin and eosin. With the finding of evidence of respiratory infection, samples of lung tissue were examined microscopically. Other tissues with even slight gross evidence of abnormality were also examined microscopically.

Clinical signs:

no effects observed

Description (incidence and severity):

The animals appeared to tolerate the drugs at the levels fed and had no toxic manifestations.
Survival was poor in all groups, including untreated control rats, until penicillin therapy was begun.

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, non-treatment-related

Description (incidence):

An unexpectedly large number of animals died early in the experiments. The pathologic findings and the clinical experience that penicillin therapy almost completely controlled these deaths support the opinion that they were usually the result of overwhelming infections superimposed on chronic respiratory disease often seen in rat colonies.

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry 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 specified

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

4 mammary tumors were detected in Experiment 2. All mammary tumors were histologically benign. Probability that the observed result might have occurred by chance, as calculated by the exact method for 2 X 2 tables: 0.18.

Three rats in the control group for Experiment 2 had mammary lesions, 2 of which were clearly benign. One lesion was considered to be an atypical fibroadenoma. The atypical lesions always contained small areas suggestive of carcinoma, but the majority of the tumor was too well differentiated to be labeled as malignant.

Other effects:

not specified

Key result

Dose descriptor:

NOAEL

Effect level:

>= 0.2 other: % in diet

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No adverse effects observed at highest dose tested

Key result

Critical effects observed:

no

Conclusions:

The test item did not show carcinogenic activity when administered to female rats at 0.2% in diet for up to 44.5 weeks.

Executive summary:

The carcinogenic activity of 5 -nitrofurfurylidene diacetate was evaluted. Female albino rats (5 and 13 rats, of 60 days and 22 days ages, in experiments 1 and 2) were exposed to 0.2% in diet for up to 44.5 weeks (33 and 44.5 weeks in experiments 1 and 2). The partially emptied food containers were weighed for 3 days at least once every 3 weeks to permit calculation of the amount of chemical consumed. The animals were inspected at least once and usually twice a day. The rats were palpated approximately biweekly at the time of weighings to detect superficial tumors. All animals were subjected to thorough postmortem examinations. The brain and the thoracic and abdominal viscera, including the lumen of the gastrointestinal tract and the lumen of the urinary bladder, were grossly examined. Specimens of all gross tumors, all bladders, and samples of the livers, kidneys, and spleens were embedded in paraffin, sectioned, and stained with hematoxylin and eosin. With the finding of evidence of respiratory infection, samples of lung tissue were examined microscopically. Other tissues with even slight gross evidence of abnormality were also examined microscopically. An unexpectedly large number of animals died early in the experiments. The pathologic findings and the clinical experience that penicillin therapy almost completely controlled these deaths support the opinion that they were usually the result of overwhelming infections superimposed on chronic respiratory disease often seen in rat colonies. 4 mammary tumors were detected in Experiment 2. All mammary tumors were histologically benign. Three rats in the control group for Experiment 2 had mammary lesions too, 2 of which were clearly benign. One lesion was considered to be an atypical fibroadenoma. The atypical lesions always contained small areas suggestive of carcinoma, but the majority of the tumor was too well differentiated to be labeled as malignant. Based on these results, the test item did not show carcinogenic activity when administered to female rats at 0.2% in diet for up to 44.5 weeks.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

chronic

Species:

rat

Quality of whole database:

Study of Klimisch 3 (significant methodological deficiencies).

Justification for classification or non-classification

Based on available data, the subtance is not classified for carcinogenicity according to the Regulation 1272/2008.