Furan

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1981

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was well documented and meets generally accepted scientific principles, and conducted in compliance with GLP.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1993

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Study conducted to determine the cumulative tox effects of repeated oral exposure to Furan and to determine the appropriate doses to be used in the rat carcinogenicity study.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Furan

EC Number:

203-727-3

EC Name:

Furan

Cas Number:

110-00-9

Molecular formula:

C4H4O

IUPAC Name:

furan

Details on test material:

- Name of test material (as cited in study report): furan
- Physical state: clear colourless liquid
- Analytical purity: >99%
- Lot/batch No.: OF20-M
- Storage condition of test material: -20 degrees C, under nitrogen, protected from light

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, NY
- Age at study initiation: 51 days
- Housing: Solid bottom polycarbonate
- Diet: NIH-07 Rat and Mouse Ration, ad libitum
- Water: Tap water, ad libitum
- Acclimation period: 19 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-26
- Humidity (%): 36-65
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: 3 March to 10 June 1981

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
Throughout the study, the dose formulations were prepared weekly by mixing appropriate amounts of furan with corn oil

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Stability studies confirmed furan formualted in corn oil stable for up to 14 days under appropriate storage conditions. During the study dose formulations analysed periodically by GC.

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

5 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 4, 8, 15, 30 or 60 mg/kg/day
Basis:
actual ingested

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: based on results of preceding 16-day study in which doses of 80 mg/kg/day and above were not tolerated.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: monthly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: No
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

ORGAN WEIGHTS: Yes (see table 1)
GROSS PATHOLOGY: Yes (see table 1)
HISTOPATHOLOGY: Yes (see table 1)

Statistics:

Conducted but m,ethods not stated.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

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:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY:
Nine males and four females from the 60 mg/kg/day group died before the end of the dosing period.
Reduced activity and occasional irregular breathing were observed in the 60 mg/kg/day group.

BODY WEIGHT AND WEIGHT GAIN:
Final mean body weights of male rats in the 15 and 30 mg/kg/day groups and of female rats in the 60 mg/kg/day group were significantly lower than controls.

ORGAN WEIGHTS:
Relative and absolute liver weights were significantly greater than controls in males administered 30 mg/kg and in females administered 8, 15, 30, or 60 mg/kg. Absolute thymus weights were significantly decreased in male rats administered 30 mg/kg and in females administered 60 mg/kg. Relative and absolute kidney weights were significantly increased in females administered 15, 30, and 60 mg/kg. There was a significant increase in the relative kidney weights in the 15 and 30 mg/kg male dose groups as well as significant differences in relative and/or absolute weights of the brain, heart, and lungs in groups of treated males and 60 mg/kg females; these differences were considered secondary to the decreased body weights.

GROSS PATHOLOGY:
The livers of rats in the 15, 30 and 60 mg/kg/day groups were noted to have pronounced lobular patterns, raised areas and nodules.

HISTOPATHOLOGY: NON-NEOPLASTIC:
Lesions associated with administration of furan were observed in the liver, kidney, thymus, testes, and ovaries.
The most prominent liver change was bile duct hyperplasia, which occurred in all dose groups. Also noted were hepatocyte degeneration and necrosis and hepatocyte hyperplasia.
Kidneys of nearly all 60 mg/kg males and females and of two 30 mg/kg males had dilatated renal tubules up to approximately twice normal diameter, tubular epithelial necrosis or enlargement were also noted.
Atrophy of thymus, testes or ovaries was noted at 60 mg/kg/day.

Effect levels

Dose descriptor:

LOAEL

Effect level:

4 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Biliary tract hyperplasia noted at all doses.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table - incidence summary of histopathological changes

	Vehicle Control	4 mg/kg	8 mg/kg	15 mg/kg	30 mg/kg	60 mg/kg
Males
Number examined	10	10	10	10	10	10
Liver - Biliary tract        cholangiofibrosis                                hyperplasia - Hepatocyte        cytomegaly                                degeneration                                necrosis                                hyperplasia nodular - Kupffer cell        pigmentation	0 0 0 0 0 0 0	4* 4* 0 0 0 0 4*	7** 9** 0 7** 0 0 6**	10** 10** 8** 9** 9** 0 10**	10** 10** 10** 10** 10** 10** 10**	10** 10** 10** 10** 10** 10** 9**
Kidney - Renal tubule      dilatation                                necrosis	0 0	- -	- -	- -	2 0	9 10
Thymus                 atrophy	0	-	-	-	0	7
Testes                    atrophy	0	-	-	-	0	9
Females
Number examined	10	10	10	10	10	10
Liver - Biliary tract        cholangiofibrosis                                hyperplasia - Hepatocyte        cytomegaly                                degeneration                                necrosis                                hyperplasia, nodular - Kupffer cell        pigmentation	0 0 0 0 0 0 0	1 7** 0 0 0 0 2	7** 10** 0 1 0 0 8**	10** 10** 10** 10** 8** 0 10**	10** 10** 10** 10** 10** 8** 10**	9** 9** 9** 10** 10** 9** 9**
Kidney - Renal tubule      dilatation                                necrosis	0 0	- -	- -	- -	0 0	8** 7**
Thymus                 atrophy	0	-	-	-	0	3
Ovaries                 atrophy	0	-	-	-	0	9**

- not examined

* significantly different from control group P<0.05 by Fisher exact test

** p<0.01

Applicant's summary and conclusion

Conclusions:

Oral administration of furan to rats for 13 weeks at doses of 4, 8, 15, 30 or 60 mg/kg/day (5 days/week) resulted in mortality and low final mean body weight at 60 mg/kg/day and increased absolute and relative liver and kidneys weights at doses between 15 and 60 mg/kg/day. Proliferative changes involving the bile ducts and hepatocytes were noted in the livers in all dose groups.