1-fluoro-2-nitrobenzene

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

No data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well conducted, sufficiently detailed, according to standardised guidelines but not GLP.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1975

Report date:

1975

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The test substance is orally administered daily in graduated doses to several groups of experimental animals, one dose level per group for a period of 5 weeks. During the period of administraion the animals are observed closely, each day for signs of toxicity.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1-fluoro-4-nitrobenzene

EC Number:

206-502-8

EC Name:

1-fluoro-4-nitrobenzene

Cas Number:

350-46-9

Molecular formula:

C6H4FNO2

IUPAC Name:

1-fluoro-4-nitrobenzene

Details on test material:

- Name of test material (as cited in study report): p. fluoronitrobenzene
- Substance type: Halogene

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

olive oil

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

5 weeks

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
5, 15 and 45 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

10 per sex per dose

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: YES

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


OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 2, 5, 7 and 9 weeks
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 5M/5F after 2 weeks, 5M/5F after 5 weeks, 5M/5F after 7 weeks and 5M/5F after 9 weeks
- Parameters checked in table [No.?] were examined.

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (liver, kidneys and spleen)

Other examinations:

No

Results and discussion

Results of examinations

Clinical signs:

no effects observed

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 examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not examined

Details on results:

PRE-TEST RESULTS:
In a pre-test, rats were orally administered the test substance at 50, 100 and 200 mg/kg bw/day. At 200 mg/kg bw/day, mortality was rapidly induced by the test substance in all animals. At 100 and 50 mg/kg bw/day, hematological effects were observed : anaemia with reticulocytosis and increasedof blood platelet (methemoglobinemia: 20 %).
At gross necropsy an enlargement of the spleen was observed. Histopatology results showed a significant effect of the test substance at 100 mg/kg bw/day at liver, spleen, kidney and testicules level. At 50 mg/kg bw/day, an effect at the spleen level was only observed.

MAIN TEST RESULTS:

CLINICAL SIGNS AND MORTALITY
No mortality was observed at any tested doses.

BODY WEIGHT AND WEIGHT GAIN
The weigth gain was similar between control and treated animals.

HAEMATOLOGY
A hemaological toxicity was observed after treatment with graduated doses of the test substance. (cf. Table 1)
Effect on percentage of Methemoglobinemia, significant at 15 and 45 mg/kg/d. This effect is reversible after 2 weeks of rest

GROSS PATHOLOGY
At 45 mg/kg bw/day, all animals showed hypertrophy of the spleen.

HISTOPATHOLOGY: NON-NEOPLASTIC
After 5 weeks, histological results showed a dose-dependant congestion of the spleen with a splenic hemosiderosis. After 9 weeks, only clusters of hemosiderin in macrophages were observed. After 4 weeks of rest, the spleen congestion disappeared, but hemosiderosis is observed and important at 45 mg/kg/d.

Effect levels

Key result

Dose descriptor:

NOEL

Effect level:

5 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Methemoglobinemia

Target system / organ toxicity

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

5 mg/kg bw/day (nominal)

System:

haematopoietic

Organ:

blood

spleen

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Any other information on results incl. tables

Table 1: Hematological effect of the test substance

Treatment	Erythroctes (E+03) and Methemoglobinemia (%)
	2 weeks	5 weeks	7 weeks	9 weeks
Control	7840	8495 (3.32)	8196 (2.0)	8002 (2.2)
45 mg/kg bw/day	6050	6536 (9.30)	7662 (3.5)	7828 (3.0)
15 mg/kg bw/day	6454	7277 (8.76)	/	/
5 mg/kg bw/day	6516	7940 (5.70)	/	/

Applicant's summary and conclusion

Conclusions:

Under the conditions of this test, the test substance induced hematological effects with a modification of the structure of the spleen.

Executive summary:

Male and female rats (10 per sex per dose) were orally administered 5, 15 and 45 mg/kg bw/day of the test substance daily during 5 weeks. At the end of the exposure, half of the animals were sacrificed and the others were kept for 4 weeks without treatment to detect recovery from toxic effects. Animals were examined for hematological effects (haemoglobin concentraion, hematocrit, platelet count, erythrocyte count). The test substance induced mainly hematological effects with alteration of the spleen. Nevertheless, as soon as the treatment is finished all animals showed reversibility of the observed effects.