1-bromo-4-fluorobenzene

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data is from peer reviewed publication

Data source

Reference

Reference Type:

publication

Title:

Subacute and Subchronic Oral Toxicity of p-Chlorotoluene in the Rat

Author:

JAMES B. TERRILL, MERREL ROBINSON, GARY W. WOLFE. And LEONARD H. BILLUPS

Year:

1990

Bibliographic source:

Journal Of The American College Of Toxicology, Volume 9, Number 5, Pg 487-495, 1990

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

90 days repeated dose oral toxicity study was performed to evaluate the toxic nature of the test compound p-Chlorotoluene

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

p-Chlorotoluene

IUPAC Name:

p-Chlorotoluene

Constituent 2

Reference substance name:

4-chlorotoluene

EC Number:

203-397-0

EC Name:

4-chlorotoluene

Cas Number:

106-43-4

Molecular formula:

C7H7Cl

IUPAC Name:

1-chloro-4-methylbenzene

Details on test material:

- Name of test material: p-Chlorotoluene
- Molecular formula: C7H7Cl
- Molecular weight: 126.585 g/mol
- Substance type: Organic
- Physical state: Clear, colorless liquid
- Impurities (identity and concentrations): > 98% pure

Test animals

Species:

rat

Strain:

other: Sprague-Dawley-derived (Crl:CD@ BR)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc. (Raleigh, NC)
- Age at study initiation: 46 days
- Weight at study initiation: 227.3-276.1 g males, 153.2-195.8 g females
- Fasting period before study: No data
- Housing: The rats were housed in stainless-steel wire-bottomed suspended cages, color-coded for dosage level. The rats within any treatment level were caged vertically to minimize light, temperature, and airflow differences between exposure groups
- Diet (e.g. ad libitum): Purina Rodent Chow No. 5002 (Ralston Purina Co., St. Louis, MO) ad libitum
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-24°C
- Humidity (%):40-60%
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12-h light-dark cycle

IN-LIFE DATES: From: To: No data

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

other: Corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: The chemical was dissolved in corn oil at dose levels of 0, 50, 200 or 800 mg/Kg/day

DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): No data
- Storage temperature of food: No data

VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn oil
- Concentration in vehicle: 0, 50, 200 or 800 mg/Kg/day
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): No data
- Purity: No data

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The purity was determined to be greater than 98% by gas chromatographic-mass spectral analysis (GC-MS)

Duration of treatment / exposure:

14 days

Frequency of treatment:

7 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 50, 200 or 800 mg/Kg/day
Basis:

No. of animals per sex per dose:

Total: 80
0 mg/Kg/day: 10 males and 10 females
50 mg/Kg/day: 10 males and 10 females
200 mg/Kg/day: 10 males and 10 females
800 mg/Kg/day: 10 males and 10 females

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The high-dose level was chosen on the basis of the effects at 600 and 1800 mg/kg per day for
2 weeks and was anticipated to be the maximum tolerated dose. The other two levels (200 and 600 mg/kg/day) were selected as possible no-effect levels.
- Rationale for animal assignment (if not random): Yes, randomized
- Rationale for selecting satellite groups: No data
- Post-exposure recovery period in satellite groups: No data
- Section schedule rationale (if not random): No data

Positive control:

No data

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily for Mortality, Morbidity. All rats were observed daily by careful cageside observation. Physical
examinations were performed weekly
- Cage side observations checked in table [No.?] were included. Mortality, Morbidity, overt signs of toxicity,

DETAILED CLINICAL OBSERVATIONS: Yes, any abnormalities in housing. food, water, or clinical signs involving general appearance, behavior, excretion, respiration, skin, pelage. or eyes were recorded
- Time schedule: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were measured prior to randomization, at initiation of dosing, and weekly thereafte

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes, Food consumption was measured weekly
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Proir to necropsy
- Dose groups that were examined: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Prior to necropsy
- Anaesthetic used for blood collection: Yes, ketamine
- Animals fasted: Yes, overnight fasting
- How many animals: All animals
- Parameters checked in table [No.?] were examined. leukocyte, erythrocyte. hematocrit, and hemoglobin tests; leukocyte differentials and cell morphology

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Prior to necropsy
- Animals fasted: Yes, overnight fasting
- How many animals: All animals
- Parameters checked in table [No.?] were examined. sodium, potassium, total protein, albumin, calcium, total bilirubin, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH). and blood urea nitrogen

URINALYSIS: Yes
- Time schedule for collection of urine: Prior to necropsy
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. pH, glucose, protein, bilirubin, occult blood. and urobilinogen

NEUROBEHAVIOURAL EXAMINATION: Y No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data

OTHER: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, Animals were weighed anesthetized with sodium pentobarbital, exsanguinated and necropsied. Organ weights were obtained for the following organs: liver, kidneys, spleen, adrenal glands, thymus, brain, heart, lung, testes with epididymis and ovaries. Organ-to-terminal body weight ratios were calculated.
Additionally, necropsies were performed on all animals that died prior to the terminal sacrifice. A full tissue list was preserved from each animal.

HISTOPATHOLOGY: Yes, The following tissues were evaluated from all animals in the 800 mg/kg per day animals as well as from five randomly selected animals per gender in corn oil control animals: adrenals, thyroid, esophagus, trachea, larynx, heart, spleen, liver, kidney, stomach, duodenum, jejunum, colon, pancreas, and gross lesions.

Other examinations:

No data

Statistics:

All appropriate data were subjected to Levene's test of homogeneity of variance and an analysis of variance. Non-homogeneous data were subjected to a series of transformations in order to achieve homogeneity . When the series of transformations were ineffective in achieving homogeneity, analysis of ranked data were performed. Group comparisons were evaluated using Dunnett's t-test at the 5.0% two-tailed probability Ievel

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):

effects observed, treatment-related

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Details on results:

Clinical signs and mortality
Clinical signs:
The daily cageside observations (conducted approximately 1 h postdosing), noted in the high-dose animals included languid behavior, prostration, sensitivity to touch, tremors, epistaxis, wheezing, dyspnea, and/or polypnea. These signs appeared closely related to the time of the animals' death. The findings noted at the weekly detailed observations (conducted prior to dosing) generally appeared in fewer animals and were generally not as severe as those seen at 1 h postdosing.

Mortality: The death observed was considered to be treatment related
At 800 mg/Kg bw-
Males- 4/10
Females- 2/10

Body weight and weight gain: The total body weight gain (initiation to Week 13) was significantly decreased for high-dose males. All comparisons between treatment and control animals were not statistically significant

Food consumption and compound intake: Food consumption was comparable in all groups

Food efficiency: No data

Water consumption and compound intake: No data

Opthalmoscopic examination: No treatment related effects were noted

Haematology: No data

Clinical chemistry: Clinical hematology data were comparable in all groups. Clinical chemistry data revealed significantly increased blood urea nitrogen, creatinine, alkaline phosphatase, and total bilirubin values, and significantly decreased sodium values in the high-dose males. The differences for alkaline phosphatase occurred in a dose-related pattern in the males; however, only the values for the high-dose males were statistically significant. The increase in the blood urea nitrogen and creatinine resulted from moderate elevations in two animals; while the increased total bilirubin was considered to be a small change. Clinical chemistry values in females were comparable in all groups.

Urinanalysis: Urinalysis data revealed generally decreased pH values (males: 7.50 ± 0.623, 7.75 ± 0.635, 6.80 ± 0.258, and 6.42 ± 0.580; females: 7.25 ± 0.755, 6.85 ± 0.474, 6.35 ± 0.412, and 6.50 ± 0.598 for Groups 1-4, respectively). The differences between treated and control animals were significant for both sexes of mid- and high-dose animals. The remaining urinalysis results were comparable in all groups

Neurobehaviour: No data

Organ weights Terminal body weight was significantly decreased in the high-dose group females, and was depressed, although not significantly, in the high-dose group males. Absolute lung weights were significantly decreased in low- and high-dose group females, but relative weights were unaffected. Absolute and relative adrenal weights were significantly increased in high-dose group males. Relative heart weight was significantly increased in the high-dose group females, and relative brain, kidney, and liver weights were increased in the high-dose group males and females.

Gross pathology: The kidneys of all high-dose group males had abnormalities including depressed area, pale area, mottled appearance, dilated renal pelvis, and/or granular/pitted/rough texture. Similar lesions were seen in the animals sacrificed or found dead prior to the scheduled sacrifice. The renal findings were accompanied by histopathology findings, and were considered to be treatment related. Dark areas in the glandular portion of the stomach were seen in all groups, and with slightly higher frequency in high-dose group animals. Few other gross lesions were seen at the terminal sacrifice and most were represented by a single incidence per group.

Histopathology: Histopathology evaluations revealed compound-related effects in the liver, adrenal gland, and kidney.

In the liver, there was centrilobular hypertrophy of hepatocytes in high-dose group animals, both in animals that died on test and in animals that were sacrificed at termination. The effect was not evident in low- and mid-dose group animals. Chronic progressive nephropathy occurred in both sexes of high-dose group animals (10/10 males and 9/10 females), The finding was also seen on 2 of 10 control males, but not in control females. This lesion was characterized by degeneration and regeneration of the tubular epithelial cells, interstitial fibrosis, and mononuclear cell infiltrates. The lesions were multifocal and primarily involved the cortex. The finding was not evident in low and mid-dose group animals.

Adrenal glands of high-dose group males and females showed hyperplasia of the zona fasciculata. No compound-related lesions were observed in adrenal glands of low-dose, mid-dose, or control animals.

Minimal mucosal erosion occurred in the glandular stomach of two high-dose groups males, three high-dose group females, one mid-dose group female, and one low-dose group female.

Effect levels

Dose descriptor:

NOAEL

Effect level:

200 other: mg/Kg/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No treatment related effects were noted

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The No observed adverse effect level (NOAEL) for the test compound p-Chlorotoluene is found to be 200 mg/Kg/day.

Executive summary:

90 days repeated dose oral toxicity study was performed to evaluate the toxic nature of the test compoundp-Chlorotoluene. Male and female Sprague Dawley rats were dosed daily at dose levels of 0, 50, 200 or 800 mg/Kg/day for 90 days. The animals were observed for cage side observations, clinical signs, body weight and food consumtion, hematology, clinical pathology parameters and urinalysis following gross and histopathology. Treatment related severe effects were noted at 800 mg/Kg/day.The No observed adverse effect level (NOAEL) for the test compound p-Chlorotoluene is found to be 200 mg/Kg/day.