Phenol, 3-bromo-5-chloro-

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2007

Report date:

2007

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Version / remarks:

2002

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3-bromo-5-chlorophenol

EC Number:

611-435-6

Cas Number:

56962-04-0

Molecular formula:

C6H4BrClO

IUPAC Name:

3-bromo-5-chlorophenol

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

Charles River Laboratories, Research Models and Services, Germany GmbH, Sanhofer Weg 7, 97633 Sulzfeld, Germany
Body weight: (at start of adaption) Male: 84.3-93.1 g; Females: 82.6-90.1 g
Age: (at start of adaption) Male 34 days; Female 35 days

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: Sesame oil (according to Pharm. Eur. V, 2005

Details on oral exposure:

Adminstration volume 10 ml/kg b.w./day

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

During treatment with the test item always before administration to the last animal/dose level group (3 samples/dose level group) by gas chromatography.

Duration of treatment / exposure:

28 days

Frequency of treatment:

Once daily

Doses / concentrations

Remarks:

Doses / Concentrations:
100, 300 and 1000 mg/kg b.w./day
Basis:
other: sesame oil

No. of animals per sex per dose:

control: 5 male + 5 female
low dose 100 mg/kg b.w./day: 5 male + 5 female
intermediate dose 300 mg/kg b.w./day: 5 male + 5 female
high dose 1000 mg/kg b.w./day: 5 male + 5 female

Control animals:

yes

Examinations

Observations and examinations performed and frequency:

Clinical signs (behavioural changes, reaction to treatment, illness, observation of skin/fur, eyes, mucous membranes, respiratory and circulatory systems, somatomotor activity and behaviour patterns) once daily.
Neurological screening in test week 4 approxomately 1 to 2 hours after dosing and before any blood sampling procedure including
observational screening: righting reflex, body temperature, salivation, startle response, respiration, mouth breathing, urination, convulsions, pilo-erection, diarrhoea, pupil size, pupil response, lacrimation, impaired gait, stereotypy, toe pinch, tail pinch, wire maneuver, hind leg splay, positional passivity, tremors, positive geotropsim, limb rotation, auditory function.
Functional tests: grip test, locomotor activity, mortality (twice daily), body weight and body weight gain (weekly), food and drinking water consumption (daily/weekly).
Laboratory examinations: haematology (twice: test day 29 and 71), clinical biochemistry (twice: test day 29 and 71)
Ophthamological examinations (thrice start, test day 28 and test day 70)

Sacrifice and pathology:

Sacrifice on test day 29 res. test day 71 (recovery animals)
The animals were sacrificed under ether anaesthesia and exsanguinated.
Histopathology: adrenal gland, aorta abdomalis, brain, epididymis, eye, heart, intestine (colon, duodenuum), kidney, liver, lung, lymph nodes, mammary gland, nerve (sciatic), oesophagus, ovary, pancreas, pituitary, prostate, salivary glands, skin, spinal cord, spleen, stomach, testicle, thymus, thyroid, trachea, urinary bladder, ueterus, vagina.

Statistics:

The test item treated groups 2 to 4 were compared statistically with the control group.
Statistical methods: STUDENT´s t-test, Multiple t-test (DUNNETT), Exact test (FISHER).

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):

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Effect levels

Dose descriptor:

NOEL

Effect level:

100 mg/kg bw/day (nominal)

Sex:

male/female

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The aim of the experiment was to obtain information on the toxicity of the test substance given daily by oral administration via gavage for 28
days to CD®-rats and to assess the reversibility of any effects after a 6-week recovery period. Rats were treated orally with dail dose levels of 100, 300 or 1000 mg/kg b.w.

Oral treatment with 300 or 1000 mg/kg b.w./day for 28 days led to signs of systemic toxicity in form of salivation and/or laboured breathing.

At 1000 mg/kg b.w./day one of 15 female animals of the high dose died prematurely during the treatment period on test day 28.

Oral treatment with 1000 mg/kg b.w./day caused a decrease in body weight and body weight gain. In addition, test item-related changes were noted for the biochemical parameters. The organ weight of the Iiver was increased in the high dosed animals.

No test item-related influence was noted on the functional observation battery, food and drinking water consumption and the eyes or optic region at any of the tested dose levels.

Macroscopic post martern examination revealed no test item-related changes.

The histopathological examination revealed a centrilobular hypertrophy of the hepatocytes of the liver at 300 and 1000 m/kg b.w./day.

All changes had subsided at the end of the 6-week recovery period.

Under the present test conditions, the NOEL was 100 mg/kg b.w./day in this 28-day subacute toxicity study.

Executive summary:

Mortality

Treatment period

One of 15 female animals (no. 58 f) of the high dose of 1000 mg/kg b.w./day assigned for recovery was found dead during the treatment phase in the morning of test day 28.Recovery period None of 9 animals treated previously with 1000 mg/kg b.w./day died prematurely.

Clinical signs

Treatment period

Slight salivation occurred in all animals treated with 300 or 1000 mg/kg b.w./day on several test days of test week 1 to 4 and/or from test week 1 onwards. Additionally, at 1000 mg/kg b.w./day, laboured breathing was noted in 3 of 5 female animals from test days 7 to 9 or on test day 10. All symptoms started up to 3 minutes after administration and lasted for up to 15 minutes.

Recovery period

All changes noted for the animals treated previously with 1000 mg/kg b.w./day had subsided immediately at the beginning of the recovery period. The faeces of all animals were of normal consistency throughout the experimental period.

Functional observations

Treatment period

Functional observations in test week 4 approximately 2 hours after administration revealed no changes in any of the parameters examined for the rats treated with either with 100, 300 or 1000 mg/kg b.w./day. No test item-related effect on the fore- and hindlimb grip strength and the spontaneous motility was noted for the male and female rats of all test item-treated groups.

Body weight and Body weight gain

Treatment period

A decrease in body weight by up to 12 % was noted for the male animals (statistically significant at p ≤ 0.01 from test week 1 onwards) and by up to 11 % for the female animals (statistically significant at p ≤ 0.01 in test week 4) treated with 1000 mg/kg b.w./day from test week 1 or 2 onwards compared to the control animals.

The body weight gain was changed accordingly.

Recovery period

The body weight and the body weight gain of the male and female rats treated previously with 1000 mg/kg b.w./day had normalised during the recovery period.

Food and drinking water consumption

Treatment period

A statistically significant decrease in food consumption was noted for the male animals (by 13 %) and female animals (by 26 %) treated with 1000 mg/kg b.w./day in test week 1.

Recovery period

The changes observed for the animals treated previously with 1000 mg/kg b.w./day had subsided during the recovery period. The drinking water consumption was not influenced throughout the experimental period.

Haematology

Treatment and recovery period

No test item-related changes were noted.

Clinical biochemistry

Treatment period

The following test item-related changes were noted at 1000 mg/kg b.w./day:

Changes in biochemical parameters on
test day 29 compared to the control [%]
Parameter	1000 mg/kg
	males	females
Albumin	none	+11**
Globulin	+13	+40**
A/G ratio	-11	-21**
Cholesterol	none	+39**
Creatine	none	+14**
Protein	none	+24**
Calcium	+6**	+10**
Chloride	none	+5**
Sodium	none	+3**

** statistically significant at p ≤ 0.01

Recovery period

The changes noted for the previously high dosed animals had subsided at the end of the 6-week recovery period.

Ophthalmological examination

Treatment and recovery period

No test item-related influence was noted.

Macroscopic post mortem findings

Treatment and recovery period

At necropsy, no test item-related changes were noted.

Organ weights

Treatment period

Oral treatment with 1000 mg/kg b.w./day resulted in an increased relative liver weight in the male (by 18 %) and female (by 25 %) animals.

Recovery period

The changes noted for the animals treated previously with 1000 mg/kg b.w./day had subsided at the end of the 6-week recovery period.

Histopathology

Treatment period

A centrilobular hypertrophy of the hepatocytes was noted in the liver of the animals treated with 300 or 1000 mg/kg b.w./day.

Recovery period

All changes had subsided at the end of the 6-week recovery period.