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Toxicological information

Repeated dose toxicity: oral

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Administrative data

sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1984-05 to 1989-03
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Experimental study conducted similar to OECD guideline and according to GLP

Data source

Referenceopen allclose all

Reference Type:
study report
Report date:
Reference Type:
review article or handbook
Report date:

Materials and methods

Test guideline
equivalent or similar to guideline
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Principles of method if other than guideline:
The test substance was orally administered to rats for 13 weeks.
GLP compliance:
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
2,4-dichlorobenzyl alcohol
EC Number:
EC Name:
2,4-dichlorobenzyl alcohol
Cas Number:
Molecular formula:

Test animals

Details on test animals or test system and environmental conditions:
- Source: Charles River, Portage, Michigan, USA
- Age at study initiation: 28+/-1 d
- Weight at study initiation: mean body weights of groups were comparable
- Fasting period before study:
- Housing: polypropylene cages with stainless steel grids and lids
- Diet: ad libitum, Labsure CRM pelleted diet (autoclaved)
- Water: ad libitum
- Acclimation period: 4 days

- Temperature (°C): 21+/-2
- Humidity (%): 50+/-10
- Air changes (per hr): 30
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
propylene glycol
Details on oral exposure:
For 7 days before treatment the animals were dosed daily with water to become accustomed to the oral dosing procedure.
The dose volume was 0.5 mL/100 g bw for all animals.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Doses / concentrations
Doses / Concentrations:
200, 400 mg/kg bw/d
actual ingested
No. of animals per sex per dose:
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: none


Observations and examinations performed and frequency:
- Time schedule: daily

- Time schedule: allocation, day before first treatment, day of first treatment and afterwards once weekly

- Time schedule for examinations: allocation and afterwards once weekly

- Recorded for each cage 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

- 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: during week before dosing, during week 13
- Dose groups that were examined: all

- Time schedule for collection of blood: timepoint 1: week 7, timepoint 2: after dosing period (from cardiac puncture)
- Anaesthetic used for blood collection: timepoint 1+2: No data
- Animals fasted: timepoint 1+2: No data
- How many animals: timepoint 1: 8 of each sex from each group, timepoint 2: all animals

- Time schedule for collection of blood: timepoint 1: week 7, timepoint 2: after dosing period (from cardiac puncture)
- Animals fasted: timepoint 1+2: No data
- How many animals: timepoint 1: 8 of each sex from each group, timepoint 2: all animals

- Time schedule for collection of urine: week 7 and 13
- Metabolism cages used for collection of urine: No data
- Animals fasted: Yes, partially. First collection overnight (16 h) and subsequent 6 h period without water


Femoral bone marrow samples were taken from all rats and smears prepared for examination after the dosing period.
Sacrifice and pathology:
Animals were sacrificied after 1, 2, 4, 6 or 24 h after final dose. The cardiac blood samples were collected afterwards.
GROSS PATHOLOGY: Yes, organs weighted: adrenals, brain, heart, kidneys, liver, pituitary, spleen, thyroids (with parathyroids) and, either testes, prostate with seminal vesicles, or ovaries.
HISTOPATHOLOGY: Yes, samples taken from adrenals, aorta, bone (femur), brain, caecum, cochleae, colon, duodenum, eyes, heart, ileum, kidneys, liver, lungs (after inflation with fixative), lymph nodes (cervical, mesenteric and inguinal), mammary gland, oesophagus, pancreas, pituitary, salivary gland (submaxillary), sciaric nerve, skeletal muscle (biceps femoris), skin, spinal cord, spleen, stomach (secretory and forestomach), thyroids (with parathyroids), trachea, thymus, tongue, urinary bladder, and either: testes and prostate with seminal vesicles or ovaries and uterus with cervix and vagina.
All the organs and tissues listed above, with the exception of cochlea, were examined from all control rats and all rats given 400 mg/kg bw/d. In addition, sections of the stomach and liver were examined from all rats given 200 mg/kg bw/d. The right cochlea from five male and five female rats in each of the control and high-dose groups were examined by light microscopy.
Other examinations:
One day after arrival, five rats of each sex were killed and a comprehensive microbiological examination was conducted. A similar examination was carried out on five male and five female Sprague-Dawley rats obtained from the Clinical Research Centre (CRC). A further five male and five female CRC rats were housed in the same room as the study, as sentinels, under identical conditions. These rats were killed during week 14 and a comprehensive microbiological examination conducted. The findings of the examination on the Charles River CD rats indicated that their health status was good, and that they were of a suitable high quality for the study. Results of the examinations of the CRC rats indicated that they had not been exposed to any subclinical infections during the course of the study.
The methods used are as described by Chappell and Scott. Significance testing was performed at p < 0.05 and p < 0.01.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
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:
Two deaths occured. One animal from 400 mg/kg bw treatment group on day 3 and one animal from 200 mg/kg bw/d treatment group on day 80. Reasons for death were not determined.
Increased salvation and stained coats were observed in all groups.
Rales and uneven breathing were observed occasionally in 12 males and 13 females of 400 mg/kg bw/d group and for 2 males and 4 females in 200 mg/kg bw/d group. One controll animal was once observed with rales.
2 females of 400 mg/kg bw /dgroup collapsed after treatment on day 81 but recovered during the same day.

Slightly lower bodyweight gains were recorded for treated females in comparison to the controls, though the differences were not statistically significant and not dose dependent. The weight gains of males were not affected by treatment.

Slightly higher mean weekly food consumption was recorded throughout the dosing period for treated males in comparison to the controls. Food consumption of female rats was not affected by treatment.

No effects detected.

There was no clear effect of treatment on haematological parameters. At week 7, treated females had slightly increased erythrocyte size, as evidenced by high PCV and MCV values, and low MCHC. These differences were greater for females given 200 mg/kg bw/d than those given 400 mg/kg bw/d. Furthermore, erythrocyte size was normal in treated males at week 7, and normal in both sexes after 13 weeks' treatment. Consequently, the difference at week 7 is considered to be of doubtful significance. There were no other differences between treated and control rats. There was no effect of treatment on myelograms.

Higher alkaline phosphatase (ALB) and cholesterol values were recorded for treated males after 6 and 13 weeks of treatment in all dose groups. A trend towards higher ALB values was also noted for treated females, though the differences from controls were not statistically significant. Treated males had higher serum urea and creatinine levels at week 7, but not after 13 weeks' treatment. Lower gamma globulin levels were recorded for males and females given 400 mg/kg bw/d at both investigations, and for males and females given 200 mg/kg bw/d after 13 weeks of treatment. Minor changes in other protein fractions were recorded for females at the higher dose. These small changes were not consistent and were not considered to be a response to treatment. At the terminal investigations, blood samples were collected over two days. Urea, triglyceride and potassium values were affected by the day of sampling. However, there was no difference between treated and control rats an each occasion.

Treatment was associated with slightly lower urinary pH in males, and there was a tendency towards higher urinary flow rate for rats given 400 mg/kg bw/d. Examination of the urinary sediment revealed increased epithelial cell counts for treated males at week 7, and of cellular detritus in the samples of treated males at both investigations. Males given 200 mg/kg bw/d showed poor concentrating ability at both collections but, since this appeared to result from high initial specific gravity in rats given 200 mg/kg bw/d and was not apparent at the higher dosage, it was considered not to be due to treatment.

Liver and kidney weights were elevated in treated males, and liver weights were elevated in females given 400 mg/kg bw/d. Statistical analysis also revealed significantly lower pituitary weights for treated females. Since the differences were not dosage-related and all individual values were normal, this was considered to be of no biological significance.

Treatment-related changes were found in the stomachs. The changes comprised discrete or diffuse raised areas on the mucosal surface (particularly in the forestomach), a wrinkled, rough or discoloured appearance of the forestomach mucosa, thickening of the limiting ridge and prominence of the stomach blood vessels. The most marked change was the presence of raised areas, and this was recorded for all males given 400 mg/kg bw and killed after 13 weeks treatment, for six females given this dose, and for one female given 200 mg/kg bw/d. Other changes were seen in all but one of the remaining females given 400 mg/kg bw/d and in 11 males and twelve females given 200 mg/kg bw/d. Discolorations of the mucosa of the secretory region of the stomach, either generally or as discrete foci or areas, were also recorded in a few treated rats. There was no macroscopic finding in other tissues that was considered to be related to treatment.

In the liver, centrilobular hepatocyte enlargement or centrilobular glycogen loss were recorded for most rats given 400 mg/kg bw/d. These changes were not present in rats given 200 mg/kg bw/d or in control rats.
In the stomach, treatment-related changes were seen in the forestomach. There were no changes in the secretory stomach. The lesions comprised epithelial damage and submucosal oedema, thickening of the epithelium, and changes in the keratin layer. Epithelial damage, that is ulceration, erosion or necrosis, was seen in one male and five females given 400 mg/kg bw/d. Submucosal oedema was seen in several rats given 400 mg/kg bw/d. In the females it was associated with epithelial damage. Thickening of the forestomach epithelium, apparent as plaques or diffuse areas, and resulting from hyperplasia, was seen in rats given 400 mg/kg bw/d. This hyperplasic change was not seen in rats given the vehicle or 200 mg/kg bw/d. Minimal generalized thickening of the forestomach epithelium was apparent in one rat given 400 mg/kg bw, nine given 200 mg/kg bw and one propylene glycol control. The higher incidence of this feature in the 200 mg/kg bw/d group may have been related to treatment. Changes in the keratin of the forestomach comprised hyperkeratosis, swelling of the keratin layers and, in one female given 400 mg/kg bw/d, a marked hydropic change. Hyperkeratosis, was recorded for most rats given 400 mg/kg bw/d, for two males given 200 mg/kg bw/d and for one control male. The distinctive swelling of the keratin, often associated with separation of the keratin layers, was seen in most treated rats but was not present in the controls.

Effect levels

open allclose all
Dose descriptor:
Effect level:
400 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: systemic toxicity
Dose descriptor:
Effect level:
< 200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: local effects in forestomach

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion