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Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
disregarded due to major methodological deficiencies
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was not conducted according to guidelines, nor under a quality assurance system. Furthermore, the method description lacks key details regarding the testing conditions (test material purity/impurities, no information on vehicle identity or purity, no information on housing and handling of the test animals) and the number of test animals used is non-standard.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1985

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The aim of the experiment was studying cumulative properties of the substance and selecting the method for chronic study.
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2,4,6-trichloroaniline
EC Number:
211-219-8
EC Name:
2,4,6-trichloroaniline
Cas Number:
634-93-5
Molecular formula:
C6H4Cl3N
IUPAC Name:
2,4,6-trichloroaniline
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Substance type: White crystalline powder
- Physical state: Solid

Test animals

Species:
rat
Strain:
other: white
Sex:
male/female

Administration / exposure

Route of administration:
other: introduced intra-peritoneally
Vehicle:
other: oil solution
Details on oral exposure:
VEHICLE
- Justification for use and choice of vehicle (if other than water): solubility in distilled water at 20°C is 26 mg/l and at 30°C – 40 mg/l
- Concentration in vehicle: 8 % oil solution
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
45 days
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
80 mg/kg bw, 8% in oil solution
Basis:
other: introduced intra-peritoneally
Remarks:
Doses / Concentrations:
160 mg/kg bw, 8% in oil solution
Basis:
other: introduced intra-peritoneally
Remarks:
Doses / Concentrations:
800 mg/kg bw, 8% in oil solution
Basis:
other: introduced intra-peritoneally
No. of animals per sex per dose:
128 white rats of both genders.
Control animals:
yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:
Before the start, on day 10, 20, 30 and 45 of the treatment blood assay was conducted to detect content of forming elements and hemoglobin quantity, nitrogen residues, pyruvic acid, catalase activity, alanine-amino-transferase (ALT) and aspartame-amino-transferase (AST) in blood serum, electrocardiogram in the second compartment, oxygen intake and bodyweight dynamic.

At the end of the experiment absolute and relative mass of internal body organs was measured as well as activity of lactate- and succinate-dehydrogenase in them (LDH and SDH respectively), histological study of testicles and ovary was also conducted.

Results and discussion

Results of examinations

Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Slower.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Hematuria.
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
Lethargy.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Increase of relative mass of heart, liver, kidneys and spleen
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Cyanosis, hair fall.
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
Clinical signs for dosage of 800 mg/kg bw/day:
BODY WEIGHT AND WEIGHT GAIN
The recorded bodyweight gain slowed down in the experimental rats compare to the control group.

HAEMATOLOGY
Hematuria was observed along with significant decrease of the hemoglobin content (on the 45th day: 12,08 ± 2,08 g% in the experimental group compare to 15,88 ± 0,82 g% in the control group, P<0,02) and of the erythrocytes (4,63 ± 0,79 million and 6,38 ± 0,25 million respectively, P<0,001). On the other hand was reported an increase of the quantity of hypochromic and polychromatophyllic erythrocytes, anyzocytosis, poykilocytosis and reticulocytosis, first leukocytosis with a later trend to leukopenia.

CLINICAL CHEMISTRY
A significant activity increase of ALT (4,69 ± 0,5 mmole in the experimental group compare to 2,57 ± 0,37 mmole in the control group, P<0,001) and of AST (3,74 ± 0,45 mmole and 2,95 ± 0,27 mmole respectively, P<0,001) was observed with a decrease ratio of activity of AST and ALT, which proves the dominating position of the liver. There was an increase of residue nitrogen (45,5 ± 6 mg% in the experimental group and 34 ± 2,4 mg% in the control group, P<0,001) and of pyruvic acid (2,36 ± 0,32 and 1,67 ± 0,1 mg% respectively, P<0,001). The activity of catalase was reduced (catalase index 0,18 ± 0,13 in experimental group and 1,04 ± 0,11 in control, P<0,001) as well as oxygen intake (42,2 ± 6,3 and 56,4 ± 7,2 ml/100 g for 15 min, P<0,01). SDH and LDH activity was inhibited in the liver and kidneys.

NEUROBEHAVIOUR
Lethargy.

ORGAN WEIGHTS
Increase of relative mass of heart, liver, kidneys and spleen.

GROSS PATHOLOGY
Cyanosis, hair fall, dystrophic changes and patchy hemorrhages in myocardium, liver, kidneys, brain and spleen.

OTHER FINDINGS
Similar but weaker symptoms were recorded in rats with Trichloroaniline dosage of 160 mg/kg. Dosage of 80 mg/kg was considered to be threshold as it showed non-significant deviations of some of the above mentioned parameters.

Effect levels

Dose descriptor:
NOEL
Effect level:
80 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Introduction in sub-chronic studies of the test item at dosage of 800 mg/kg bw/day led to decrease of coefficients of mass and volume of testicles, increase of numbers of tubuleswithdesquamatedspermatogenic epithelium, which may be resulted by general not specific toxic impact. Lower dosages did not cause changes of the tubule structure. All the tested dosages did not demonstrate structural and functional changes of ovaries.

Applicant's summary and conclusion

Conclusions:
The NOEL is 80 mg/kg bw per day.
Executive summary:

To assess the toxicity potentialThe test item in a solution within an oil vehicle was administered intra-peritoneally. Three doses were chosen to conduct the experiment (80, 160 and 800 mg/Kg bw/day) over 45 days. The test animals were examined before the beginning of the experiment, then on day 10, 20, 30 and 45. The NOEL is 80 mg/kg bw per day.