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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1985
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Study design comparable to guideline study , but without histopathological evaluation.

Data source

Reference
Reference Type:
publication
Title:
Toxicology of 1,1,2-trichloroethane in the mouse
Author:
White, K.L. Jr., Sanders, V.M., Barnes, D.W., Shopp, G.M.|Jr., Munson, A.E.
Year:
1985
Bibliographic source:
Drug Chem Toxicol., 8|(5): 333-355.

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
The test conditions during test and prior testing not indicated; no evaluation of the clinical signs and histopathological findings were not reported.
Principles of method if other than guideline:
Method: other: not mentioned (described in White and al. Immunotoxicological investigations in the mouse. General approach and methods, Drug Chem. Toxicol., (1985))
GLP compliance:
no
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Name of the test substance (as cited in the test report) : 1,1,2-trichloroethane.
- Analytical purity: 95%
- Stability under test conditions: no stabilizers were present with this chemical
- Storage condition of test material: no preservatives were present with this chemical
- Batch number: 070177 and 061197
- Source: Aldrich Chemical Co.

Test animals

Species:
mouse
Strain:
CD-1
Sex:
male/female
Details on test animals and environmental conditions:
no data

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
Test substance was diluted in deionised water to achieve the desire concentration. The solutions were maintained in amber-coloured bottles with stainless-stell pouts fitted through cork stoppers. bottles were changed twice weekly.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Less than 10% of test substance was lost during the 3 or 4 days between bottle changes, as measured by GLC with head space analysis.
Duration of treatment / exposure:
90 days
Frequency of treatment:
Continuously
Doses / concentrations
Remarks:
Doses / Concentrations:
20, 200, 2000 mg/l (calculated daily doses, female mice: 3.9; 44; 384 mg/kg/day; male mice: 4.4; 46; 305 mg/kg/day)
Basis:
nominal in water
No. of animals per sex per dose:
32/dose/sex, except control group: 48/dose/sex
Control animals:
yes
Details on study design:
- Dose selection rationale: based on the results of the 14-day gavage study (White et al. 1985)
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data


DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations: approximately twice weekly



WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: twice weekly


OPHTHALMOSCOPIC EXAMINATION: No data


HAEMATOLOGY: Yes
- Time schedule for collection of blood: 90 days
- How many animals: 14-16 per dose group, 23-24 in control
- Parameters examined: hematocrit, haemoglobin, leucocytes, erythrocytes, platelets, fibrinogen, prothrombin time, activated partial prothrombin time


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 90 days
- Animals fasted: No data
- How many animals: 14-16 per dose group, 24 in control
- Parameters examined: calcium, phosphorous, sodium, chloride, potassium, protein, glucose, , cholesterol, serum glutavic oxaloacetic transaminase (SGOT), serum alkaline phosphatase (SAP), lactate deshydrogenase (LDH), serum glutamic pyruvic transaminase (SGPT), blood urea nitrogen (BUN), creatinine, glutathione


URINALYSIS: No data


NEUROBEHAVIOURAL EXAMINATION: No data



OTHER: Hepatic microsomal activities,
Parameters examined at the end of the 90-d exposure in 8 mice per sex/group: microsomal proteins, cytochrome p450, cytochrome b5, aminopyrine N-demethylase, aminopyrine hygroxylase.
Sacrifice and pathology:
Organ weight: brain, testes, liver, kidneys, spleen, lungs, thymus
Other examinations:
No data
Statistics:
-Statistical Evaluation:
If a one-way analysis of variance of the means showed treatment effects, a Duncan's Multiple Range Test was performed. Values which differ from vehicle control at p < 0.05 were considered statistically significant. Each of the values represents the mean +/-SE.

Results and discussion

Results of examinations

Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
- Body weight: strongly low body weight gain was observed in males at 2 mg/mL.
- Fluid consumption: there was a 30% decrease in fluid consumption in male mice drinking the highest concentration of 1,1,2-trichloroethane over the 90 day period. However, there was no 1,1,2-trichloroethane-related change in fluid consumption for the female mice.
- Organ weights:
* Males, there were no significant changes in weights for the brain, spleen, lungs, and thymus. On a mg basis, liver weights in male mice exposed to 0.2 and 2.0 mg/mL 1,1,2-trichloroethane were 11 and 12% smaller than the control group. This decreased liver weight was proportional to the decreased body weight; therefore, no significant changes could be measured on a percent of body weight basis. Similarly, kidneys weights were decreased of 12 and 16% on a mg basis for the groups receiving 0.2 and 2.0 mg/mL. Testicular weights of males exposed to the two highest concentrations increased 11 and 12% above control, but only on a percent of body weight basis
* Females responded differently in that the group receiving 2.0 mg/mL 1,1,2-trichloroethane had a 32% increase in absolute liver weight and a 26% increase when expressed as percent of body weight. Spleen and kidney weights of females exposed to the highest concentration were significantly increased on a mg basis only
- Hematology: there were few 1,1,2-trichloroethane exposure-related alterations in the hematological or blood coagulation parameters in the male mice . Male mice exposed to the highest concentration of 1,1,2-trichloroethane had decreased percent of polymorphonuclear leukocytes and increased percent of lymphocytes. Hemoglobin and hematocrit values of female mice exposed to 2.0 mg/mL 1,1,2-trichloroethane decreased by 6 and 5% (p < 0.05), as compared to the mice receiving deionized water. Erythrocytes also decreased, but not significantly. Platelet counts increased in all groups, but not in a dose-dependent fashion. Fibrinogen levels increased in females exposed to all three exposure levels, while prothrombin times decreased in the two highest exposure groups.
- Clinical chemistry: 14 serum chemistry parameters were evaluated. Some serum chemistry values were changed in males, which could be considered exposure-related regarding the 28% increase in cholesterol levels and the 61% increase in SAP activity in mice exposed to the highest concentration of 1,1,2-trichloroethane. The exposure-related alterations in the females included a 36% increase in cholesterol levels and a 63% increase in SGPT activity at the highest dose level, and SGOT and SAP increases at all dose levels (not dose dependent). Liver glutathione levels decreased dose dependently in males exposed to the two highest concentrations of 1,1,2-trichloroethane by 16 and 28% . Female mice exposed to the highest concentration of 1,1,2-trichloroethane showed a 13% increase in glutathione levels.
- Hepatic microsomal activities: In males, there were no perturbations of microsomal protein, cytochrome p-450 and b5 content. Microsomal enzymes that demethylate aminopyrine or hydroxylate aniline were not affected . Changes did occur with some of these parameters in the female mice. Cytochrome p-450 content and aniline hydroxylase activity were reduced dose dependently, while microsomal protein, cytochrome b5, and aminopyrine demethylase activity were unaffected.

Effect levels

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Dose descriptor:
NOAEL
Effect level:
3.9 mg/kg bw (total dose)
Sex:
female
Dose descriptor:
NOAEL
Effect level:
4.4 mg/kg bw (total dose)
Sex:
male
Dose descriptor:
LOAEL
Effect level:
44 mg/kg bw (total dose)
Sex:
male/female
Basis for effect level:
other: In females, reduction of cytochrome P450 content and aniline hydrolase activity. in males, reduction of liver glutathione

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In a 90-day drinking water study with mice at concentrations of 0, 20, 200 or 2000 mg/L, NOAEL was considered to be 3.9 mg/kg/day (corresponding to 20 mg/L), and targen organ was determined to be the liver.
Executive summary:

A 90 day drinking water study was performed, in which mice were administered test substance at 4.4, 46, and 305 mg/kg for males and 3.9, 44, and 384 mg/kg for females. The liver was determind to be the target organ in both sexes as demonstrated by dose-dependent alterations in hepatic microsomal enzyme activities and serum enzyme levels. The erythroid element of the female mice was also affected, as indicated by significantly decreased hematocrit and hemoglobin levels. The lowest effect level seen in females was 0.2 mg/mL (44 mg/kg), which resulted in a reduction of cytochrome p-450 levels and aniline hydroxylase activity. The no adverse effect level was 0.02 mg/mL (3.9 mg/kg) in females. In males, the lowest effect level was 0.2 mg/mL (46 mg/kg), which resulted in reduction of liver glutathione, and the no adverse effect level was 0.02 mg/mL (4.4 mg/kg).

NOAEL was derived at 3.9 mg/kg bw/d in females and 4.4 mg/kg bw/d in males, corresponding to 20 mg/L in drinking water.