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EC number: 200-262-8 | CAS number: 56-23-5
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Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1986
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Scientifically sound study, but no individual data, limited biochemical and histological investigations.
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- publication
- Title:
- Oral toxicity of carbon tetrachloride: acute, subacute, and subchronic studies in rats.
- Author:
- Bruckner, J., V.; MacKenzie, W.,F.; Muralidhara, S.; Luthra, R.; Kyle, G., M.; Acosta, D.;
- Year:
- 1 986
- Bibliographic source:
- Fundamental and applied toxicology, vol. 6, p. 16-34
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- - rats (15 - 16 animals per dose, 4 doses) were treated with orally via gavage.
- dosing regime: 5 days a week
- blood samples were taken from 5 rats of each group at 2, 4, 6, 8, 10 and 12 weeks after study initiation, every rat was selected as blood donor 2 times with an interval of 6 weeks - GLP compliance:
- no
- Limit test:
- no
Test material
- Reference substance name:
- Carbon tetrachloride
- EC Number:
- 200-262-8
- EC Name:
- Carbon tetrachloride
- Cas Number:
- 56-23-5
- Molecular formula:
- CCl4
- IUPAC Name:
- tetrachloromethane
- Details on test material:
- - Name of test material (as cited in study report): carbon tetrachloride
- Analytical purity: analytical grade
- Supplier: Matheson, Colemn and Bell (Norwood, Ohio, U.S.A.)
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: TIMCO Breeding Laboratories (Houston)
- Weight at study initiation: 200-250 g (used for second experiment)
- Housing: in group of 5 or 6 animals in stainless-steel cages
- Diet (e.g. ad libitum): Ralston Purina Formulab chow, ad libidum
- Water (e.g. ad libitum): tap water, ad libidum
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 / 12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- - Dose preparation: concentrations were adjusted so that required doses were applied at 1 mL/animal
- Vehicle: of Mazola corn oil from Best Foods CPC international (Engleufood Cliffs, N.J., U.S.A.) - Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- - 12 weeks
- Frequency of treatment:
- - 5 days a week
Doses / concentrations
- Remarks:
- Doses / Concentrations:
1, 10, 33 mg/kg bw
Basis:
- No. of animals per sex per dose:
- 15-16, males only
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - blood samples were taken from 5 rats of each group at 2, 4, 6, 8, 10 and 12 weeks after study initiation, every rat was selected as blood donor 2 times with an interval of 6 weeks (see remark1 for details)
- 7 to 9 animals were killed after 12 weeks of treatment, the rest of the respective group (6-9 animals) were kept for additional 13 days recovery period (no treatment with substance or vehicle)
- liver and kidneys weighted at final necropsy
- histopathology of liver and kidney samples after final sacrifice (see remark 2) - 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: twice weekly
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
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: No
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after sacrifice
- Animals fasted: No
- How many animals: 5 per group
- Parameters checked in table 1 were examined.
URINALYSIS: Yes / No / No data
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.
NEUROBEHAVIOURAL EXAMINATION: Yes / No / No data
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:
OTHER: relative weight of organ/bodyweight determined for liver and kidneys - Sacrifice and pathology:
- GROSS PATHOLOGY: No
HISTOPATHOLOGY: Yes, liver and kidney slices - Statistics:
- - Students paired and unpaired t-test
- one way ANOVA
Results and discussion
Results of examinations
- Clinical signs:
- not examined
- Mortality:
- not examined
- 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):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- - body weight development was reported only graphically: significant decrease only in the high dose group (becoming significant from day 30)
Effect levels
open allclose all
- Dose descriptor:
- LOAEL
- Effect level:
- 10 mg/kg bw/day (nominal)
- Sex:
- male
- Basis for effect level:
- other: - biochemistry: moderate increase in SDH levels - histological findings: mild centrilobular vacuolization
- Dose descriptor:
- NOAEL
- Effect level:
- 1 mg/kg bw/day (nominal)
- Sex:
- male
- Basis for effect level:
- other: - absence of significant effects
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
- table 2: Clinical Chemistry Data from Subchronic Study
Week of evaluation after study initiation |
Daily dose of CCl4 (mg/kg) |
Total dose of CCl4 (mg/kg) |
OCT activity (mmol CO2/ml) |
SDH activity (IU/ml) |
GPT activity (IU/ml) |
BUN (mg/dl) |
2 |
0 |
0 |
43 ± 17 |
2.9 ± 0.7 |
23 ± 1 |
ND |
1 |
10 |
44 ± 13 |
8.3 ± 4.0 |
21 ± 1 |
ND |
|
10 |
100 |
31 ± 10 |
7.3 ± 1.5 |
25 ± 2 |
ND |
|
33 |
330 |
240 ± 56 d |
111.5 ± 17.0 d |
117 ± 28 d |
ND |
|
4 |
0 |
0 |
21 ± 6 |
2.6 ± 0.1 |
22 ± 1 |
15.6 ± 1.5 |
1 |
20 |
18 ± 4 |
ND |
23 ± 2 |
17.8 ± 1.2 |
|
10 |
200 |
26 ± 3 |
2.9 ± 0.3 |
22 ± 1 |
18.5 ± 1.2 |
|
33 |
660 |
140 ± 29 d |
90.2 ± 14.7 d |
75 ± 21 d |
18.4 ± 0.5 |
|
6 |
0 |
0 |
55 ± 13 |
2.5 ± 0.5 |
10 ± 1 |
16.2 ± 0.2 |
1 |
30 |
44 ± 5 |
2.4 ± 0.0 |
14 ± 2 |
15.4 ± 0.8 |
|
10 |
300 |
40 ± 10 |
8.8 ± 0.8 d |
16 ± 2 |
15.4 ±1.3 |
|
33 |
990 |
251 ± 58 d |
119.3 ± 16.9 d |
82 ± 20 d |
15.0± 0.8 |
|
8 |
0 |
0 |
18 ± 3 |
2.2 ± 0.2 |
21 ± 1 |
ND |
1 |
40 |
34 ± 9 |
1.6 ± 0.3 |
21 ± 1 |
ND |
|
10 |
400 |
30 ± 4 |
4.2 ± 1.5 |
19 ± 2 |
ND |
|
33 |
1320 |
151 ± 21 d |
110.6 ± 10.0 d |
130 ± 41 d |
ND |
|
10 |
0 |
0 |
28 ± 8 |
3.5 ± 0.4 |
18 ± 1 |
14.8 ± 0.5 |
1 |
50 |
23 ± 3 |
2.3 ± 0.6 |
20 ± 1 |
16.6 ± 1.0 |
|
10 |
500 |
55 ± 10 |
7.6 ± 2.5 d |
23 ± 1 |
17.6 ± 0.5 |
|
33 |
1650 |
148 ± 48 d |
134.8 ± 15.0 d |
617 ± 334 d |
18.2 ± 2.5 |
|
12 |
0 |
0 |
45 ± 4 |
3.2 ± 0.4 |
20 ± 0.3 |
16.6 ± 0.7 |
1 |
60 |
61 ± 12 d |
1.9 ± 0.1 |
19 ± 1 |
17.1 ± 0.6 |
|
10 |
600 |
69 ± 16 |
8.7 ± 2.0 d |
27 ± 2 d |
15.3 ± 1.2 |
|
33 |
1980 |
247 ± 31 d |
145.7 ± 57.9 d |
502 ± 135 d |
16.2 ± 0.8 |
|
14 ( 2weeks recovery phase) |
0 |
0 |
169 ± 33 |
4.7 ± 0.5 |
20 ± 2 |
15.1 ± 0.5 |
1 |
60 |
111 ± 25 |
3.4 ± 0.5 |
20 ± 1 |
16.8 ± 0.3 |
|
10 |
600 |
169 ± 42 |
4.3± 0.8d |
19 ± 1 |
16.7 ± 0.4 |
|
33 |
1980 |
174 ± 24 |
6.0 ± 0.8 d |
40 ± 7 d |
14.6 ± 2.0 |
ND: not determined
d: significantly different from control at p0.05, paired I test
e: significant increase with increasing dose at p0.05, analysis of variance
- table 3: Severity of Liver Lesions in the Subchronic Studies
Time point of sacrifice after study initiation |
Daily dose of CCl4 (mg/kg) |
Lipid vacuolization |
Nuclear and cellular polymorphism |
Bile duct hyperplasia |
Periportal fibrosis |
12 weeks |
0 |
0.0 + 0.0 |
0.0 + 0.0 |
0.0 + 0.0 |
0.0 + 0.0 |
1 |
0.0 + 0.0 |
0.0 + 0.0 |
0.0 + 0.0 |
0.0 + 0.0 |
|
10 |
3.7 + 0.7 |
3.5 + 0.3 |
0.0 + 0.0 |
0.0 + 0.0 |
|
33 |
4.0 + 0.4 |
5.7 + 0.7 |
4.0 + 0.6 |
3.7 + 0.7 |
|
14 weeks |
0 |
0.0 + 0.0 |
0.0 + 0.0 |
0.0 + 0.0 |
0.0 + 0.0 |
1 |
0.0 + 0.0 |
0.0 + 0.0 |
0.3 + 0.3 |
0.0 + 0.0 |
|
10 |
2.9 + 1.0 |
0.0 + 0.0 |
0.0 + 0.0 |
0.0 + 0.0 |
|
33 |
1.4 + 0.7 |
2.6 + 0.7 |
3.4 + 0.8 |
2.9 + 0.8 |
Extent of lesions was graded on a scale of 0 (absent) to 8 (mean values of 7 – 9 rats)
Applicant's summary and conclusion
- Conclusions:
- The present study (Bruckner 1986) presents for CTC a LOAEL of 10 mg/kg bw in rats for subchronic repeated dose toxicity via oral exposure (12 weeks, treatment 5 d/week)
- Executive summary:
- The present study (Bruckner 1986) presents for CTC a LOAEL of 10 mg/kg bw in rats for subchronic repeated dose toxicity via oral exposure (12 weeks, treatment 5 d/week). Basis are biochemical parameters indicative for liver and kidney injury (moderate increase in SDH levels) and histological findings (mild centrilobular vacuolization). The corresponding NOAEL for subchronic oral toxicity is 1 mg/kg bw. The repeated dose toxicity of CTC (cited as carbon tertrachloride in the report) was evaluated in a 12 week oral toxicity study in rats following no official guideline. Male Sprague Dawley rats were treated with the test substance by oral gavage at 5 days a week. Approximately half of the animals of each dose group were killed at the end of the treatment period while the other half was kept for a recovery period of 13 days without any treatment before sacrifice. Blood samples were taken from 5 rats of each group at 2, 4, 6, 8, 10 and 12 weeks after study initiation, every rat was selected as blood donor 2 times throughout the study with an interval of 6 weeks. Three parameters of liver injury (OCT activity, SDH activity and GPT activity) and one parameter for kidney injury (blood urea nitrogen (BUN)) were determined. Liver and kidney lesions were analyzed histologically and graded with a scoring system. Body weights were recorded and relative organ weights of liver and kidney determined. No mortality was reported. Liver toxicity and nephrotoxicity parameters were not elevated for the two lower dose groups except for the SDH value in the mid dose group after 6 weeks and at the end of the treatment phase (fully reversible after the recovery period). In the high dose group lipid vacuolization, nuclear and cellular pleomorphism, bile duct hyperplasia and periportal fibrosis were apparent after the treatment period and only partly reversible within the recovery period). In the mid dose group (10 mg/kg bw) only lipid vacuolization was apparent and partly reversible within the recovery period. Based on these findings a LOAEL of 10 mg/kg bw (rat, subschronic (12 weeks), oral) can be derived. The corresponding NOAEL is 1 mg/kg bw.
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