Carbon tetrachloride

Endpoint summary

Description of key information

- Oral:           LD50 > 2000 mg/kg bw  in rat

- Dermal:      LD50 > 2000 mg/kg bw in guinea pig

- Inhalation: LC50 > 20 mg/l (46260 g/m³ (= 7228 ppm) for 6 h exposure in rat (Bonnet,1980))

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: New testing design followed (in line with OECD TG 401). No individual data, limited reporting of experimental details

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Principles of method if other than guideline:

- this survey study was conducted to evaluate a new strategy for determination of LD50 values with a lower number of animals
- nevertheless in total 11 animals were used for each dose group

GLP compliance:

no

Test type:

standard acute method

Species:

rat

Strain:

not specified

Sex:

male

Details on test animals or test system and environmental conditions:

- Acclimation period: 5 d
- no further details reported

Route of administration:

oral: gavage

Vehicle:

not specified

Details on oral exposure:

- no details reported

Doses:

1500, 2000, 2800, 3900 mg/kg bw

No. of animals per sex per dose:

in total 11

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days or longer until the surviving animals stated gaining weight again
- Frequency of observations and weighing: days 0, 7, 14 and weekly thereafter if necessary
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs daily

Statistics:

Method of Rosiello et al. (RosieUo AP, Essigmana JM, Wogan GN (1977) Rapid and accurate determination of the median lethal dose (LDSo) and its error with a smalI computer. J Toxicol Environm Health 3: 797-809), based on the method by Bliss (1938).

Sex:

male

Dose descriptor:

LD50

Effect level:

2 500 mg/kg bw

Mortality:

1500 mg/kg bw 0/11
2000 mg/kg bw 5/11
2800 mg/kg bw 6/11
3900 mg/kg bw 11/11

Clinical signs:

other: - not reported

Gross pathology:

- not reported

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: other: According to EU directive 67/548/EEC and EU RegAccording to EU directive 67/548/EEC and EU Regulation (EC) N0. 1272/2008 (CLP)

Conclusions:

The present study (Lorke, 1983) states a LD50 (rat, oral) of 2500 mg/kg bw after single oral application via gavage.

Executive summary:

The potential of the test substance CTC (carbon tetrachloride) to induce toxicity upon exposure via the oral route was evaluated in a survey study on different substances following generally OECD TG 401. The scope of the study was to evaluate a new strategy to determine LD50 values with a lower amount of animals. Nevertheless the total amount of tested animals in each dose group allowed for CTC a classical determination of a LD50 value according to OECD TG 401. Male rats (unspecified strain) were treated at a single oral dose bw with CTC (unknown vehicle). Observation period was 14 d and further experimental details were not reported but stated to be conducted according to OECD TG 401.

The mortality incidences were 0/11 at 1500 mg/kg bw, 5/11 at 2000 mg/kg, 6/11 at 2800 mg/kg and 11/11 at 3900 mg/kg.

The LD 50(rat, oral) was therefore assessed to be 2500 mg/kg bw after single oral application via gavage.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 500 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

46 260 mg/m³ air

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 130 mg/kg bw

Additional information

Oral toxicity:

Several studies of different quality are available. In 5 acute toxicity studies in rats (Lorke, 1983; Kennedy, 1985; Jenkins, 1972; Garner, 1968; Kutepov, 1968), the LD50s were higher than 2000 mg/kg bw. The lowest value was 2500 mg/kg bw (Lorke, 1983) in rat. In most studies, clinical signs were not reported. For other species, higher values are reported: LD50 (mouse) = 11’000 – 12’000 mg/kg bw (Hayes, 1986); LD50 (guinea pig, rabbit) = 5760 mg/kg bw (Kutepov, 1968). The other studies show that CTC is hepatotoxic after a single oral dose. Toxic but non-lethal effects are reported by Magos (1982) at 594 mg/kg bw (rat, slight hepatic lesions), by Garner (1968) at 396 mg/kg bw (rat, plasma isocitrate dehydrogenase activity, bilirubin plasma concentration, liver water content and liver fat content) and by Akahori (1983) at 31.7 mg/kg bw (mouse, blood sugar levels, blood cholesterol levels, serum AST levels, fatty change and centrilobular necrosis).

 

Dermal toxicity:

Several studies are available to estimate the acute LD50 (Roudabush, 1964, rabbit and guinea pig; Wahlberg, 1979, guinea pig; Kinkead, 1980, rabbit). The lowest value for the acute dermal LD50 was 2130 mg/kg bw in guinea pigs (Wahlberg 1979). No information is available on rats.

 

Inhalation toxicity:

Several studies of different quality are available for this route. In the 4 most appropriate studies (Adams 1952, rat; Bonnet 1980, rat; Gradiski 1978, mouse; Svirbely 1947, mouse), the lowest value for 6-h LC50 was 46'260 mg/m3 (Bonnet, 1980) in rat. Whatever the kind of the study (nose only or whole body exposure), the 4h-LC50 or the 6h-LC50 were very high. The animals elicited signs of somnolence and at necropsy, clear hepatic injury. Based on these data, the rat shows a comparable sensitivity to the mouse toward CTC applied via the inhalation route. All these studies failed to report data on body weight development, gross necropsy or histology complicating the assessment of persistent, non-lethal effects.

Results of supporting studies are reported because they show the hepatotoxicity following acute inhalation exposure to CTC. Toxic

but non-lethal effects are stated by Watanabe (1969) at 800 ppm and 3 h exposure (mouse, lowering of hepatic ATP levels and rising hepatic lipid content), by Magos (1982) at 1250 ppm and 4 h exposure (rat, rise of serum glutamic-pyrivic transaminase (SGPT) levels 20 h post exposure end) and by Uemitsu (1984) at 2500 ppm and 3 h exposure (rat, time course of serum GOT (= AST) levels). Uemitsu (1984) shows that 1350 ppm during 3 h had no adverse effect in the rat as determined by serum GOT activity: effects up to 5200 ppm (3 h exposure) were reversible.

 

Other routes of exposure:

In a study where guinea pigs were exposed by intraperitoneal route (Wahlberg 1979), the LD50 was found to be more than 2000 mg/kg (as for oral and dermal exposure). This result supports the low acute toxicity of carbon tetrachloride in animals.

 

Human information:

As reported in the ATSDR Toxicological profile on carbon tetrachloride (2005), human fatalities from ingestion of carbon tetrachloride have been reported, usually following intake of a large amount of carbon tetrachloride. Fatalities occurred at lower intake in case of heavy alcohol consumption. The initial acute effects of carbon tetrachloride in humans exposed by inhalation are similar to effects reported from humans exposed orally; these effects include gastro-intestinal symptoms (nausea and vomiting, diarrhea, abdominal pain), hepatic effects (elevated serum asparagine aminotransferase, mild jaundice, and, in fatal cases, necrosis of the liver), and neurological effects (headache, dizziness, weakness). In the past, inhalation exposure to high concentrations of carbon tetrachloride - most of the time concomitantly to exposure via the dermal route – was reported to be responsible for a considerable number of deaths in humans.

Justification for classification or non-classification

The acute toxicity of CTC in rodents via the oral, dermal and inhalation route is low and therefore no classification for this endpoint is needed, based on the results animal studies. In acute toxicity studies at high dose levels, effects in the liver (centrilobular necrosis) have been observed.

The substance is listed in Annex VI of EU Directive 67/548/EE and in Annex I of CLP Regulation for acute oral, dermal and inhalation toxicity, probably because of the cases of human poisoning following exposure to CTC.