Registration Dossier

Administrative data

Description of key information

 The oral and dermal LD50 values and the inhalation LC50 values indicate that the acute toxicity of tetrachloroethylene is low. In animals, as in humans, the main signs of acute inhalation toxicity are indicative of CNS depression. A concentration of 40 ppm (275 mg/m3) is concluded to be a concentration without the occurrence of these effects in humans.

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: Comparable to guideline study, GLP status unknown, published in peer reviewed literature, acceptable for assessment
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
not specified
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS- Source: Charles River breeding laboratories (Wilmington, Mass.)- Age at study initiation: 22-30 days of age- Weight at study initiation: males 165-208 g and females 120-175 g- Fasting period before study: 16 hour- Housing: computer randomized, caged individually, and quarantined for 1 week prior to initiation of the study. Maintained in stainless steel wire-bottomed suspended cages, color coded for dosage level- Diet: ad libitum- Water: ad libitum- Acclimation period: 1 weekENVIRONMENTAL CONDITIONS- Temperature (°C): 21-24- Humidity (%): 40-60- Air changes (per hr): no data- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
other: polyoxityethylated vegetable oil (Emulphor)
Details on oral exposure:
Exposure by gavage following an overnight fast (16 hours).The volume administered was 10 ml/kg bw.The doses were based upon initial range-finding studies (no more details reported).
Doses:
2200-8850 mg/kg for males,2200-5500 mg/kg for females
No. of animals per sex per dose:
eight dosage groups, consisting of five rats per sex per group
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days- Frequency of observations and weighing: hourly observations were made during the first 9 hr after administration of the substance followed by twice-daily observations for the next 14 days- Necropsy of survivors performed: yes- Other examinations performed: clinical signs, body weight, gross pathology
Statistics:
no data
Preliminary study:
not applicable
Sex:
male
Dose descriptor:
LD50
Effect level:
3 835 mg/kg bw
95% CL:
3 318 - 4 437
Sex:
female
Dose descriptor:
LD50
Effect level:
3 005 mg/kg bw
95% CL:
2 689 - 3 358
Mortality:
All deaths occurred within the first 24 hr with a trend toward decreasing time to death with increasing dosage.
Clinical signs:
Tremors were observed at all doses. Tremors, ataxia, and central nervous system depression preceded death. Gross necropsy findings of the rats that died were essentially negative; hemorrhagic lungs and adrenals were observed in some animals.
Body weight:
No effects were reported.
Gross pathology:
No gross pathology was observed in the animals that survived the 14-day postadministration observation period.
Other findings:
Not reported.
Interpretation of results:
not classified
Remarks:
Migrated informationCriteria used for interpretation of results: EU
Endpoint conclusion
Quality of whole database:
Good

Acute toxicity: via inhalation route

Endpoint conclusion
Value:
275 mg/m³
Quality of whole database:
Good

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Animal data

The main signs of acute inhalation toxicity are indicative of CNS depression. Acute lethality is low, with LC50 values for rat and mouse mostly being greater than the classification cut-off of 3000 ppm (20 mg/l) (Bonnet et al, 1980; Pozzani et al, 1959; National Toxicology Programme, 1986; Rowe et al, 1952; Gradiski et al, 1978; Friberg et al, 1953).

Tetrachloroethylene also has low acute oral toxicity, with all LD50 values reported for rat and mouse being greater than the classification cut-off of 2 g/kg (Pozzani et al, 1959; Withey and Hall, 1975; Hayes et al, 1986; Dybing and Dybing, 1946). Signs of toxicity in the decedents included tremors and ataxia as well as CNS depression.

Regarding acute dermal toxicity, brief details are available of a study in which groups of 4 rabbits were exposed for 24 hours to undiluted tetrachloroethylene by dermal application under an occlusive dressing (Wolf, 1956). Mortality data (0/4 at 1.3 g/kg, 1/4 at 2.5, 5 and 10 g/kg and 2/4 at 20 g/kg) indicate low toxicity, with the estimated LD50 being greater than 10 g/kg. Convulsions occurred in 2‑5 minutes at 20 g/kg, and there was necrosis at application sites at all doses.

 

Human data

Accidental inhalation by humans of unmeasured but undoubtedly very high concentrations of tetrachloroethylene has led to death.

No good-quality information is available for adults following ingestion of tetrachloroethylene, although its previous extensive use as a deworming agent suggests a lack of serious acute toxicity at low doses. Large accidental intakes (estimated at 1.6‑4.8 g·kg‑1) in children have led to effects such as vomiting, gastro-intestinal bleeding, shock and, in one case, death (Lemburg et al, 1979; Koppel et al, 1985).

Regarding inhalation exposure, two human volunteer studies are considered key with regard to DNEL derivation for central nervous system effects. In the first study (Rowe et al, 1952), groups of 2-6 men were exposed to mean concentrations of tetrachloroethylene of 1060 ppm (7314 mg/m3) for a period of 1 or 2 minutes, 600 ppm (4140 mg/m3) for 10 minutes, 280 or 216 ppm (1932 or 1490 mg/m3) for up to 2 hours or 106 ppm (731 mg/m3) for 1 hour. Irritation was noted at 216 ppm and above. Dizziness occurred in at least some of the subjects at 216 ppm and above, along with drowsiness (216 ppm), a sensation of congestion of the frontal sinuses (216 and 280 ppm), impaired motor co-ordination and tightness about the mouth (280 and 600 ppm) and some loss of inhibitions (600 ppm). No significant effects were apparent at 106 ppm. In nearly all cases recovery was complete within 1 hour. Although there were no controls, the dose response trend seen lends credence to the findings as reliable representations of tetrachloroethylene effects.

In the second volunteer study (Stewart et al, 1970), 16 men and 1 woman were exposed to 100 ppm (690 mg/m3) tetrachloroethylene for 7 hours. When they were asked, subjective effects including headache, sleepiness, difficulty with speech and light-headedness were each affirmed in 25-40% of the subjects. There were also complaints of irritation. The only objective response was a decreased balancing ability (modified Romberg test) obtained in 4 subjects, and 3 of these gave a normal test when it was repeated. Although there were no control exposures in this study, only one concentration was tested and the reported symptoms are rather unspecific, an incidence of 40% for subjective CNS effects is too high to be considered a chance finding. Furthermore, these effects observed at 100 ppm (690 mg/m3) for a 7-hour exposure are consistent with those reported at 216 ppm (1490 mg/m3) for a 2-hour exposure in the other volunteer study available.

Although both these human volunteer studies are limited in their study design, the studies are considered to be sufficiently robust to be taken used for DNEL derivation. Based on these studies, a LOAEC of 100 ppm (690 mg/m3) (7 hours exposure) and a NOAEC of 106 ppm (1 hour exposure) are derived. The SCOEL recommends based on these data a STEL of 40 ppm (275 mg/m3). This value will be used as DNEL for acute inhalation exposure.

 

No information is available for acute toxicity to humans following dermal exposure.


Justification for selection of acute toxicity – oral endpoint
Comparable to guideline study, GLP status unknown, published in peer reviewed literature, acceptable for assessment

Justification for selection of acute toxicity – inhalation endpoint
Based on human volunteer study - Although both the human volunteer studies are limited in their study design, the studies are considered to be sufficiently robust to be taken used for DNEL derivation. Based on these studies, a LOAEC of 100 ppm (690 mg/m3) (7 hours exposure) and a NOAEC of 106 ppm (1 hour exposure) are derived. The SCOEL recommends based on these data a STEL of 40 ppm (275 mg/m3). This value will be used as DNEL for acute inhalation exposure

Justification for selection of acute toxicity – dermal endpoint
In accordance with column 2 of REACH Annex VIII-X, in addition to the oral route, for substances other than gases, an acute toxicity study for at least one other route is required. The choice of the second route will depend on the nature of the substance and the likely route of human exposure. As inhalation is the most likely route of exposure and acute inhalation toxicity data is available, no data gap exists.

Justification for classification or non-classification

On the basis of the observed CNS effects in human volunteer studies, tetrachloroethylene should be regarded as a substance which produces vapours that may cause drowsiness and dizziness (R67) according to Directive 67/548/EEC. According to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, the substance should be classified as STOT - Single exposure Cat 3; H336.

 

Based on the oral and dermal LD50 and inhalation LC50 values, classification for acute toxicity is not warranted according to EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.