Reaction mass of carbon tetrachloride and chloroform and 1,2-dichloroethane

Endpoint summary

Description of key information

- Skin Corrosion/irritation : irritating based on the rules of the CLP Regulation for classification of mixtures

- Seriou eye damage/eye irritant: Serious eye irritation based on the rules of the CLP Regulation for classification of mixtures

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: The study was not carried out according to generally accepted guidelines and the documentation is insufficient for an assessment of the quality of the study.

Principles of method if other than guideline:

Dermal application following Draize's method; interpretation of results and scoring following official scoring method for cosmetics

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

Female rabbits weighing between 2.4 and 3.0 kg

Type of coverage:

not specified

Preparation of test site:

not specified

Vehicle:

not specified

Controls:

no

Amount / concentration applied:

no data

Duration of treatment / exposure:

no data

Observation period:

no data

Number of animals:

six

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

other: no data

Score:

5.6

Reversibility:

no data

Irritation parameter:

erythema score

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritation parameter:

edema score

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritant / corrosive response data:

Macroscopic observations included moderate to severe erythema and oedema with some superficial peripheral necrosis.

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Conclusions:

It can be concluded that chloroform is irritating to the rabbit's skin.

Executive summary:

The skin irritation potential of chloroform was tested in female New Zealand rabbits according to the principles of the Draize test. A single application of pure chloroform resulted in moderate to severe erythema and moderate to severe oedema. The primary dermal irritation index of chloroform was 5.6. Chloroform was classified as a severe skin irritant.

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1976

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Early standard study, very limited documentation, exposure regimen fails to allow interpretation on the basis of current standards (4-h exposure).

Reason / purpose for cross-reference:

reference to other study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

not specified

Principles of method if other than guideline:

Acc. to Draize (described in Duprat et al., 1974)

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

- Sex: female
- Weight at study initiation: 2.4-3.0 kg

Type of coverage:

occlusive

Preparation of test site:

other: scarified and intact skin

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

undiluted

Duration of treatment / exposure:

24 hours

Observation period:

no data

Number of animals:

30 animals

Details on study design:

Comparative study including various chlorinated solvents: Dermal application of 0.5 mL under occluded conditions on the scarified and intact skin. Skin was histologically examined on day 3 post-exposure.

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

other: 72 h

Score:

4.7

Max. score:

8

Irritation parameter:

erythema score

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritation parameter:

edema score

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritant / corrosive response data:

Only overall rating was given (by primary irritation index), but effects specified could not be exactly allocated to the individual test substance. An appraisal was not possible but through comparison relative to the findings on the other substances involved.  For example, chloroform and perchloroethylene were graded as "severe" irritants (PI = 5.6 and 6.1, resp., of max. 8 scores), tetrachloromethane was assigned "moderate" (PI = 4.2).

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Conclusions:

A primary irritation index of 4.7 was measured for skin irritation of 1,2-dichloroethane in rabbits. According to CLP Regulation (1272/2008/EC) the substance was classified as irritant (GHS, cat. 2).

Executive summary:

In a primary dermal irritation study, New Zealand White rabbits (6 females) were dermally exposed to 0.5 mL of undiluted 1,2-dichloroethane for 4 hours. Animals then were observed for at least 3 days. Irritation was scored by the method of Draize. A primary irritation index of 4.7 was measured for skin irritation of 1,2-dichloroethane. According to CLP Regulation (1272/2008/EC) the substance was classified as irritant (GHS, cat. 2).

Reference 3

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: A scientifically sound study, but no individual data, limited methodological information.

Qualifier:

no guideline followed

Principles of method if other than guideline:

- application of CTC and other chlorinated solvents to the skin of rabbits
- at day 3 histologic examinations of the treated skin regions
- a non-discribed ranking system for skin lesions (differentiating between erythema and edema) was used to classify the skin lesions macroscopically

GLP compliance:

no

Species:

rabbit

Strain:

other: New Zealand

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: not reported
- Age at study initiation: not reported
- Weight at study initiation: 2.4 - 3.0 Kg
- Housing: not reported
- Diet (e.g. ad libitum): not reported
- Water (e.g. ad libitum): not reported
- Acclimation period: not reported


ENVIRONMENTAL CONDITIONS
- Temperature (°C): not reported
- Humidity (%): not reported
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light):not reported

Type of coverage:

not specified

Preparation of test site:

not specified

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): very likely 0.5 mL (methods not detailed, only referenced to other publication)
- Concentration (if solution): unclear
- Purity > 99.5 %


VEHICLE
- not reported

Duration of treatment / exposure:

24 h

Observation period:

72 h, observations at 24, 48 and 72 h post treatment

Number of animals:

6

Details on study design:

TEST SITE
- Area of exposure:
- % coverage:
- Type of wrap if used:


REMOVAL OF TEST SUBSTANCE
- Washing (if done):
- Time after start of exposure:


SCORING SYSTEM: Draize scoring system

Irritation parameter:

other: I.I.C.P (very likely: primary skin irritation index)

Basis:

mean

Time point:

other: 24 and 72 h

Score:

4.2

Reversibility:

fully reversible within: 2 weeks or less

Irritation parameter:

erythema score

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritation parameter:

edema score

Time point:

24/48/72 h

Remarks on result:

not determinable

- the authors classify the skin irritation potency of CTC as medium in ranking comprising the stages: non irritating, almost non irritating, medium irritant and severely irritant.

Interpretation of results:

other: medium irritating

Remarks:

expert judgment

Conclusions:

The present publication (Duprat 1976) states CTC to be medium irritating to the skin of rabbits after single application.

Executive summary:

Individual data from different time points of observation are not presented, so a clear classification according to OECD GHS is not possible.

The publication is a survey report on the irritative potential of different chlorinated solvents. Rabbits were dermaly exposed with CTC (and other solvents) and the skin reaction was observed macroscopically as well as microscopically and scored by an undisclosed scoring system (very likely the Draize score system). Observation periods and dosing also remains unclear.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: The documentation of the study is insufficient to assess the quality. The results are considered to be not reliable.

Principles of method if other than guideline:

according to Draize's test and interpretation according to Kay and Calandra

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

female animals weighing between 2.4 and 3.0 kg

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

no data

Duration of treatment / exposure:

no data

Observation period (in vivo):

at least two to three weeks

Number of animals or in vitro replicates:

six

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: no data

Score:

41

Reversibility:

not fully reversible within: 3 weeks

Remarks on result:

other: One rabbit had ocular lesions after 3 weeks

Irritation parameter:

cornea opacity score

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritation parameter:

iris score

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritation parameter:

conjunctivae score

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritation parameter:

chemosis score

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritant / corrosive response data:

severe irritation and lesions of the conjunctivae with occurrence of purulent corneal discharge; mydriasis; developing, aggravating keratitis with apparition of translucent zones in the cornea in 4/6 rabbits, with pannus noted in two animals and hypopyon noted in one animal; recovery from these ocular effects took 2 to 3 weeks for most animals, except for one animal which still had corneal opacity after 3 weeks

Interpretation of results:

Category 2 (irritating to eyes) based on GHS criteria

Conclusions:

Chloroform is irritating to the eyes.

Executive summary:

An eye irritation test with chloroform was performed according to Draize's method with six female New Zealand rabbits. Instillation of pure, liquid chloroform led to severe irritation and lesions of the conjunctivae with occurrence of purulent corneal discharge. Other effects included corneal inflammation. Recovery from these ocular effects took 2 to 3 weeks for most animals, except for one animal which still had corneal opacity after 3 weeks. According to the scoring system of Kay and Calandra, chloroform was considered to be highly irritating to the rabbit's eye.

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1976

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study, limited documentation.

Reason / purpose for cross-reference:

reference to other study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

not specified

Principles of method if other than guideline:

Draize Test

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

- Sex: female
- Weight at study initiation: 2.4-3.0 kg

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

undiluted
amount applied: 0.1 mL

Duration of treatment / exposure:

single exposure

Observation period (in vivo):

14 days

Number of animals or in vitro replicates:

6 animals

Details on study design:

Eyes were not rinsed.
Comparative study including various chlorinated solvents, 6 animals used per test. For evaluation of irritating effects, a primary irritation index was derived by means of the "Draize Score" on a scale from 0-110 scores. The range of categorisation for "mild" irritant was given as 4 

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: not indicated

Score:

7

Max. score:

110

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: total observation time: 14 days

Irritation parameter:

cornea opacity score

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritation parameter:

iris score

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritation parameter:

conjunctivae score

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritation parameter:

chemosis score

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritant / corrosive response data:

After instillation of 0.1 mL of 1,2-dichloroethane into the conjunctival sac, moderate lacrimation, mild-moderate catarrhal conjunctivitis and corneal epithelium abrasion were visible in the slit lamp using fluorescein. On day 7 after instillation, keratitis was still evident, but regenerating, and fully disappeared after another 7 days. The effects were graded as "mild" with an overall irritation index of 7 (of 110 scores). [note: Chloroform reached an index of 41 (of 110 scores).]

Interpretation of results:

Category 2 (irritating to eyes) based on GHS criteria

Conclusions:

Eye irritation test with 1,2-dichloroethane in female rabbits. The effects were graded as "mild" with an overall irritation index of 7 (of max. 110 scores).  

Executive summary:

In a primary eye irritation study, 0.1 mL of undiluted 1,2-dichloroethane was instilled into the conjunctival sac of new Zealand rabbits (6 females). Eyes were not rinsed. Animals then were observed for 14 days. Irritation was scored by the method of Draize. After instillation, moderate lacrimation, mild-moderate catarrhal conjunctivitis and corneal epithelium abrasion were visible in the slit lamp using fluorescein. On day 7 after instillation, keratitis was still evident, but regenerating, and fully disappeared after another 7 days. The reversible effects were graded as "mild" with an overall irritation index of 7 (of max. 110 scores).

1,2 -dichloroethane was a mild eye irritant in rabbits under the conditions of this study.

Reference 3

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Scientifically sound study, but no individual data, limited methodological information

Qualifier:

no guideline followed

Principles of method if other than guideline:

The system of eye irritation scoring by Kay and Calandra (John H. Kay , Joseph C. Calandra , Interpretation of eye irritation tests (1962), Journal of Cosmetic Science, Vol. 13, No. 6, pp. 281-290) was used to classify the skin lesions macroscopically

GLP compliance:

no

Species:

rabbit

Strain:

other: New Zealand

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: not reported
- Age at study initiation: not reported
- Weight at study initiation: 2.4 - 3.0 Kg
- Housing: not reported
- Diet (e.g. ad libitum): not reported
- Water (e.g. ad libitum): not reported
- Acclimation period: not reported


ENVIRONMENTAL CONDITIONS
- Temperature (°C): not reported
- Humidity (%): not reported
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light):not reported

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
- Concentration (if solution): 100 %


VEHICLE
- not applicable

Duration of treatment / exposure:

single application, no wash out

Observation period (in vivo):

7 d

Number of animals or in vitro replicates:

6

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): not reported



SCORING SYSTEM: Draize Scoring (see "Any other information on materials and Methods")


TOOL USED TO ASSESS SCORE: not reported

Irritation parameter:

other: irritation score as defined by Kay and Calandra (1962)

Basis:

mean

Time point:

other: unclear

Score:

5

Reversibility:

fully reversible within: 2 weeks

Irritation parameter:

cornea opacity score

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritation parameter:

iris score

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritation parameter:

conjunctivae score

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritation parameter:

chemosis score

Time point:

24/48/72 h

Remarks on result:

not determinable

- according to Kay and Calandra (1962) a score of 5 is equivalent with minimally irritating

Interpretation of results:

other: slightly irritating

Remarks:

expert judgment

Conclusions:

The present publication (Duprat 1976) states CTC to be minimally irritating to the eye of rabbits after single application.

Executive summary:

The publication is a survey report on the irritative potential of different chlorinated solvents. Rabbits were ocular exposed with CTC (and other solvents) and the reaction of the eye was observed macroscopically as well as microscopically and scored by the scoring system of Kay and Calandra (1962). Individual data from different time points of observation are not presented. The effects are reported to be reversible within 1 to 2 weeks.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

SKIN IRRITATION

Carbon tetrachloride:

In an old skin irritation study performed similarly to the Draize test, slight to moderate irritating potential was observed for CTC (Duprat, 1976). In another hand, a skin sensitization test (LLNA) recently performed (Rokh, 2010), CTC did not induce any local reaction at the highest tested concentration (100%). Therefore, it is considered as non-irritant.

Chloroform and Dichloroethane:

These constituents were also tested for skin irritation by Duprat in 1976. In the studies, moderate to severe irritation reactions were observed. Chloroform and dichloroethane are therefore considered to be skin irritants.

EYE IRRITATION:

Carbon tetrachloride:

Mild irritation reaction of the rabbit eye after treatment with CTC were reported in an old eye irritation study, but the data and the information on methods (including doses) are very limited. A recovery period of 1 to 2 weeks was reported in this study. Therefore the substance is not considered to be an eye irritant.

Chloroform and Dichloroethane:

The constituents were also tested for eye irritation by Duprat in 1976. In these studies, moderate to severe irritation and lesions were observed. Chloroform and dichloroethane are therefore considered to be eye irritants.

RESPIRATORY IRRITATION:

Based on the effects observed in inhalation studies performed on chloroform and dichloroethane, these constituents are considered to be irritating to the respiratory tract.

CONCLUSION:

The decision logic for classification of mixtures from the ECHA Guidance on the Application of the CLP Criteria was used to determine the skin and eye irritating potential of the registered substance.

The registered substance has not been tested itself in appropriate in vitro or in vivo tests but some of its constituents are classified as skin irritant Cat.2 and eye irritant Cat.2 and are present above the CLP generic concentration limit of 10 and 3% for skin and eye irritation, respectively, that triggers classification of the mixture. Moreover, 1,2 -dichloroethane is also classified as respiratory irritant STOT-SE 3 and is above the generic concentration limit of 20%.

Therefore, the registered substance is a skin, eye and respiratory tract irritant.

Justification for classification or non-classification

Harmonized classification:

The registered substance has no harmonized classification according to the Regulation (EC) No.1272/2008 (CLP).

Self-classification:

Based on the available information and typical composition, the registered substance is classified as skin irritant: Skin Irritant Category 2 (H315: Causes skin irritation), Eye irritant Category 2 (H319: Causes serious eye irritation) according to the criteria of the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.

Regarding respiratory irritation, the criteria for classification as STOT-SE 3 (H335: may cause respiratory irritation) are met but this classification is deemed unnecessary because more severe organ effects including in the respiratory system are observed in the Acute Toxicity study by inhalation, and is considered covered by the ATI Cat.3 (H331).