Registration Dossier

Administrative data

Description of key information

Acute toxicity oral:

Acute oral LD50 value for the test compound Chloral hydrate in random bred  CD1- male mice is 1442 mg/kg/bw  with 95% C.I. (1290-1605  mg/kg/bw ) and 1265  mg/kg/bw  with 95% C.I. (1097-1405 mg/Kg/bw) in female mice.

Acute toxicity of chloral hydrate to rat by oral (gavage) route indicates that chloral hydrate is likely to exhibit acute toxicity by the oral route in Toxicity Category IV as per the CLP classification criteria. However, the chemical has harmonized classification as Acute toxicity 3 (oral route) and this dossier agrees to the harmonized classification as per the CLP regulation.

Acute toxicity inhalation:

The LC50 for the given test material Chloral Hydrate is found to be >100 ppm (>603mg/m3).

This value indicates that the substance is not toxic via inhalation route and thus considered as Not classified for Acute toxicity inhalataion as per CLP classification criteria.

Acute toxicity dermal:

The acute dermal LD50 value of the substance Chloral Hydrate was determined to be 3030 mg/kg bw for rats.

This value indicates that the substance is not toxic via dermal route of exposure and hence is considered as Not classified for acute dermal toxicity as per CLP classification criteria.

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:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
Data is from peer-reviewed open access journal
Qualifier:
according to
Guideline:
other: as mentioned below
Principles of method if other than guideline:
The purpose of this study was to evaluate the acute and subchronic toxicology of chloral hydrate in the random-bred CD-1 mouse, to provide data for risk assessment.
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
mouse
Strain:
CD-1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, MA.
- Age at study initiation:6 week old
- Weight at study initiation: No data available
- Fasting period before study: 18 hr
- Housing: Mice were housed four per cage in plastic shoebox cages containing sawdust bedding (PWI Hardwood Sawdust, Lowville, N.Y.).
- Diet (e.g. ad libitum): Agway Lab Chow ad libitum
- Water (e.g. ad libitum):drinking water ad libitum
- Acclimation period: No data available

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-24°C
- Humidity (%):40-60%
- Air changes (per hr):No data available
- Photoperiod (hrs dark / hrs light): The light/dark cycle was maintained on 12-hr intervals.

IN-LIFE DATES: From: To:No data available
Route of administration:
oral: gavage
Vehicle:
other: Deionized water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 0, 300, 600, 900, 1200, 1500 and 1800 mg/kg
- Amount of vehicle (if gavage): No data available
- Justification for choice of vehicle: No data available
- Lot/batch no. (if required): No data available
- Purity: No data available

MAXIMUM DOSE VOLUME APPLIED: 0.01 mL/g bw

DOSAGE PREPARATION (if unusual): Solutions of chloral hydrate were prepared fresh daily in deionized water

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: A 14 day range finding study was conducted using chloral hydrate by oral gavage at doses of 14.4 and 144 mg/Kg which were 1/100 and 1/10 the LD50 value.
Doses:
0, 300, 600, 900, 1200, 1500 and 1800 mg/kg
No. of animals per sex per dose:
8/sex/dose
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Following gavage, the mice were observed continuously for 4 hr and then twice daily for 14 days.
- Necropsy of survivors performed: Yes
- Other examinations performed: clinical signs, Neurobehavioral and gross pathology were examined.
Statistics:
Log probit analysis was used to determine the LD50, 95% confidence limits and the LOG probit slope.
Sex:
female
Dose descriptor:
LD50
Effect level:
1 265 mg/kg bw
Based on:
test mat.
95% CL:
>= 1 097 - <= 1 405
Sex:
male
Dose descriptor:
LD50
Effect level:
1 442 mg/kg bw
Based on:
test mat.
95% CL:
>= 1 290 - <= 1 605
Mortality:
Find the details in tables mentioned below for male and female.
Clinical signs:
Within 10 min of gavage, the mice became sedated at the low doses, while at the intermediate and higher doses, the animals became lethargic and exhibited loss of righting reflex. Respiration was markedly inhibited with the higher dosages; this inhibition appeared to be the immediate cause of death.

For female:
Within 10 min of gavage, the mice became sedated at the low doses, while at the intermediate and higher doses, the animals became lethargic and exhibited loss of righting reflex. Respiration was markedly inhibited with the higher dosages; this inhibition appeared to be the immediate cause of death.
Body weight:
No data available
Gross pathology:
Animals necropsied after death showed gastric hypermia, but were otherwise unremarkable.
Other findings:
No data available

Table for results on mortality:(for male)

Concentration mg/kg

Mortality observed (8)

1200

1

1500

4

Table for results on mortality:(for female)

Concentration mg/kg

Mortality observed (8)

1200

3

1500

7

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Acute oral LD50 value for the test compound Chloral hydrate in random bred CD1- male mice is 1442 mg/kg/bw with 95% C.I. (1290-1605 mg/kg/bw ) and 1265 mg/kg/bw with 95% C.I. (1097-1405 mg/Kg/bw) in female mice.
Executive summary:

Acute oral toxicity study was conducted on random-bred CD-1 male/female mice to evaluate the toxicity effect of the test compound Chloral hydrate during the 14 days study period.

 

Seven doses of the test compound were administered: 0, 300, 600, 900, 1200, 1500 and 1800 mg/kg. Eight mice of each sex were in each dose group. Following gavage, the mice were observed for behavioral and toxicological effects and gross pathology was performed at the end of 14 days.

 

Within 10 min of gavage, the mice became sedated at the low doses, while at the intermediate and higher doses, the animals became lethargic and exhibited loss of righting reflex. Respiration was markedly inhibited with the higher dosages; this inhibition appeared to be the immediate cause of death. Animals necropsied after death showed gastric hypermia, but were otherwise unremarkable. Most deaths occurred within 4 hr at the highest dose. At lower dosages, some deaths occurred after 4 hr, with all deaths occurring within 24 hr.

Acute oral LD50 value for the test compound Chloral hydrate in random bred  CD1- male mice is 1442 mg/kg/bw  with 95% C.I. (1290-1605  mg/kg/bw ) and 1265  mg/kg/bw  with 95% C.I. (1097-1405 mg/Kg/bw) in female mice.

Acute toxicity of chloral hydrate to rat by oral (gavage) route indicates that chloral hydrate is likely to exhibit acute toxicity by the oral route in Toxicity Category IV as per the CLP classification criteria. However, the chemical has harmonized classification as Acute toxicity 3 (oral route) and this dossier agrees to the harmonized classification as per the CLP regulation.

 

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 265 mg/kg bw
Quality of whole database:
The data is K2 level as the data has been obtained from the peer reviewed journal.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data is from authoritative review article and database.
Qualifier:
according to
Guideline:
other: as mentioned below
Principles of method if other than guideline:
Acute inhalation toxicity was determined for the test substance 2,2,2-trichloroethane-1,1-diol (Chloral hydrate) in mice following 6 hour exposure.
GLP compliance:
not specified
Test type:
other: No data
Limit test:
yes
Specific details on test material used for the study:
- Name of test material: 2,2,2-Trichloroethane-1,1-diol (Chloral hydrate)
- Molecular formula: C2-H3-Cl3-O2
- Molecular weight: 165.4026g/mol
- Smiles notation: C(C(O)O)(Cl)(Cl)Cl
- InChl: RNFNDJAIBTYOQL-UHFFFAOYSA-N
- Substance type: Organic
- Physical state: Solid
Species:
mouse
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
No data
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
not specified
Vehicle:
not specified
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
6 h
Concentrations:
100 ppm (20mg/Kg bw)
No. of animals per sex per dose:
No data available
Control animals:
not specified
Details on study design:
No data available
Statistics:
No data available
Key result
Sex:
not specified
Dose descriptor:
LC50
Effect level:
> 603 mg/m³ air
Based on:
test mat.
Exp. duration:
6 h
Remarks on result:
other: Following cessation of exposure, the animals regained consciousness.
Mortality:
no mortality observed
Clinical signs:
other: Clinical Signs observed were Deep narcosis, following effects were induced in the lung: formation of vacuoles in the Clara cells, scaling off of the epithelium and pulmonary edema (increase of the lung weight by a factor of 1.5).
Body weight:
not specified
Gross pathology:
not specified
Other findings:
Following cessation of exposure, the animals regained consciousness.
Interpretation of results:
other: not toxic
Conclusions:
The LC50 for the given test material Chloral Hydrate is found to be >100 ppm (>603mg/m3).
Executive summary:

Mice were exposed to the test material chloral hydrate at a concentration of 100 ppm ( 603mg/m3) for 6 hours. 

Inhalation exposure resulted in deep narcosis but following cessation of exposure, the animals regained consciousness. The following effects were induced in the lung: formation of vacuoles in the Clara cells, scaling off of the epithelium and pulmonary edema (increase of the lung weight by a factor of 1.5).

Acute inhalation study conducted shows that the LC50 for the given test material Chloral Hydrate is found to be >100 ppm (>603 mg/m3).

This value indicates thta the substance is not toxic via inhalation route and thus considered as Not classified for Acute toxicity inhalataion as per CLP classification criteria.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
603 mg/m³
Quality of whole database:
The data is K2 level as the data has been obtained from authoritative database and review article.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data is from Gestis database
Qualifier:
according to
Guideline:
other: as mentioned below
Principles of method if other than guideline:
To evaluate the acute dermal toxicity of Chloral hydrate in rats.
GLP compliance:
not specified
Test type:
other: not specified
Specific details on test material used for the study:
- Name of test material: 2,2,2-Trichloroethane-1,1-diol (Chloral hydrate)
- Molecular formula: C2-H3-Cl3-O2
- Molecular weight: 165.4026g/mol
- Smiles notation: C(C(O)O)(Cl)(Cl)Cl
- InChl: RNFNDJAIBTYOQL-UHFFFAOYSA-N
- Substance type: Organic
- Physical state: Solid
Species:
rat
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
not specified
Type of coverage:
not specified
Vehicle:
not specified
Details on dermal exposure:
not specified
Duration of exposure:
not specified
Doses:
not specified
No. of animals per sex per dose:
not specified
Control animals:
not specified
Details on study design:
not specifiednot specified
Key result
Sex:
not specified
Dose descriptor:
LD50
Effect level:
3 030 mg/kg bw
Based on:
test mat.
Mortality:
Yes, 50% mortality observed at 3030 mg/kg dose
Clinical signs:
not specified
Body weight:
not specified
Gross pathology:
not specified
Other findings:
not specified
Interpretation of results:
other: not toxic
Conclusions:
The acute dermal LD50 value of the substance Chloral Hydrate was determined to be 3030 mg/kg bw for rats.
Executive summary:

The acute dermal toxicity of Chloral hydrate in rats was evaluated.50% mortality was observed at 3030 mg/kg dose. Hence the acute dermal LD50 value of the substance Chloral Hydrate was determined to be3030 mg/kg bw for rats.

This value indicates that the substance is not toxic via dermal route of exposure and hence is considered as Not classified for acute dermal toxicity as per CLP classification criteria.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
3 030 mg/kg bw
Quality of whole database:
The data is K2 level as the data has been obtained from authoritative database.

Additional information

Acute toxicity oral:

Different studies from peer reviewed journals has been reviewed for the endpoint acute toxicity to classify the substance chloral hydrate for acute toxicity via oral route of exposure. The same is summarised below as weight of evidence approach:

Acute oral toxicity study was conducted on random-bred CD-1 male/female mice to evaluate the toxicity effect of the test compound Chloral hydrate during the 14 days study period ( Environmental Health Perspectives Vol. 44, pp. 137-146, 1982). Seven doses of the test compound were administered: 0, 300, 600, 900, 1200, 1500 and 1800 mg/kg. Eight mice of each sex were in each dose group. Following gavage, the mice were observed for behavioral and toxicological effects and gross pathology was performed at the end of 14 days. Within 10 min of gavage, the mice became sedated at the low doses, while at the intermediate and higher doses, the animals became lethargic and exhibited loss of righting reflex. Respiration was markedly inhibited with the higher dosages; this inhibition appeared to be the immediate cause of death. Animals necropsied after death showed gastric hypermia, but were otherwise unremarkable. Most deaths occurred within 4 hr at the highest dose. At lower dosages, some deaths occurred after 4 hr, with all deaths occurring within 24 hr. Acute oral LD50 value for the test compound Chloral hydrate in random bred  CD1- male mice is 1442 mg/kg/bw  with 95% C.I. (1290-1605  mg/kg/bw ) and 1265  mg/kg/bw  with 95% C.I. (1097-1405 mg/Kg/bw) in female mice.

Further supporting values were obtained from Toxicology And Applied Pharmacology 18, 185-207 (1971) presented as below:

The acute toxicity of Chloral hydrate in adult Charles River Sprague-Dawley rats was evaluated. 50% mortality was observed at 479 mg/kg dose. Hence the acute oral LD50 was determined to be 479 mg/kg bw in adult Charles River Sprague-Dawley adult rat for Chloral Hydrate.

Also, the acute toxicity of Chloral hydrate in 1-2 days aged Charles River Sprague-Dawley rats were evaluated. 50% mortality was observed at 285 mg/kg dose. Hence the acute oral LD50 was determined to be 285 mg/kg bw in 1-2 days aged Charles River Sprague-Dawley rat for Chloral Hydrate.

Thus from the above data it can be observed that the acute oral LD50 value of the substance chloral hydrate is in the range of 285 - 1442 mg/kg bw. Although some acute toxicity value of chloral hydrate to rat by oral route indicates that it is likely to exhibit acute toxicity via oral route in Toxicity Category IV as per the CLP classification criteria, however the chemical has harmonized classification as Acute toxicity 3 (oral route) and this dossier agrees to the harmonized classification as per the CLP regulation.

Acute toxicity inhalation:

Available data for the target substance Chloral hydrate (CAS 302 -17 -0) and data for its read across substance Chloral (CAS 75 -87 -6) were reviewed to classify the target substance for acute inhalation toxicity. The same is presneted below as weight of evidence approach:

Data obtained from Gestis authoritative database and IPCS monogrpah indictaes that mice were exposed to the test material chloral hydrate at a concentration of 100 ppm (603mg/m3) for 6 hours. Inhalation exposure resulted in deep narcosis but following cessation of exposure, the animals regained consciousness.The following effects were induced in the lung: formation of vacuoles in the Clara cells, scaling off of the epithelium and pulmonary edema (increase of the lung weight by a factor of 1.5). Acute inhalation study conducted shows that the LC50 for the given test material Chloral Hydrate is found to be >100 ppm (>603 mg/m3).

Similarly data from same source i.e. Gestis substance database suggests acute inhalation toxicity value for dogs was determined for the read across substance 2, 2, 2-trichloroacetaldehyde (Chloral; CAS No. 75 -87 -6). The exposed animals exhibited mostly eye irritations and neurotoxic effects. 4-hour LC50 value of the substance 2, 2, 2-trichloroacetaldehyde for dogs is determined to be 5,900 mg/m³.

Further acute inhalation toxicity study was performed in rats at 0.44mg/l (440 mg/m3) concentration for 2 hrs of exposure of the read across substance 2, 2, 2-trichloroacetaldehyde (Chloral; CAS No. 75 -87 -6). . 2 rats were taken for the test (as cited in NTRL report 1992). After exposure period 1 rat died and other hadacute pulmonary edema. Therefore, the LC50 value  was considered to be 440 mg/m3 concentration when rats inhaled with 2, 2, 2-trichloroacetaldehyde.

Thus from the above data for target as well as its read across substance and by applying weight of evidence approach it can be concluded

that the substance Chloral hydrate is not toxic via inhalation route and thus considered as Not classified for Acute toxicity inhalataion as per CLP classification criteria.

Acute toxicity dermal:

Available data for the target substance 2,2,2-trichloroethane-1,1-diol (Chloral hydrate; CAS 302 -17 -0) and data for its read across substance 1,1,1-trichloroethane (CAS 71 -55 -6) were reviewed to classify the target substance for acute dermal toxicity. The same is presneted below as weight of evidence approach:

Data obtained from Gestis substance database indicates that the acute dermal toxicity of Chloral hydrate in rats was evaluated. 50% mortality was observed at 3030 mg/kg dose. Hence the acute dermal LD50 value of the substance Chloral Hydrate was determined to be 3030 mg/kg bw for rats.

Supporting above data for target, the study referred from OECD HPV dossier 2009 suggests a single dose of 2000 mg read across substance 1,1,1-trichloroethane/kg b.w. (CAS 71 -55 -6) was applied for 24 hours under an occlusive dressing to the shaved intact skin of five male and five female rats. A control group received the occlusive dressing only. The animals were weighed the day before dosing, on the day of dosing and at 2, 7 and 14 days after dosing. Any sign of intoxication occurring during the 14-day observation periodwas recorded. At the end of the 14-day observation period the animals were subjected to gross necropsy. The livers, lungs, kidneys and testes were removed and weighed. No rats died. Examination of the animals revealed an increased incidence of swollen livers. The acute dermal LD50 value of the substance1,1,1-trichloroethanewas determined to be> 2000 mg/kg bw for rats.

Thus from the above data for target as well as its read across substance and by applying weight of evidence approach it can be concluded

that the substance Chloral hydrate is not toxic via dermal route and thus considered as Not classified for Acute toxicity dermal as per CLP classification criteria.

Justification for classification or non-classification

Based upon the study results and available information, the substance Chloral hydrate is expected to show acute toxicity effect by the oral route and thus will be considered for further classification. Though available data indicates acute oral toxicity in category 4, but since the chemical chloral hydrate has a harmonized classification of Acute oral toxicity Category 3, the same has been considered for Acute oral classification.

Available data for target as its read acros substances and application of weight of evidence approach indicates that the substance Chloral hydrate is not likley to exhibit acute toxicity by the inhalation and dermal route of exposure.