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Description of key information

Repeated dose toxicity: oral

NOAEL was considered to be 14.4 mg/kg bw/day in male mice when exposed to Chloral Hydrate for 14 days by (oral) gavage.

Repeated dose toxicity: inhalation

Data available for acute toxicity by the inhalation route does not indicate inhlation toxicity in short term study. Also according to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking intoaccount the particle size distribution of the substance the majority of the particles were found to be in the size of 150 micrometer which is much larger size range compared to the inhalable particulate matter. Thus, exposure to inhalable dust, mist and vapour of the chemical chloral hydrate is highly unlikely. Therefore this study is considered for waiver.

Repeated dose toxicity: dermal

The acute toxicity value for chloral hydrate(as provided in section 7.2.3) is >2000 mg/kg body weight. Also considering the use of chloral hydrate as a medicine for sedation/hypnotic adverse effect by repeated exposure by the dermal route is highly unlikely. In addition, there is no data available that suggests that chloral hydrate shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
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:
In range finding Study the toxic effect of Chloral Hydrate was observed in CD1-male mice for 14 days by gavage.
GLP compliance:
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:
mouse
Strain:
CD-1
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, MA.
- Age at study initiation: 6 week old mice.
- Weight at study initiation: 25.1 ± 0.2 to 25.5 ± 0.2 g
- Fasting period before study: No data available.
- Housing: Mice were housed four per cage in plastic shoebox cages containing sawdust bedding (PWI Hardwood Sawdust, Lowville, N.Y.). Identified by ear punching
- Diet (e.g. ad libitum): Agway Lab Chow ad libitum
- Water (e.g. ad libitum): Deionized water, ad libitum
- Acclimation period: 1 week

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

IN-LIFE DATES: From: To: No data available


Route of administration:
oral: gavage
Vehicle:
other: Deionized water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: Chloral hydrate was diluted in deionized water in the concentrations of 14.4 and 144 mg/kg and administered by gavage in a volume of 0.01 ml/g body weight.
Drinking water solutions were maintained at room temperature in amber-colored bottles fitted with sipper spouts and was changed twice weekly.

VEHICLE
- Justification for use and choice of vehicle (if other than water): Deionized water
- Concentration in vehicle: 0, 14.4 and 144 mg/kg body weight/day
- Amount of vehicle (if gavage): 0.01 ml/g
- Lot/batch no. (if required): No data available
- Purity: No data available
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dose was analysis by using GLC and head space analysis.
Duration of treatment / exposure:
14 days
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
0(control),14.4 and 144 mg/kg/bw/day
Basis:
no data
No. of animals per sex per dose:
Total animals: 188
Control: 68 males
14.4 mg/kg/day: 60 males
144 mg/kg/day: 60 males
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations checked in table [No.?] were included: Mortality was observed.

DETAILED CLINICAL OBSERVATIONS: No data available
- Time schedule: No data available

BODY WEIGHT: Yes
- Time schedule for examinations: On day 1, 8 and 15 of treatment.

FOOD CONSUMPTION : No data available

COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data available

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: Yes / No / No data: No data available

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study):
- Time schedule for examinations: No data available: No data available

OPHTHALMOSCOPIC EXAMINATION: No data available
- Time schedule for examinations:
- Dose groups that were examined:

HAEMATOLOGY: Yes,
- Time schedule for collection of blood: At the termination of study.
- Anaesthetic used for blood collection: Yes, chloroform was used.
- Animals fasted: No data available
- How many animals: All 188 animals were examined.
- Parameters checked in table [No.?] were examined: Hematocrit, Hemoglobin, Leukocytes, Fibrinogen and Prothombin time were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the termination of study.
- Anaesthetic used for blood collection: Yes, chloroform was used.
- Animals fasted: No data available
- How many animals: All 188 animals were examined.
- Parameters checked in table [No.?] were examined: Lactic dehydrogenase, serum glutamic pyruvic transaminase, blood urea nitrogen were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: At the termination of study.
- Metabolism cages used for collection of urine: No data available
- Animals fasted: No data available
- Parameters checked in table [No.?] were examined. No data available

NEUROBEHAVIOURAL
EXAMINATION: No data available

OTHER:
Organ weight: Yes

Organ examined: Brain, Liver, Spleen, Lungs, Thymus, Kidneys and Testes were examined.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes ,The organs (brain, liver, spleen, lungs, thymus, kidneys, and testes) were removed,trimmed, weighed, and gross pathological examinations were performed on all mice.
HISTOPATHOLOGY: No data available
Statistics:
Statistical analysis is performed by using one-way analysis of variance, If a one-way analysis of variance of the means showed treatment effects; a Dunnett's T-test was performed. Values which differ from vehicle control at p < 0.05 are noted. Each of the values is given as the mean +standard error (SE) of the mean.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS:No data available

MORTALITY:One male mice from both 14.4 and 144 mg/kg body weight /day died on second week.
Death were probably not compound-related since two mice of control group were also died during 14 day treatment period.

BODY WEIGHT AND WEIGHT GAIN:No effect was observed on body weight and body weight gain of treated mice as compared to control.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):No data available

FOOD EFFICIENCY:No data available

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study):No data available

OPHTHALMOSCOPIC EXAMINATION:No data available

HAEMATOLOGY:No effect was observed on Hematological and coagulation values of treated mice as compared to control.

CLINICAL CHEMISTRY:When treated with 144 mg/kg body weight/day, statistically significant decreased in lacticdehydrogenase activity were observed in treated mice as compared to control.

URINALYSIS:No data available

NEUROBEHAVIOUR:No data available

ORGAN WEIGHTS:When treated with 144 mg/kg body weight/day, significant increased in absolute and relative liver weight and significant decreased in relative spleen weight were observed as compared to control.

When treated with 14.4 mg/kg body weight/day, decreased in relative kidneys weight was observed in treated mice as compared to control.

The observed changes for 14.4 mg/kg bw/day treated mice are not significantly different from control.

GROSS PATHOLOGY:Increase in liver size and decrease in spleen size were observed in 144 mg/kg bw/day treated mice as compared to control.

Changes were also observed in 14.4 mg/kg bw/day treated mice but the changes are not significantly different from control.


HISTOPATHOLOGY: NON-NEOPLASTIC:No data available
Key result
Dose descriptor:
NOAEL
Effect level:
14.4 other: mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No adverse effect on Body weight and weight gain, haematology, clinical chemistry, organ weights and gross pathology.
Key result
Critical effects observed:
no
Conclusions:
NOAEL was considered to be 14.4 mg/kg bw/day in male mice when exposed to Chloral Hydrate for 14 days by (oral) gavage.
Executive summary:

In repeated dose toxicity study, Random – bred CD1 male mice were exposed to Chloral Hydrate by oral gavage in the concentrations of 0 (control), 14.4 and 144 mg/kg//body weight/day.

Result shows statistically significant decreased in  lactic dehydrogenase activity, increased  in absolute and relative liver weight and significant decreased in relative spleen weight. In addition, Increase in liver size and decrease in spleen size was observed in 144 mg/kg bw/day treated mice as compared to control. Changes were also observed in organ weight and gross pathology of 14.4 mg/kg bw/day treated mice but the changes are not significantly different from control.

Therefore, NOAEL was considered to be 14.4 mg/kg body weight/day in male mice when exposed to Chloral Hydrate for 14 days by oral gavage. 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
14.4 mg/kg bw/day
Study duration:
subacute
Species:
mouse
Quality of whole database:
K2 level data has been obtained from peer reviewed journal

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: dermal
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated dose oral:

No. of studies of Chloral hydrate were reviewed for repeated dose oral toxicity from reliable sources having Klimisch rating 2. The summary of the results are presented below:

In a key repeated dose toxicity study from Environmental Health Perspectives Vol. 44, pp. 137-146, 1982, Random – bred CD1 male mice were exposed to Chloral Hydrate by oral gavage in the concentrations of 0 (control), 14.4 and 144 mg/kg//body weight/day. Result shows statistically significant decreased in  lactic dehydrogenase activity, increased  in absolute and relative liver weight and significant decreased in relative spleen weight. In addition, Increase in liver size and decrease in spleen size was observed in 144 mg/kg bw/day treated mice as compared to control. Changes were also observed in organ weight and gross pathology of 14.4 mg/kg bw/day treated mice but the changes are not significantly different from control. Therefore, NOAEL was considered to be 14.4 mg/kg body weight/day in male mice when exposed to Chloral Hydrate for 14 days by oral gavage. 

From same publication in a subchronic toxicity study, Random – bred CD-1 male and female mice were exposed to Chloral Hydrate in the concentration of 0, 0.07 and 0.7 mg/ml. Change in body weight and body weight gain, haematological and clinical parameters, change in relative weight of brain, lung and liver of male and female treated with 0.07 mg/ml as compared to control. In addition,increased hepatic microsomal aminopyrine N-demthylase and aniline hydroxylase activity and increased ctyochrome b5 content of male mice and aniline hydroxylase activity was increased, while liver nonprotein sulfhydryl and cytochrome b5 levels were decreased in female mice when treated with 0.07 mg/ml as compared to control. Therefore, LOAEL was considered to be 0.7 mg/ml (16 mg/kg/day for male and 18 mg/kg/day for female) when male and female Random – bred CD-1 mice were exposed to Chloral Hydrate orally in drinking water for 90 days.

 

Further in a Combined repeated and reproductive screening toxicity study from Reproductive Toxicology, Vol. 9, No. 6. pp. 571-578, 1995, F344 male rat were exposed to chloral hydrate in the concentration of 0, 55.0 and 188.0 mg/kg/day by oral drinking water. No significant effect were observed on clinical sign, body weight, organ weight, gross pathology and histopathology but significant decrease were observed in percentage of motile sperm (MOT) and percentage of progressively motile sperm (PMOT). In addition, Mean straight-line velocities average path and straight-line velocity distributions were shifted to a lower modal velocity range in 188.0 mg/kg/day reated rat as compared to control. The observed effect is on sperm parameters of treated rat. Therefore NOAEL was considered to be 55.0 mg/kg bw/day when F344 male rats were exposed to chloral hydrate on the basis of no significant effect were observed on clinical sign, body weight, organ weight, gross pathology, histopathology and effect on sperm parameters . While LOAEL was considered to be 188.0 mg/kg/day on the basis of significant decrease were observed in percentage of motile sperm (MOT) and percentage of progressively motile sperm (PMOT).

Based on the studies summarized above it can be observed that LOAEL value varies from 16 to 188 mg/kg/day in mice and rat respectively, whereas the no observed adverse effect value (NOAEL) value in mice is 14.4 and 55.0 mg/kg bw/day in mice and rat respectively. Also at any of the mentioned dose no significant effects on any target organ was observed. Thus the substance does not classify for repeated dose toxicity via the oral route.

Repeated dose toxicity: inhalation

Data available for acute toxicity by the inhalation route does not indicate inhlation toxicity in short term study. Also according to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking intoaccount the particle size distribution of the substance the majority of the particles were found to be in the size of 150 micrometer which is much larger size range compared to the inhalable particulate matter. Thus, exposure to inhalable dust, mist and vapour of the chemical chloral hydrate is highly unlikely. Therefore this study is considered for waiver.

Repeated dose toxicity: dermal

The acute toxicity value for chloral hydrate(as provided in section 7.2.3) is >2000 mg/kg body weight. Also considering the use of chloral hydrate as a medicine for sedation/hypnotic adverse effect by repeated exposure by the dermal route is highly unlikely. In addition, there is no data available that suggests that chloral hydrate shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Justification for classification or non-classification

At any of the mentioned dose no significant effects on any target organ was observed. Thus the substance does not classify forrepeated dose toxicity via the oral route. Whereas the repeated dose toxicity by the inhalation and dermal route were considered for waivers.