Registration Dossier

Administrative data

Description of key information

90 days inhalation NOAEC (rats) = 50310 mg/m³ (NTP, 1989)

90 days inhalation NOAEC (mice) = 50310 mg/m³ (NTP, 1989)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
March 1981 - June 1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
yes
Remarks:
no clinical pathology performed; food and water consumption, organ weights (except liver) not determined; no monitoring of exposure conditions (e.g. test concentration)
GLP compliance:
yes
Limit test:
no
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories (Portage, MI, USA)
- Age at study initiation: 8-9 weeks
- Weight at study initiation: males: 23.1 - 24.2 g; females: 18.5 - 20.7 g
- Housing: individually in stainless steel wire cages (Hazleton Systems, Inc., Aberdeen, MD, USA); no bedding
- Diet (e.g. ad libitum): NIH 07 Rat and Mouse Ration (Zeigler Bros., Inc., Gardners, PA, USA); available ad libitum during non-exposure periods
- Water (e.g. ad libitum): automatic watering system (Edstrom Industries, Waterford, WI, USA); available ad libitum
- Acclimation period: 21 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.7 - 23.3
- Humidity (%): 40 - 65
- Air changes (per hr): 10 during exposure; 20 during non-exposure
- Photoperiod (hrs dark / hrs light): 12 / 12


IN-LIFE DATES: From: February 1981 To: June 1981
Route of administration:
inhalation: gas
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: vapour generation system; the liquid to be vaporized was forced under pressure, at a metered rate, directly from the shipping container into a stainless steel boiler that was maintained at about 32 °C by a controlled-temperature water bath. The vapour was routed through a gas metering valve and a purge/expose valve into a pipe at the chamber inlet, where the vapour was mixed with dilution air entering the chamber.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
6 hours/day
Frequency of treatment:
5 days/week for 13 weeks
Dose / conc.:
2 500 ppm (nominal)
Remarks:
corresponding to 6596 mg/m³
Dose / conc.:
5 000 ppm (nominal)
Remarks:
corresponding to 13192 mg/m³
Dose / conc.:
10 000 ppm (nominal)
Remarks:
corresponding to 26384 mg/m³
Dose / conc.:
19 000 ppm (nominal)
Remarks:
corresponding to 50130 mg/m³
No. of animals per sex per dose:
10
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: the absence of compound-induced mortality and toxic effects was the basis for selecting 19000 ppm as the highest exposure concentration in the 13-weeks studies.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 3 times per day during exposure

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: once per week

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No

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: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: liver weight at necropsy
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (performed on all control and high dose animals)

Tissues examined include: adrenal glands, bone marrow, brain, colon, oesophagus, gallbladder, heart, jejunum, kidneys, larynx, liver, lungs and bronchi, mammary gland, mandibular lymph nodes, nasal cavity, pancreas, parathyroid glands, pituitary gland, prostate/testes or ovaries/uterus, salivary glands, seminal vesicles, skin, spleen, stomach, thymus, thyroid gland, trachea and urinary bladder.
Statistics:
Survival analyses: estimated by the product-limit procedure of Kaplan and Meier (1985). Statistical analyses for a possible compound-related effect on survival used the method of Cox (1972). All reported P values for the survival analysis are two-sided.

Calculation of incidence: The incidence of neoplastic or non-neoplastic lesions is given as the ratio of the number of animals bearing such lesions at a specific anatomic site to the number of animals in which that site was examined.
Details on results:
CLINICAL SIGNS AND MORTALITY
One of 10 male mice exposed to 10000 ppm chloroethane died before the end of the study.
No compound related clinical signs were seen.

BODY WEIGHT AND WEIGHT GAIN
The final mean body weights of all exposed groups were generally higher than those of controls.

ORGAN WEIGHTS
The liver weight to body weight ratio for female mice exposed to 19000 ppm was significantly greater than that for controls (P < 0.01); however no microscopic liver changes were observed. The effects was considered to be adaptive.

GROSS PATHOLOGY/HISTOPATHOLOGY:
Nasal cavity haemorrhage of minimal severity was observed grossly in 3/10 male and 6/10 female mice exposed to 19000 ppm but was considered to be an artefact of necropsy and unrelated to exposure to chloroethane because no microscopic lesions associated with exposure to chloroethane were observed in the nasal mucosa of these animals.

Key result
Dose descriptor:
NOAEC
Effect level:
50 130 mg/m³ air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: non-toxicologically relevant increased relative liver weights; decreased body weight
Key result
Critical effects observed:
no
Conclusions:
In a 13-week study, mice were exposed to 0, 2500, 5000, 10000, or 19000 ppm chloroethane. No compound-related deaths occurred. Final mean body weights of exposed mice were generally higher than those of controls. No compound-related clinical signs or gross or microscopic pathologic effects were seen. The liver weight to body weight ratios for female mice exposed to 19000 ppm were greater than those for controls.
Executive summary:

Male and female mice were exposed to 0, 2500 ppm, 5000 ppm, 10000 ppm, or 19000 ppm chloroethane for 6 hours/day, 5 days/week for 13 weeks (National Toxicology Program, 1989). All animals lived to the end of the study; except one male mouse of the 10000 ppm dose group, which died during the first week of exposure. The final mean body weights of all exposed mice were generally higher than those of controls. No compound-related clinical signs were seen. The liver weight to body weight ratio for female mice exposed to 19000 ppm was significantly greater than that for controls, but no microscopic liver changes were observed. In the 13-week study in mice (National Toxicology Program, 1989), the liver weights were 1557+46, 1604+35, 1580+40, 1540+39, and 1993+66 mg at 0, 2500, 5000, 10000 and 19000 ppm, respectively. A statistically significant increase in liver weight was noted only at 19000 ppm (P < 0.01). Nasal cavity hemorrhage of minimal severity was observed grossly in 3/10 male and 6/10 female mice exposed to 19000 ppm but was considered to be not related to chloroethane because no microscopic lesions were observed in the nasal mucosa of these animals. 

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
March 1981 - June 1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
yes
Remarks:
no clinical pathology performed; food and water consumption, organ weights (except liver) not determined; no monitoring of exposure conditions (e.g. test concentration)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: F344/N
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories (Portage, MI, USA)
- Age at study initiation: 7 - 8 weeks
- Weight at study initiation: males: 160 - 163 g; females: 124 g
- Housing: individually in stainless steel wire cages (Hazleton Systems, Inc., Aberdeen, MD, USA); no bedding
- Diet (e.g. ad libitum): NIH 07 Rat and Mouse Ration (Zeigler Bros., Inc., Gardners, PA, USA); available ad libitum during non-exposure periods
- Water (e.g. ad libitum): automatic watering system (Edstrom Industries, Waterford, WI, USA); available ad libitum
- Acclimation period: 21 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.7 - 23.3
- Humidity (%): 40 - 65
- Air changes (per hr): 10 during exposure; 20 during non-exposure
- Photoperiod (hrs dark / hrs light): 12 / 12


IN-LIFE DATES: From: February 1981 To: June 1981
Route of administration:
inhalation: gas
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: vapour generation system; the liquid to be vaporized was forced under pressure, at a metered rate, directly from the shipping container into a stainless steel boiler that was maintained at about 32 °C by a controlled-temperature water bath. The vapour was routed through a gas metering valve and a purge/expose valve into a pipe at the chamber inlet, where the vapour was mixed with dilution air entering the chamber.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
6 hours/day
Frequency of treatment:
5 days/week for 13 weeks
Dose / conc.:
2 500 ppm (nominal)
Remarks:
corresponding to 6596 mg/m³
Dose / conc.:
5 000 ppm (nominal)
Remarks:
corresponding to 13192 mg/m³
Dose / conc.:
10 000 ppm (nominal)
Remarks:
corresponding to 26384 mg/m³
Dose / conc.:
19 000 ppm (nominal)
Remarks:
corresponding to 50130 mg/m³
No. of animals per sex per dose:
10
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: the absence of compound-induced mortality and toxic effects in a subacute study was the basis for selecting 19000 ppm as the highest exposure concentration in the 13-weeks studies.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 3 times per day during exposure

DETAILED CLINICAL OBSERVATIONS: No


BODY WEIGHT: Yes
- Time schedule for examinations: once per week

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No

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: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: liver weight at necropsy
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (performed on all control and high dose animals)

Tissues examined include: adrenal glands, bone marrow, brain, colon, oesophagus, heart, jejunum, kidneys, larynx, liver, lungs and bronchi, mammary gland, mandibular lymph nodes, nasal cavity, pancreas, parathyroid glands, pituitary gland, prostate/testes or ovaries/uterus, salivary glands, skin, spleen, stomach, thymus, thyroid gland, trachea and urinary bladder.
Statistics:
Survival analyses: estimated by the product-limit procedure of Kaplan and Meier (1985). Statistical analyses for a possible compound-related effect on survival used the method of Cox (1972). All reported P values for the survival analysis are two-sided.

Calculation of incidence: The incidence of neoplastic or non-neoplastic lesions is given as the ratio of the number of animals bearing such lesions at a specific anatomic site to the number of animals in which that site was examined.
Details on results:
CLINICAL SIGNS AND MORTALITY
All rats lived to the end of the study.


BODY WEIGHT AND WEIGHT GAIN
The final mean body weights of rats exposed to 19000 ppm was 8% lower than that of controls for males and 4% lower for females. The limited change (<10%) was not considered to be toxicologically relevant.


ORGAN WEIGHTS
The liver weight to body weight ratio for male rats exposed to 19000 ppm was significantly greater than that for the controls (control: 38.3 +/-1.08; 19000 ppm: 43.5 +/- 0.78; P < 0.01). This is considered to be an adaptive response to the test substance exposure.


GROSS PATHOLOGY/HISTOPATHOLOGY:
No compound-related clinical signs or gross or microscopic pathologic effects were seen.
Key result
Dose descriptor:
NOAEC
Effect level:
50 130 mg/m³ air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: non-toxicologically relevant increased relative liver weights; reduced body weight
Critical effects observed:
no
Conclusions:
In a 13-week study, rats were exposed to 0, 2500, 5000, 10000, or 19000 ppm chloroethane. No compound-related deaths occurred in rats. The final mean body weight of rats exposed to 19000 ppm was 8% lower than that of controls for males and 4% lower for females. No compound-related clinical signs or gross or microscopic pathologic effects were seen in rats. The liver weight to body weight ratios for male rats exposed to 19000 ppm were greater than those for controls.
Executive summary:

A thirteen-week study was conducted to evaluate the cumulative toxic effects of repeated whole body inhalation exposure to chloroethane and to determine the exposure concentrations to be used in a 2-year study (National Toxicology Program, 1989). Groups of 10 rats/sex were exposed to air containing chloroethane at target concentrations of 0, 2500, 5000, 10000, or 19000 ppm, 6 hours per day, 5 days per week for 13 weeks (65 exposures). Rats were observed three times per day. Individual animal weights were recorded once per week. At the end of the 13-week study, survivors were killed. A necropsy was performed on all animals. Histologic exams were performed on all control and high dose animals. Tissues examined included: adrenal glands, bone marrow, brain, colon, esophagus, heart, jejunum, kidneys, larynx, liver, lungs and bronchi, mammary gland, mandibular lymph nodes, nasal cavity, pancreas, parathyroid glands, pituitary gland, prostate/testes or ovaries/uterus, salivary glands, skin, spleen, stomach, thymus, thyroid gland, trachea, and urinary bladder; liver weighed at necropsy. Chamber concentrations were determined by GC-FID. All rats lived to the end of the study. The final mean body weights of all exposed groups were lower than those of controls; the final mean body weight of rats exposed to 19000 ppm was 8% lower than that of controls for males and 4% lower for females. No compound-related clinical signs or gross or microscopic pathologic effects were seen. The liver weight to body weight ratio for male rats exposed to 19000 ppm was significantly greater than that for controls. 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
50 310 mg/m³
Study duration:
subchronic
Species:
other: rat and mouse
Quality of whole database:
The available information comprises an adequate and reliable study, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, of Regulation (EC) No 1907/2006.
System:
hepatobiliary
Organ:
liver

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
March 1981 - June 1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
yes
Remarks:
no clinical pathology performed; food and water consumption, organ weights (except liver) not determined; no monitoring of exposure conditions (e.g. test concentration)
GLP compliance:
yes
Limit test:
no
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories (Portage, MI, USA)
- Age at study initiation: 8-9 weeks
- Weight at study initiation: males: 23.1 - 24.2 g; females: 18.5 - 20.7 g
- Housing: individually in stainless steel wire cages (Hazleton Systems, Inc., Aberdeen, MD, USA); no bedding
- Diet (e.g. ad libitum): NIH 07 Rat and Mouse Ration (Zeigler Bros., Inc., Gardners, PA, USA); available ad libitum during non-exposure periods
- Water (e.g. ad libitum): automatic watering system (Edstrom Industries, Waterford, WI, USA); available ad libitum
- Acclimation period: 21 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.7 - 23.3
- Humidity (%): 40 - 65
- Air changes (per hr): 10 during exposure; 20 during non-exposure
- Photoperiod (hrs dark / hrs light): 12 / 12


IN-LIFE DATES: From: February 1981 To: June 1981
Route of administration:
inhalation: gas
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: vapour generation system; the liquid to be vaporized was forced under pressure, at a metered rate, directly from the shipping container into a stainless steel boiler that was maintained at about 32 °C by a controlled-temperature water bath. The vapour was routed through a gas metering valve and a purge/expose valve into a pipe at the chamber inlet, where the vapour was mixed with dilution air entering the chamber.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
6 hours/day
Frequency of treatment:
5 days/week for 13 weeks
Dose / conc.:
2 500 ppm (nominal)
Remarks:
corresponding to 6596 mg/m³
Dose / conc.:
5 000 ppm (nominal)
Remarks:
corresponding to 13192 mg/m³
Dose / conc.:
10 000 ppm (nominal)
Remarks:
corresponding to 26384 mg/m³
Dose / conc.:
19 000 ppm (nominal)
Remarks:
corresponding to 50130 mg/m³
No. of animals per sex per dose:
10
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: the absence of compound-induced mortality and toxic effects was the basis for selecting 19000 ppm as the highest exposure concentration in the 13-weeks studies.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 3 times per day during exposure

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: once per week

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No

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: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: liver weight at necropsy
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (performed on all control and high dose animals)

Tissues examined include: adrenal glands, bone marrow, brain, colon, oesophagus, gallbladder, heart, jejunum, kidneys, larynx, liver, lungs and bronchi, mammary gland, mandibular lymph nodes, nasal cavity, pancreas, parathyroid glands, pituitary gland, prostate/testes or ovaries/uterus, salivary glands, seminal vesicles, skin, spleen, stomach, thymus, thyroid gland, trachea and urinary bladder.
Statistics:
Survival analyses: estimated by the product-limit procedure of Kaplan and Meier (1985). Statistical analyses for a possible compound-related effect on survival used the method of Cox (1972). All reported P values for the survival analysis are two-sided.

Calculation of incidence: The incidence of neoplastic or non-neoplastic lesions is given as the ratio of the number of animals bearing such lesions at a specific anatomic site to the number of animals in which that site was examined.
Details on results:
CLINICAL SIGNS AND MORTALITY
One of 10 male mice exposed to 10000 ppm chloroethane died before the end of the study.
No compound related clinical signs were seen.

BODY WEIGHT AND WEIGHT GAIN
The final mean body weights of all exposed groups were generally higher than those of controls.

ORGAN WEIGHTS
The liver weight to body weight ratio for female mice exposed to 19000 ppm was significantly greater than that for controls (P < 0.01); however no microscopic liver changes were observed. The effects was considered to be adaptive.

GROSS PATHOLOGY/HISTOPATHOLOGY:
Nasal cavity haemorrhage of minimal severity was observed grossly in 3/10 male and 6/10 female mice exposed to 19000 ppm but was considered to be an artefact of necropsy and unrelated to exposure to chloroethane because no microscopic lesions associated with exposure to chloroethane were observed in the nasal mucosa of these animals.

Key result
Dose descriptor:
NOAEC
Effect level:
50 130 mg/m³ air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: non-toxicologically relevant increased relative liver weights; decreased body weight
Key result
Critical effects observed:
no
Conclusions:
In a 13-week study, mice were exposed to 0, 2500, 5000, 10000, or 19000 ppm chloroethane. No compound-related deaths occurred. Final mean body weights of exposed mice were generally higher than those of controls. No compound-related clinical signs or gross or microscopic pathologic effects were seen. The liver weight to body weight ratios for female mice exposed to 19000 ppm were greater than those for controls.
Executive summary:

Male and female mice were exposed to 0, 2500 ppm, 5000 ppm, 10000 ppm, or 19000 ppm chloroethane for 6 hours/day, 5 days/week for 13 weeks (National Toxicology Program, 1989). All animals lived to the end of the study; except one male mouse of the 10000 ppm dose group, which died during the first week of exposure. The final mean body weights of all exposed mice were generally higher than those of controls. No compound-related clinical signs were seen. The liver weight to body weight ratio for female mice exposed to 19000 ppm was significantly greater than that for controls, but no microscopic liver changes were observed. In the 13-week study in mice (National Toxicology Program, 1989), the liver weights were 1557+46, 1604+35, 1580+40, 1540+39, and 1993+66 mg at 0, 2500, 5000, 10000 and 19000 ppm, respectively. A statistically significant increase in liver weight was noted only at 19000 ppm (P < 0.01). Nasal cavity hemorrhage of minimal severity was observed grossly in 3/10 male and 6/10 female mice exposed to 19000 ppm but was considered to be not related to chloroethane because no microscopic lesions were observed in the nasal mucosa of these animals. 

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
March 1981 - June 1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
yes
Remarks:
no clinical pathology performed; food and water consumption, organ weights (except liver) not determined; no monitoring of exposure conditions (e.g. test concentration)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: F344/N
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories (Portage, MI, USA)
- Age at study initiation: 7 - 8 weeks
- Weight at study initiation: males: 160 - 163 g; females: 124 g
- Housing: individually in stainless steel wire cages (Hazleton Systems, Inc., Aberdeen, MD, USA); no bedding
- Diet (e.g. ad libitum): NIH 07 Rat and Mouse Ration (Zeigler Bros., Inc., Gardners, PA, USA); available ad libitum during non-exposure periods
- Water (e.g. ad libitum): automatic watering system (Edstrom Industries, Waterford, WI, USA); available ad libitum
- Acclimation period: 21 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.7 - 23.3
- Humidity (%): 40 - 65
- Air changes (per hr): 10 during exposure; 20 during non-exposure
- Photoperiod (hrs dark / hrs light): 12 / 12


IN-LIFE DATES: From: February 1981 To: June 1981
Route of administration:
inhalation: gas
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: vapour generation system; the liquid to be vaporized was forced under pressure, at a metered rate, directly from the shipping container into a stainless steel boiler that was maintained at about 32 °C by a controlled-temperature water bath. The vapour was routed through a gas metering valve and a purge/expose valve into a pipe at the chamber inlet, where the vapour was mixed with dilution air entering the chamber.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
6 hours/day
Frequency of treatment:
5 days/week for 13 weeks
Dose / conc.:
2 500 ppm (nominal)
Remarks:
corresponding to 6596 mg/m³
Dose / conc.:
5 000 ppm (nominal)
Remarks:
corresponding to 13192 mg/m³
Dose / conc.:
10 000 ppm (nominal)
Remarks:
corresponding to 26384 mg/m³
Dose / conc.:
19 000 ppm (nominal)
Remarks:
corresponding to 50130 mg/m³
No. of animals per sex per dose:
10
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: the absence of compound-induced mortality and toxic effects in a subacute study was the basis for selecting 19000 ppm as the highest exposure concentration in the 13-weeks studies.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 3 times per day during exposure

DETAILED CLINICAL OBSERVATIONS: No


BODY WEIGHT: Yes
- Time schedule for examinations: once per week

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No

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: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: liver weight at necropsy
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (performed on all control and high dose animals)

Tissues examined include: adrenal glands, bone marrow, brain, colon, oesophagus, heart, jejunum, kidneys, larynx, liver, lungs and bronchi, mammary gland, mandibular lymph nodes, nasal cavity, pancreas, parathyroid glands, pituitary gland, prostate/testes or ovaries/uterus, salivary glands, skin, spleen, stomach, thymus, thyroid gland, trachea and urinary bladder.
Statistics:
Survival analyses: estimated by the product-limit procedure of Kaplan and Meier (1985). Statistical analyses for a possible compound-related effect on survival used the method of Cox (1972). All reported P values for the survival analysis are two-sided.

Calculation of incidence: The incidence of neoplastic or non-neoplastic lesions is given as the ratio of the number of animals bearing such lesions at a specific anatomic site to the number of animals in which that site was examined.
Details on results:
CLINICAL SIGNS AND MORTALITY
All rats lived to the end of the study.


BODY WEIGHT AND WEIGHT GAIN
The final mean body weights of rats exposed to 19000 ppm was 8% lower than that of controls for males and 4% lower for females. The limited change (<10%) was not considered to be toxicologically relevant.


ORGAN WEIGHTS
The liver weight to body weight ratio for male rats exposed to 19000 ppm was significantly greater than that for the controls (control: 38.3 +/-1.08; 19000 ppm: 43.5 +/- 0.78; P < 0.01). This is considered to be an adaptive response to the test substance exposure.


GROSS PATHOLOGY/HISTOPATHOLOGY:
No compound-related clinical signs or gross or microscopic pathologic effects were seen.
Key result
Dose descriptor:
NOAEC
Effect level:
50 130 mg/m³ air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: non-toxicologically relevant increased relative liver weights; reduced body weight
Critical effects observed:
no
Conclusions:
In a 13-week study, rats were exposed to 0, 2500, 5000, 10000, or 19000 ppm chloroethane. No compound-related deaths occurred in rats. The final mean body weight of rats exposed to 19000 ppm was 8% lower than that of controls for males and 4% lower for females. No compound-related clinical signs or gross or microscopic pathologic effects were seen in rats. The liver weight to body weight ratios for male rats exposed to 19000 ppm were greater than those for controls.
Executive summary:

A thirteen-week study was conducted to evaluate the cumulative toxic effects of repeated whole body inhalation exposure to chloroethane and to determine the exposure concentrations to be used in a 2-year study (National Toxicology Program, 1989). Groups of 10 rats/sex were exposed to air containing chloroethane at target concentrations of 0, 2500, 5000, 10000, or 19000 ppm, 6 hours per day, 5 days per week for 13 weeks (65 exposures). Rats were observed three times per day. Individual animal weights were recorded once per week. At the end of the 13-week study, survivors were killed. A necropsy was performed on all animals. Histologic exams were performed on all control and high dose animals. Tissues examined included: adrenal glands, bone marrow, brain, colon, esophagus, heart, jejunum, kidneys, larynx, liver, lungs and bronchi, mammary gland, mandibular lymph nodes, nasal cavity, pancreas, parathyroid glands, pituitary gland, prostate/testes or ovaries/uterus, salivary glands, skin, spleen, stomach, thymus, thyroid gland, trachea, and urinary bladder; liver weighed at necropsy. Chamber concentrations were determined by GC-FID. All rats lived to the end of the study. The final mean body weights of all exposed groups were lower than those of controls; the final mean body weight of rats exposed to 19000 ppm was 8% lower than that of controls for males and 4% lower for females. No compound-related clinical signs or gross or microscopic pathologic effects were seen. The liver weight to body weight ratio for male rats exposed to 19000 ppm was significantly greater than that for controls. 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
50 310 mg/m³
Study duration:
subchronic
Species:
other: rat and mouse
Quality of whole database:
The available information comprises an adequate and reliable study, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Under normal conditions chloroethane exists as a gas. Therefore, repeated dose studies have been conducted by the inhalation route of exposure.

Animal data

Data on subacute and subchronic chloroethane exposure are available from experiments with mice, rats, dogs and rabbits (Landry et al., 1982 and 1989; NTP, 1989; Dow Chemical Company, 1941; Gohlke and Schmidt, 1972).

 

In a subacute toxicity study performed according to OECD Guideline 412, Fischer-344 rats (6 per sex and dose) were exposed to 0, 1600, 4000 or 10000 ppm chloroethane 6 hours/day, 5 days/week for 14 days (Landry et al., 1982). Clinical observations and chemistry, haematology, urinalysis and complete histopathology were performed. Rats in the highest dose group may have been slightly lethargic during exposure. The liver weight to body weight ratios were significantly increased in the 4000 and 10000 ppm exposed male rats, although the increases were small (increase of 4.9% and 7.5% respectively compared to controls). In addition, a small but statistically significant depletion of non-protein sulfhydryl (NPSH) was observed in rats exposed to 4000 and 10000 ppm (1600 ppm: 95 +/- 6%, 4000 ppm: 88 +/- 4%, 1000 ppm: 89 +/- 6% NPSH of the control mean). Although there was not a clear dose-response relationship in liver NPSH depletion, the effect was thought to be treatment related, because it correlated with the slight response seen in relative liver weights. No toxicologically significant treatment-related effects on body weights, clinical chemistry, haematology, urinalysis parameters, gross pathology or histopathology were seen. On the basis of these results a NOAEC for systemic effects of 1600 ppm (4222 mg/m³) was derived from this subacute inhalation study for rats.

Male Beagle dogs (2 animals per dose) were exposed to chloroethane under the same exposure conditions as rats in a subacute inhalation study (Landry et al., 1982). The chloroethane treatment did not result in any significant changes in body weight or clinic-chemical, haematological or urinalytical parameters. No visible lesions were observed in any dogs during the opthalmoscopic examination. No neurological abnormalities were observed in the treated or control groups. Gross and histopathology were without pathological findings. The mean relative liver weight of dogs exposed to 10000 ppm was 15% less compared to control animals. However, this was not statistically significant and was not considered to be compound related. Thus, the NOAEC in this subacute toxicity studies with dogs was considered to be 10000 ppm (26384 mg/m³).

In a later study, Landry et al. (1989) continuously exposed B6C3F1 mice (7 animals per sex and dose) for 11 days, 23 hours/day to 0, 250, 1250 and 5000 ppm chloroethane. Parameters studied were clinico-chemical, haematological and histological types. In addition, body and organ weights were recorded. A blind neurobehavioral observation battery was conducted on the 12th day. The only effects observed occurred in the 5000 ppm dose group: an increase in the mean liver weights of male and female mice. In the highest dose group increased relative liver size in two males and one female was also observed. Although this is a very limited number of mice, it was consistent with the relative liver weight data. There was a minimal increase in the degree of hepatocellular vacuolization in four of the seven mice per sex exposed to 5000 ppm. Since mice are not fasted prior to necropsy, vacuolization (glycogen or fat) is routinely noted upon histopathological examination. On the basis of these results a NOAEC for systemic effects of 1250 ppm (3298 mg/m³) was derived from this subacute inhalation study for mice.

The National Toxicology Program (1989) also performed subacute studies on rats and mice (5 animals per sex and dose). The animals were exposed to a limit concentration of 19000 ppm chloroethane for 6 hours/day, 5 days per week for 2 weeks. All rats survived and no clinical signs of toxicity were seen. The final mean body weight of exposed male rats was higher compared to controls (+11%). However, weight gain was not affected by exposure to chloroethane. There were no compound-related gross lesions at necropsy, nor any compound-related microscopic findings. No clinical pathology was performed and no organ weights were determined. In mice, the final mean body weights of exposed mice were increased (+6% for males and +12% for females), but this body weight gain was also not considered compound-related. There were no clinical symptoms and no pathological or histopathological changes relative to the control animals.

In a 90-day inhalation study equivalent to OECD Guideline 413 F344/N rats (10 per sex and dose) were exposed to air containing chloroethane at target concentration of 0, 2500, 5000, 10000 and 19000 ppm for 6 hours/days, 5 days/week (NTP, 1989). Animals were observed 3 times per day during exposure and body weight was determined once per week. At the end of the study all surviving animals were killed and necropsied. Histopathology was performed on all control and high dose animals. In addition the liver weight was determined at necropsy. No death occurred during the study. The final mean body weight of male rats exposed to 19000 ppm chloroethane was 8% lower compared to controls and 4% lower for female rats. No compound-related clinical signs or gross pathological effects were observed. The liver weight to body weight ratio for male rats exposed to 19000 ppm was significantly greater than that for the controls. As no histopathological effects were noted, the liver weight changes were considered to be adaptive. On the basis of these results a NOAEC for systemic effects of 19000 ppm was derived from the 90-day inhalation study for rats.

B6C3F1 mice were exposed to chloroethane under the same conditions as the F344/N rats in a 90-day inhalation study (NTP, 1989). All mice except one of 10 male mice of the 10000 ppm dose group lived to the end of the study. No compound-related clinical signs were seen. The final mean body weights for all exposed groups were generally higher than those of control animals. Nasal cavity haemorrhage of minimal severity was observed grossly in 3/10 males and 6/10 female mice of the highest dose group. This finding was not considered to be compound-related since no microscopic lesions were observed in the nasal mucosa of these animals. The liver weight to body weight ratio for female mice exposed to 19000 ppm was significantly increased compared to controls (control: 1557 ± 46 mg, 19000 ppm: 1993 ± 66 mg), but no microscopic liver changes were observed. Therefore the changes were considered to be adaptive. As in the 90-day inhalation study for rats, the NOAEC for systemic effects in mice was considered to be 19000 ppm.

In a subchronic study 4 rabbits/group were exposed to approximately 9620 ppm for 7.5 - 8 hours/day, 5 days per week for 6.5 months (Dow Chemical Company, 1941). There were no effects on weight gain, liver weights, histopathology (including lungs), or clinical signs were noted. No pathological lesions of the eyes were observed following ophthalmoscopic examination.

 

A combination exposure with chloroethane and ethanol was investigated in rats (Gohlke and Schmidt, 1972; Schmidt et al., 1972). Rats were exposed to 0 or 1150 mg/m³ chloroethane for 10 days and some of the animals received additionally ethanol (4 g/kg bw) after the 1st, 3rd and 7th exposure. With or without additional ethanol treatment an increased ACTH-content in the hypophysis, changes in the serum protein fractions and total lipid content of liver and kidney were observed in rats. Decreases of succinate dehydrogenase and unspecific esterase and an increase of acid phosphatase, especially in animals subjected to additional ethanol treatment were determined.

Human data

Information concerning chronic effects of chloroethane in humans are casuistic observations made on chloroethane sniffers.

Neurological effects wer reported in a case history of a 52-year-old man, sniffing chloroethane for 30 years periodically with increasing abuse (at least 100 mL/day) over the last 4 months (Nordin et al., 1988). Abuse of chloroethane led to a complex syndrome with both neurological and mental manifestations (ataxia, dysarthria, nystagmus, dysdiadochokinesia and difficulties in walking, feeling of dizziness and unsteadiness). A transient amnesic syndrome and a grand mal seizure also occurred. Both the neurological and the mental changes regressed without any residual symptoms despite 30 years of abuse. The study authors indicated that it was not possible to determine if the nervous system effects were toxic effects of chloroethane or withdrawal symptoms.

A case of cerebellar disorder affecting a 28-year–old woman, a known drug addict, who had sniffed chloroethane for four months (200 – 300 mL/day) was reported by Hes et al. (1979). The woman presented the following symptoms: general fatigue, abdominal discomfort, dizziness, ataxia, nystagmus, inability to walk straight, clumsiness of her hands, tremor of her fingers and a speech disturbance. When inhaling chloroethane she experienced both pleasant and unpleasant hallucinations, which were accompanied by a subjective experience of pulsation in the head. Physical examination revealed her liver to be enlarged (3 cm), which was accompanied by mild and transient disturbance of liver function as biochemical investigations pointed out. After a month in hospital her signs were fully remitted.

The death of a young college student following abuse of chloroethane was reported by Yacoub et al. (1993). The man was found unresponsive, head down in his pillow with a metal canister containing chloroethane in or beside his right hand. Although the blood concentration of chloroethane was 65 mg/dL in this man shortly after death, the study authors believed, that because of resuscitative efforts for about 65 minutes, concentrations of chloroethane resulting in death were actually greater than the measured concentration. No other drugs or volatiles were found. Thus death was subsequently attributed to an overdose or adverse reaction to this product.

 

References:

Dow Chemical Company (1941) The Toxicity of Ethyl Chloride. TSCATS document number 86 -870002251. 8/4/1941 (as cited in OECD SIDS, Chloroethane, 2006)

Yacoub, I. et al.(1993) Death attributed to ethyl chloride. J. Analytical Toxicology 17(6): 384-385 (as cited in OECD SIDS, Chloroethane, 2006 and ATSDR, 1998)

 

Justification for classification or non-classification

The data is conclusive but not sufficient for classification according to CLP (1272/2008/EC).