Registration Dossier

Administrative data

Description of key information

Oral route:
None of the studies described fulfilled completely the requirements from internationally accepted guidelines or were documented with deficiencies. Thus, in a weight of evidence approach from out of 5 studies with conclusive results the lowest LD50 of 413 mg/kg bw determined in mice (Munson, 1982) was chosen for classification/labelling and risk assessment.
Inhalation route:
For inhalation toxicity, a 4-h LC50 of 1886 ppm (approx. 7758 mg/m³) in albino rats was derived from a dose-response graph (Spencer, 1951). Additional information, Hotchkiss study (2010), clearly suggest that the 4-h LC50 is higher that 2000 ppm (approx. 10000 mg/ m³).
Dermal route:
The dermal route was waived since more reliable data were available for exposure routes with higher relevance, i.e. oral and inhalation route. However, the mean LD50-value for acute dermal toxicity after application of 1,2-dichloroethane under occluded conditions to rabbits was 4890 mg/kg bw with a 95 % confidence interval of 4270–5600 mg/kg bw based on a study by Mellon Inst. Industr. Research (1948).

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
Study period:
1982
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Very few information, animals were observed for 14 days but no information on the number of animals and tested dose. Only LD50 values are reported.
Reason / purpose:
reference to other study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
not specified
GLP compliance:
no
Test type:
other: no data
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, Mass., U.S.A.
- Age at study initiation: 6 weeks old
- Fasting period before study: 18 hours prior to dosing
- Housing: In goups of four animals in shoebox plastic cages with sawdust bedding
- Diet: Agway Lab Chow ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature: 70-75 degree F (about 21-24 degree C)
- Humidity: 40-60 %
- Photoperiod: 12 hours dark/ 12 hours light
Route of administration:
oral: gavage
Vehicle:
not specified
Details on oral exposure:
Solutions of dichloroethane were prepared fresh daily for acute studies and the appropriate concentrations were administered by gavage in a volume of 0.01 mL/g bw to achieve the desired dose. The chemical was administered to male and female mice by an 18-gauge stainless steel stomach tube 18 hours after fasting from food.
Doses:
no data
No. of animals per sex per dose:
no data
Control animals:
not specified
Details on study design:
Following gavage, the mice were observed for overt toxicological effects continously for 4 hours and then twice daily for 14 days. Mice dying during the experimental procedure were necropsied, and gross pathological changes were described. Mice surviving the 14-day observation period were sacrificed and gross pathology described.
Gross pathology: brain, liver, spleen, lungs, thymus,  kidneys, testes (organ weight)
Statistics:
Log probit analysis was used to determine the LD50 and the 95% confidence limits.
Preliminary study:
no data
Sex:
male
Dose descriptor:
LD50
Effect level:
489 mg/kg bw
95% CL:
424 - 552
Sex:
female
Dose descriptor:
LD50
Effect level:
413 mg/kg bw
95% CL:
337 - 499
Mortality:
The mice died over a 48-hour period. Those surviving 48 hours recovered and appeared normal at the end of the 14-day observation period.
LD50 (male) = 489 mg/kg bw (95 % CL: 424-552 mg/kg bw); LD50 (female) = 413 mg/kg bw (95 % CL = 337-499 mg/kg bw).
Clinical signs:
no data
Body weight:
no data
Gross pathology:
Target organs appeared to be liver and lungs.
Other findings:
none
Interpretation of results:
Category 4 based on GHS criteria
Remarks:
Migrated information
Conclusions:
Oral administration of 1,2-dichloroethane to mice by gavage:
LD50 (male) = 489 mg/kg bw; LD50 (female) = 413  mg/kg bw
Executive summary:

In an acute oral toxicity study, groups of fasted (18 hours), 6 -week-old CD-1 mice were given a single oral dose of 1,2 -dichloroethane and observed for 14 days.

The mice died over a 48 -hour period. Those surviving 48 hours recovered and appeared normal at the end of the 14 -days observation period. Macroscopically, target organs appeared to be liver and lungs. The calculated LD50 values using log probit analysis were 489 mg/kg bw (95% C.I. 424 -552 mg/kg bw) and 413 mg/kg bw (95% C.I. 337-499 mg/kg bw) for male and female mice, respectively.

1,2 -dichloroethane is of low acute oral toxicity based on the LD50 in male and female CD-1 mice.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
413 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1951
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comprehensive and comparative study, basic data given, based on scientific principles apparently meeting current standards.
Reason / purpose:
reference to other study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
not specified
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: albino rats
Sex:
male/female
Details on test animals and environmental conditions:
The albino rats were raised in this laboratory of stock originally obtained from Wistar Institute of Anatomy and Biology in 1938. They were maintained on a modified Sherman diet consisting of freshly ground whole wheat (55 %), dried whole milk (25 %), dried extracted liver (12 %), dried brewer's yeast (5 %), iodized table salt (2 %) and calcium carbonate (1 %).
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
A glass-walled chamber of about 160 L capacity was used. Two large copper tubes (closed with rubber stoppers) were soldered into the model top of the chamber so that rats could be introduced conveniently after a vapour concentration had been established. A constant air flow was maintained through the chamber, the lowest rate for any experiment being 15 L/min and the highest about 30 L/min. The desired vapour concentration was obtained by metering liquid 1,2-dichloroethane at a constant rate into the tube through which air entered the chamber, heat being applied at the point of vaporization as needed to effect complete volatilization.
The rats were introduced in groups of 5 to 12 within a period of 15 sec and were removed through the chamber door within a similar interval of time at the end of the exposure. It was shown by a continuously recording analyzer that the animals were introduced without appreciable alterations of the vapour concentration.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
All vapour concentrations with animals in the chamber were checked repeatedly from time to time by combustion analyses; the results averaged better than 90 % of the calculated theroretical concentrations of 1,2-dichloroethane.
Duration of exposure:
>= 0.1 - <= 8 h
Concentrations:
200, 300, 600, 800, 1000, 1500, 3000, 12000 and 20000 ppm (corresponding to 823, 1234, 2468, 3290, 4113, 6169, 12339, 49354 and 82256 mg/m³) at various exposure times.
No. of animals per sex per dose:
between 10 and 54 rats
Control animals:
not specified
Details on study design:
All the rats were selected on the basis of general appearance and apparent good health, males and females being used in approximately equal numbers. Animals were observed as to their behavior, body weight changes, and time of death. Survivors were observed for two to three weeks, or until it was certain that they had fully recovery of weight.
Evidence of organ pathology: Special, additional groups of animals were killed at various intervals within the time-frame of 0.2-h to 20-h exposure to determine body weight, liver and kidney weight, blood parameters (urea nitrogen concentration, plasma prothrombin clotting time, serum phosphatase activity), liver lipids, and histopathological changes (liver, kidney, adrenals).
Statistics:
Statistics according to the method of Litchfield and Wilcoxon was performed.
Preliminary study:
no data
Sex:
male/female
Dose descriptor:
LC50
Effect level:
7 758 mg/m³ air
95% CL:
7 485.38 - 8 061.15
Exp. duration:
4 h
Remarks on result:
other: corresponding to approx. 1886 ppm
Mortality:
Mortality occurred at different exposure concentrations and exposure times. For details see the section "Remarks on results including tables and figures".
Clinical signs:
Please refer to the section "Remarks on results including tables and figures".
Body weight:
In special groups of animals (exposure causing 99.9, 50 or 0.01 % death), reported signs of exposure mediated toxicity were decreased body weights.
Gross pathology:
In special groups of animals (exposure causing 99.9, 50 or 0.01 % death), reported signs of exposure mediated toxicity were increased liver and kidney weights and slight parenchymatous degeneration to severe haemorrhagic necrosis (kidney, liver, adrenals), congestion (kidney, liver, adrenals, lungs) and oedema (kidney, lungs), increase in blood urea nitrogen concentration, plasma prothrombin clotting time, liver lipids, decrease in serum phospatase activity.
Other findings:
none

The 4-h LC50 corresponded to approx. 1886 ppm (approx. 7758.5 mg/m³) and was derived from the data by Standard Probit analysis (please refer to "Seuils de Toxicité aiguë 1,2-Dichloroéthane from Groupe d’Experts Toxicologues du Ministère de l’Ecologie, de l’Energie, du Développement Durable et de l’Aménagement du Territoire" dated 2008-12-03).

With 22000 ppm (approx. 90420 mg/m³), death occurred within 24 min after deep anaesthesia by depression of the central nervous system. At 12000 ppm and lower concentrations this depressant action resulted in varying degrees of "drunkenness".

In special groups of animals (exposure causing 99.9, 50 or 0.01 % death), reported signs of exposure mediated toxicity were decreased body weights, increased liver and kidney weights and slight parenchymatous degeneration to severe haemorrhagic necrosis (kidney, liver, adrenals), congestion (kidney, liver, adrenals, lungs) and oedema (kidney, lungs), increase in blood urea nitrogen concentration, plasma prothrombin clotting time, liver lipids, decrease in serum phospatase activity.

The following concentrations and exposure times were not lethal:

300 ppm (approx. 1200 mg/m³) after 7 h (20 animals)

600 ppm (approx. 2400 mg/m³) after 5 h (20 animals)

1500 ppm (approx. 6100 mg/m³) after 2 h (10 animals)

3000 ppm (approx. 12100 mg/m³) after 0.5 h (22 animals)

20000 ppm (approx. 81000 mg/m³) after 0.1 h (10 animals)

The following concentrations were void of adverse effects:

200 ppm (approx. 800 mg/m³) for 7 h

300 ppm (approx. 1200 mg/m³) for 3 h (but effects at 5.5 h)

1000 ppm (approx 4000 mg/m³) for 1.5 h (but effects at 3 h).

Interpretation of results:
Category 3 based on GHS criteria
Remarks:
Migrated information
Conclusions:
The 4-h LC50 in rats derived by Standard Probit analysis was 1886 ppm (approx. 7758 mg/m³).
Executive summary:

In an acute inhalation toxicity study, groups of young adult albino rats (10-54/dose, approximately equal numbers of males and females) were whole body exposed to 1,2 -dichloroethane for 0.1 to 8 hours at concentrations of 200, 300, 600, 800, 1000, 1500, 3000, 12000 or 20000 ppm (corresponding to 823, 1234, 2468, 3290, 4113, 6169, 12339, 49354 and 82256 mg/m³). Animals then were observed for 2 to 3 weeks. At 20000 ppm, death occurred within 24 min after deep anaesthesia by depression of the central nervous system. At 12000 ppm and lower concentrations this depressant action resulted in varying degrees of "drunkenness". According to authors, deaths tended to occur at three different time intervals and in such a manner as to suggest three separate toxic actions of fatal degree:

1. At very high concentrations (e.g. 20000 ppm), deaths occurred due to depression and paralysis of CNS functions.

2. At all vapour concentrations causing death, a large proportion died rather suddenly and quietly a few hours after termination of exposure, showing marked cyanosis, reduced body temperature, stupor or coma and failing respiration. The character and sudden development of this response suggested "shock" or cardiovascular collapse.

3. All other deaths occurred delayed over a period of 2 to 7 days with progressive loss of body weight and other evidence of toxic effects, suggesting organ failure, probably due to kidney lesions.

The 4 -h LC50 derived by Standard Probit analysis in this acute inhalation study in rats was 1886 ppm (approx. 7758 mg/m³).

1,2 -dichloroethane is of low acute oral toxicity based on the LC50 (4 hours) in male and female albino rats.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
7 758 mg/m³

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
Study period:
1948
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparative study, screening test, basic data given, based on scientific principles, results conclusive.
Reason / purpose:
reference to other study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
not specified
GLP compliance:
no
Test type:
other: no data
Limit test:
no
Species:
rabbit
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
no details given
Type of coverage:
occlusive
Vehicle:
not specified
Details on dermal exposure:
no data
Duration of exposure:
no data
Doses:
Occluded applications : 3.16, 3.98, 4.45 and 5.0 mL/kg for 24 h (= 3972, 5000, 5594 and 6285 mg/kg bw)
No. of animals per sex per dose:
6-11 animals
Control animals:
not specified
Details on study design:
no data
Statistics:
Probit analysis
Preliminary study:
no data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
4 890 mg/kg bw
95% CL:
4 270 - 5 600
Mortality:
Mortality observed within 14 days:
2/6 animals at 3972 mg/kg bw  within 5-10 days
3/11 animals at 5000 mg/kg bw within 1-5 days
8/9 animals at 5594 mg/kg bw within 1-11 days
5/6 animals at 6285 mg/kg bw within 1 day
The LD50 calculated using the method of probits was 3.89 mL/kg bw (3.40-4.46 mL/kg bw) or 4890 mg/kg bw (4270-5600 mg/kg bw).
Clinical signs:
No data
Body weight:
Weight loss was reported in most survivors.
Gross pathology:
Gross necropsy evaluation revealed no adverse effects.
Other findings:
none
Interpretation of results:
study cannot be used for classification
Remarks:
Migrated information
Conclusions:
Acute dermal toxicity to male rabbits:
The calculated LD50 by the method of probits was 3.89 mL/kg bw (3.40-4.46 mL/kg bw) or 4890 mg/kg bw (4270-5600 mg/kg bw).
Executive summary:

In an acute dermal toxicity study, groups of male rabbits (6 -11 animals/dose level) were dermally exposed to 1,2 -dichloroethane at doses of 3972, 5000, 5594 or 6285 mg/kg bw and observed for 14 days. Mortality was observed in 2/6 at 3972 mg/kg bw within 5 -10 days, 3/11 at 5000 mg/kg bw within 1 -5 days, 8/9 at 5594 mg/kg bw within 1 -11 days and 5/6 at 6285 mg/kg bw within 1 day. Weight loss was reported in most survivors. Gross necropsy evaluation revealed no adverse effects. The calculated LD50 by the method of probits was 3.89 mL/kg bw (3.40 -4.46 mL/kg bw) or 4890 mg/kg bw (4270–5600 mg/kg bw).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
4 890 mg/kg bw

Additional information

The acute toxicity of 1,2-dichloroethane was investigated by the oral, dermal and inhalation routes of administration. By the oral or inhalation route the test substance proved to be moderately toxic and virtually non-toxic after dermal application to the animals tested.

 

Oral route:

After oral administration to rats, LD50-values determined were in the range of 770-967 mg/kg bw. Signs of toxicity were characterised by lung congestion, pale kidneys and livers as well as congestion of intestinal blood vessels (Mellon Inst. Industr. Research, 1948; Smyth et al., 1969). A single maximum tolerated dose (MTD) of 625 mg/kg (oral, gavage) in SD rats was reported to produce liver effects: a slight decrease in hepatic porphyrin and cytochrome-P450 content and a more pronounced in the activity of hepatic aminolaevulinic acid dehydratase activity and the level of glutathione (Moody and Smuckler, 1986). In mice, LD50-values determined were in the range of 413–911 mg/kg bw. LD50-value of about 910 mg/kg bw and >2500 mg/kg bw were reported for rabbits and dogs, respectively (Barsoum and Saad, 1934; Heppel et al., 1945; Mellon Inst. Industr Research, 1948; Munson et al. 1982). The solvent was reported to act as a cardiac depressant in dogs, but deaths occurred through respiratory arrest prior to cardiac failure (Barsoum and Saad, 1934). None of the studies described fullfilled completely the requirements from internationally accepted guidelines or were documented with deficiencies. Thus, in a weight of evidence approach out of 5 studies with conclusive results the lowest LD50 of 413 mg/kg bw in mice (Munson, 1982) was chosen for classification/labelling and risk assessment.

 

Inhalation route:

After acute inhalation exposure to 1,2-dichloroethane, LC50-values obtained in rats ranged from 4100 mg/m³/7.2 h to 49400 mg/m³/0.5 h (Spencer et al., 1951). In compliance with these results, another 6-h LC50 was found at about 1650 ppm (= 6670 mg/m³) (Bonnet et al., 1980). A 4 -h LC50 in rats of about 7800 mg/m³ (= 1900 ppm) was derived from a concentration-response graph (Spencer et al., 1951). In mice, the LC50 after a 6 -h exposure was 272 ppm (= 1080 mg/m³) (Gradiski et al., 1978), and in guinea pigs an LC50 of 6400 mg/m³/7 h was reported (Heppel et al., 1945). In principal, results from other acute studies in rats, mice and rabbits lacking a sufficient data base to establish a defined LC50 (Heppel et al., 1945; Frankovitch et al., 1986) were consistent with those findings. The comprehensive study by Spencer et al. (1951) provided the following non-lethal concentration-time exposures in female rats (post-exposure observation for 2 to 3 weeks):

Determinations of LC0:

- 300 ppm (approx. 1200 mg/m³) [7 h] ,

- 500 ppm (approx. 6200 mg/m³) [2 h],

- 3000 ppm (approx. 12400 mg/m³) [0.5 h]

Determinations of NOAELs (based on blood parameters and histopathology):

- 200 ppm (approx. 800 mg/m³) [7 h];

- 300 ppm (approx. 1200 mg/m³) [3 h] (but effects at 5.5 h)

- 1000 ppm (approx. 4000 mg/m³) [1.5 h] (but effects at 3 h).

The 4-h LC50 of 1886 ppm (7758 mg/m³) was derived from the dose-response graph provided in the report. In addition, in a very recent study by Hotchkiss et al. (2010), rats were exposed to 1,2-dichloroethane vapor at 0, 50, 200, 600 or 2000 ppm for 4 h in order to assess neurobehavioral and neuropathologic effects. The animals were observed for 14 days for neurobehavioral signs and mortality. No mortality occurred during the observation period (10 rats were used). Although these results demonstrated that the LC50 (4 h) is probably higher than 2000 ppm, the Spencer study (1951) was chosen as key study.

 

Dermal route:

The mean LD50-value for acute dermal toxicity of 1,2-dichloroethane after application under occluded conditions to rabbits was 4890 mg/kg bw with a 95 % confidence interval of 4270–5600 mg/kg bw (Mellon Inst. Industr. Research, 1948).

 

Summary:

In particular after inhalation exposure, a steep concentration-response relationship associated with sudden, often unexpected mortality was characteristic for 1,2-dichloroethane toxicity (see Bonnet et al., 1986; Gradiski et al., 1978; Spencer et al., 1951; Mellon Inst. Industr. Research, 1948). For example, among dose groups of SD rats covering just an increment of 400 ppm 1,2-dichloroethane (1300-1700 ppm), mortality increased steeply from about 17 to 75 % (Bonnet et al., 1986), and the incidences of mortality observed in male albino rats were 0/10 animals at 500 mg/kg, 3/10 at 630 mg/kg bw after 1 to 5 days, 5/10 at 795 mg/kg after 1 day and 8/10 at 1000 mg/kg bw after 2 to 3 days. Similar results were seen with rabbits and mice (Mellon Inst. Industr. Research, 1948).

Regardless of the route of administration chosen, signs of toxicity in rats, mice, guinea pigs and rabbits after administration of high doses were characterized by liver damage (fatty degeneration and haemorrhagic necrosis, increased hepatic enzyme activities and reduction of glutathione levels), kidney damage (congestion, haemorrhage, necrosis, interstitial oedema, dilatation of renal tubules, fatty degeneration of the tubular epithelium and hypertrophy of tubular cells) and damage to the lungs (congestion, haemorrhage, oedema, fluid in the pleural and peritoneal space).


Justification for selection of acute toxicity – oral endpoint
In a weight of evidence approach out of 5 studies with conclusive results, the lowest LD50 of 413 mg/kg in mice (Munson, 1982) was chosen for classification/labelling and risk assessment.

Justification for classification or non-classification

According to the lethal doses determined in rodents after oral administration or inhalation exposure, 1,2-dichloroethane has to be classified as follows:

- Oral route:

Xn, R22 (harmful if swallowed) according to Directive 67/548/EEC and acute tox. oral cat. 4 (H302: harmful if swallowed) according to CLP (Regulation 1272/2008/EC)

In a weight of evidence approach out of 5 studies with conclusive results, the lowest LD50 of 413 mg/kg in mice (Munson, 1982) was chosen for classification/labelling and risk assessment.

- Inhalation route:

Xn, R20 (harmful by inhalation) according to Directive 67/548/EEC, and acute tox. inhal. cat. 3 (H331: toxic if inhaled) according to CLP (Regulation 1272/2008/EC).

- Dermal route:

1,2-dichloroethane was uncritical after dermal application, and based on this result the substance is not subject to classification and labelling for acute dermal toxicity according to Directive 67/548/EEC and Regulation 1272/2008/EC.