Registration Dossier

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
not reported.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted in accordance with generally accepted scientific principles, possibly with incomplete reporting or methodological deficiencies, which do not affect the quality of the relevant results.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1952

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Animals were exposed (whole-body) to air borne concentrations (vapour) of the test material for 0.02 to 16 hours. Animals were observed for two to three weeks or until they had fully recovered. Animals were assessed for gross appearance, bodyweight and behaviour. Some of the exposed animals were sacrificed on day 1-2 or at the end of the observation period, sacrificed animals were subject to gross necropsy.
GLP compliance:
no
Remarks:
Pre-dates GLP
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
The material used in the vapor-inhalation studies consisted of three individual samples of a commercial product, all purified by redistillation. The infrared adsorption spectra of these samples indicated a purity of essentially 100%.

Test animals

Species:
other: Rats and Guinea pigs tested.
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
The source and the feeding of the animals used in the vapor experiments and the techniques and the chambers employed in exposing them to ethylene dibromide vapor were essentially the same as those previously described (Spencer et al, 1951).

Spencer, H. C.; Rowe, V. K.; Adams, E. M.; McCollister, D. D., and Irish, D. D. (1951) Vapor Toxicity of Ethylene Dichloride Determined by Experiments on Laboratory Animals, A. M. A. Arch. Indust. Hyg. Vol.4, pp.482-493,

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
not specified
Details on inhalation exposure:
- Animals and Apparattus:
The source and the feeding of the animals used in the vapor experiments and the techniques and the chambers employed in exposing them to ethylene dibromide vapor were essentially the same as those previously described (Spencer et al, 1951).
For the single exposures, all vapor concentrations with animals in the chamber were checked repeatedly from time to time by combustion analyses. Some difficulty was encountered in achieving complete combustion to hydrobromic acid, particularly for the vapor concentrations above 1,600 ppm. Therefore, the nominal values are given for 5,000 and 10,000 ppm. For the lower concentrations, however, the analytical results were within ± 10% of the calculated theoretical values.
Animals that received single exposures 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 recovered from the effects of the exposure as judged by gross appearance,
behavior, and recovery of body weight.

SINGLE EXPOSURES HAVING NO ADVERSE EFFECT
The studies made to determine the nature of the toxic effects caused by the inhalation of ethylene dihromide were extended to permit an estimation of the single exposures of maximum intensity without any evidence of toxic injury. It was found that an increase of the weight of the liver and slight histopathological changes in this organ were the most sensitive criteria for this evaluation. The results of these experiments using groups of 10 female rats each are summarized in Table 5. From these data the line EF, Chart 1, was drawn to represent the most severe single exposures without detectable adverse effect in rats (NOAEL).
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
0.02 - 16 h
Remarks on duration:
See Tables 3-4 for each exposure time.
Concentrations:
Rats: 100, 200, 400, 800, 1000, 3000, 5000 & 10000 ppm
Guinea pigs: 200 & 400 ppm
No. of animals per sex per dose:
Varies from 4-30 depending on dose and time exposed. Generally there were around 20 in each dose group (see Tables 3-4 for details).
Control animals:
no
Details on study design:
- Duration of observation period following administration:
Survivors were observed for two to three weeks, or until it was certain that they had fully recovered from the effects of the exposure as judged by gross appearance, behaviour and recovery of body weight.

- Frequency of observations and weighing:
not reported.

- Necropsy of survivors performed:
no

- Other examinations performed:
behaviour, body weight, time of death
Statistics:
Statistical analysis was conducted according to the method described by Litchfield & Wilcoxon (1949).

Litchfield, J.T.Jr. & Wilcoxon, F. (1949) A Simplified Method of Evaluating Dose-Effect Experiments, J. Pharmacol. & Exper. Therap. Vol. 96, pp. 99-113.

Results and discussion

Preliminary study:
not applicable.
Effect levels
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 200 ppm
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: Equivalent to >1.54 mg/l.
Mortality:
- Mortality of Rats:
The total number of rats (mixed sex groups) used and the number that died from each exposure are listed in Table 3. From the
data at 10,000. 5,000, 1.600. 400, and 200 ppm, the exposures producing 0.01, 50, and 99.99% mortality were determined statistically according
to the method described by Litchfield and Wilcoxon.16 These points were plotted on log-log ordinates, and the lines AB, XY, and CD of Chart 1 were drawn to represent the exposures, on a varying concentration-versus-period-of-exposure basis, which can be expected to produce death in essentially all rats (L.D.99.91l ), in 50% of rats (L.D.5O), and in essentially no rats (L.D.o.o1 ), respectively. The average factors for obtaining 19/20 confidence limits were 1.16 for the L.D.r.o points and 1.67 for the two extremities. The breaks in the lines AB, XY, and CD of Chart 1 at concentrations below 400
ppm are significant. Although data sufficient for statistical analysis were not available, the observed results of exposing 20 rats for 16 hours to 100 ppm ethylene dibromide are included in the chart as confirmatory evidence. All 20 of the rats surviyed this exposure, as did additional groups of 20 rats each that were exposed to 100 ppm for 8.5 and 12.0 hours (Table 3).

- Mortality of Guinea Pigs:
Additional single exposures were made using concentrations of 400 and 200 ppm ethylene dibromide vapor and mixed sex groups of guinea pigs. The results are summarized in Table 4. From these data, guinea pigs appear to be slightly less susceptible to fatal effects than do rats exposed to the same concentrations (Table 3).
Clinical signs:
other: - Nature of Acute Toxic Effects: Ethylene dibromide has but slight anesthetic action at the intensities of exposure employed. However, depression of the central nervous system was observed in the animals exposed to higher concentrations. Deaths resulting
Body weight:
not reported.
Gross pathology:
The examination of special groups of rats killed 16 to 24 hours after receiving single exposures within the range bounded by ABCD, Chart 1, revealed an increase in weight of the lungs, the livers and the kidneys and histopathological chandes of vary ing degree in these organs. The lungs showed congestion, edema, hemorrhages, and inflammation and the kidneys, slightly interstitial congestion and edema, with slight cloudy swelling of the tubular epithelium in some cases.
Other findings:
- Single Exposures Having No Adverse Effect:
The studies made to determine the nature of the toxic effects caused by the inhalation of ethylene dibromide were extended to permit an estimation of the single exposures of maximum intensity without any evidence of toxic injury. It was found that an increase of the weight of the liver and slight histopathological changes in this organ were the most sensitive criteria for this evaluation. The results of these experiments using groups of 10 female rats each atre summarised in Table 5. From these data the line EF, Chart 1, was drawn to represent the most severe single exposures without detectable adverse effect in rats.

Any other information on results incl. tables

Table 3. Mortality of Rats Exposed to Various Concentration of Ethylene Dibromide Vapor for Single Periods.

CH2Br-CH2Br Concentration Period of Exposure (Hr.) Total Number of Rats Number That Died
PPM Mg./L.
10,000 77 0.1 20 20
0.07 10
0.05 4 2
0.03 20 1
0.02 20 0
5,000 38.5 0.14 20 20
0.1 10 9
0.07 15 5
0.05 30 3
0.04 20 0
3,000 23.1 0.2 10 5
0.1 20 0
1,000 12.3 0.5 20 20
0.4 15 12
0.3 15 4
0.2 30 0
800 6.16 0.8 20 13
0.63 20 10
0.5 20 4
0.4 20 4
400 3.08 5 20 20
3 20 17
2.5 20 19
2 25 16
1.4 25 5
1 20 2
0.8 20 1
0.6 20 0
200 1.54 16 20 19
12 20 10
8.5 20 9
7 11 4
5 10 3
4 5 0
3 11 1
2 5 0
1.4 20 0
100 0.77 16 20 0
12 20 0
8.5 20 0

Table 4. Mortality of Guinea Pigs Exposed to Ethylene Dibromide Vapour for Single Periods.

CH2Br-CH2Br Concentration Period of Exposure (Hr.) Total Number of Rats Number That Died
PPM Mg./L.
400 3.08 7 20 20
5 20 18
3 10 5
2 20 0
200 1.54 7 15 0

Table 5. Estimation of Single Periods of Inhalation of Ethylene Dibromide Vapors Having No Adverse Effect in Female Rats.

Vapour Concentration Hours of Exposure
PPM Mg/L Without Adverse Effect With Adverse Effect
800 6.16 0.1 0.15
200 1.54 0.7 1
100 0.77 2.5 4
50 0.38 7 -

Applicant's summary and conclusion

Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The 4 hours LC50 value is considered to be >200 ppm (1.54 mg/l) as there are no deaths among the 5 rats exposed at this conentration. Ethylene dibromide is therefore classified as harmful according to EU criteria.
Executive summary:

Experimental work with rats has shown that the vapors of ethylene dibromide are highly toxic if inhaled.

The hazard from breathing acutely dangerous concentrations of ethylene dibromide vapors probably is not as great as its toxicity might indicate. Vapor concentrations of ethylene dibromide below those which are hazardous to life upon short exposure have a definite and sickening odor. While this property of the vapor may not be sufficiently disagreeable to drive a person out of an acutely dangerous atmosphere, it certainly will warn of the presence of the vapor.

In evaluating the hazards of single exposures for human subjects, the practicing toxicologist or industrial hygienist may find the values represented by the line EF of Chart 1 quite helpful. It is suggested that for such purposes these values be considered as maximal.

The 4 hours LC50 value is considered to be >200 ppm (1.54 mg/l) as there are no deaths among the 5 rats exposed at this conentration. Ethylene dibromide is therefore classified as harmful according to EU C&L.