Registration Dossier

Administrative data

Endpoint:
epidemiological data
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1937 to 1938
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
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. Result of the study conducted on humans shows clear evidence of skin sensitisation in test individuals with repeated exposure.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1938

Materials and methods

Study type:
cohort study (prospective)
Endpoint addressed:
skin irritation / corrosion
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Following accidental exposure of a worker to a sealing fluid in a water level indicator (containing 1,2-dibromoethane) and a subsequent sensitisation reaction, a number of experiments were conducted to determine which component was responsible for the reaction. A preliminary test on guinea pigs was conducted, which proved negative. Testing then progressed to human volunteers to assess the effect of the test material when applied dermally both in acute and repeat exposure experiments. A series of 15 experiments on 9 human volunteers were performed on usin the original fluid and also studying the components individually.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): ethylene dibromide
- Name of test material (as cited in study report): Sealing fluid. According to the company's information, the mixture consists of 55 parts ethylene dibromide (CH2Br ¿ CH2Br); 30 parts tetrachloroethane (CHCl2 • CHCl2); 15 parts paraffin oil; a trace of Sudan Red B. In experiments 1-4 the fluid was obtained from an isolated water level indicator, in experiment 15, a control was conducted by mixing the individual components of the fluid according to the manufacturers reported ratios.

Method

Type of population:
occupational
Ethical approval:
confirmed, but no further information available
Details on study design:
Experiments 1-4 were performed on the original sealing fluid, experiments 5-11 were performed on the other individual components of the sealing fluid, not ethylene dibromide. Experiments 5-11 are described in section “Any other information on materials and methods incl. tables”.

Experiment 1. 1 cm3 of the original sealing fluid was applied to the palm of the hand and rubbed between both hands for approximately 1 minute. After this, residues of the fluid could no longer be seen on the skin. Some of it was absorbed by the skin and some evaporated. Hands were washed 2 hours later with water and soap.

Experiment 2. 1 cm3 of the fluid was rubbed into the skin of the right forearm for 1 minute. Residues of the fluid could then no longer be seen on the skin. Washing after 2 hours.

Experiment 3. 1 cm3 of the fluid was applied to a small sterile lint swab, the swab was placed on the skin of the left forearm, covered with gutta-percha, exposure time 2 hours.

Experiment 4. In order to rule out the possibility (which was suspected by non-specialists) that the boot leather could somehow affect the substance, a control experiment was also carried out as follows: A palm-sized piece of woollen sock was placed on the skin of a test subject and covered with a corresponding piece of old boot leather. 1 cm3 of fluid was dripped slowly onto the leather; after 1 1/2 minutes it had completely soaked in. Exposure time 2 hours.

Experiment 12. 1/2 cm3 ethylene dibromide was rubbed completely into the skin of the forearm for 1 minute, washing with water and soap after 1/2 hour.

Experiment 13. 1/2 cm3 ethylene dibromide was applied for exposure for 10 minutes with the aid of a swab and covering, then removal of the swab and washing with water and soap.

Experiment 14. 1/2 cm3 ethylene dibromide was applied for exposure for 1/2 hour with the aid of swab and covering, then washing with water and soap.

Experiment 15. Control experiment: The remote water level fluid was mixed using the different individual constituents in the above-described ratio. 1 cm3 of this was applied to the skin with the aid of swab and covering, exposure time 1 hour.
Exposure assessment:
measured
Details on exposure:
TYPE OF EXPOSURE:
Dermal, see details on study design for exposure specific to each experiment.

TYPE OF EXPOSURE MEASUREMENT:
Gross visual inspection and questioning of the test individual.

EXPOSURE LEVELS:
See details on study design.

EXPOSURE PERIOD:
See details on study design.

POST EXPOSURE PERIOD:
See details on study design.

DESCRIPTION / DELINEATION OF EXPOSURE GROUPS / CATEGORIES:
See details on study design.
Statistical methods:
No statistical method was used.

Results and discussion

Results:
All referenced figures are included in the attached pdf document. Experiments 5-11 were not performed on ethylene dibromide and are presented as a comparison to rule out their participation in the effects noted in the original sealing fluid.

Experiment 1. None of the test subjects exhibited any symptoms on the day of the experiment or later on.

Experiment 2. The test subjects had no symptoms at all, either directly after the treatment or later.

Experiment 3. After a few minutes, all persons reported a feeling of heat under the swab, some of them a pronounced burning of the skin. After the 2 hours of exposure, a varying level of (mild or severe) reddening of the skin of the size of the swab consistently appeared, in one case pinhead-sized peripheral blisters were recorded. In the 12 hours following, severe burning pain began, and small blisters developed which soon after merged into one big one.

Fig. 1 shows such a blister 19 hours after exposure. The contents of the blister were initially clear, amber-yellow and thick, but showed a pronounced tendency to coagulate as a result of its high protein content. The area surrounding the directly affected area was more or less swollen in an oedematous manner, in one case the swelling extended from the fingertips to the upper arm. An involvement of the lymph glands was only observed in one case; in this case the lymph glands of the armpit were moderately swollen and painful.

Treatment and course. In half of the test subjects, the blister was pierced, with the raised skin being retained, and the fluid was drained (10 - 15 cm3). Within a few (3 - 5) hours the blister had refilled and had to be drained again. This extraordinarily severe discharge lasted for a long time and only gradually came to a stop after 5 - 7 days. During this time the injury was provided with a sterile covering. In the other half of the test subjects, the blister was completely removed, the intensely red wound surface wept an extraordinary amount in this case too. The dressings had to be changed every 2 - 3 hours initially. The wound dried out after 4 - 5 days. After the acute state had abated, cod liver oil ointment dressings were used in each case. The skin grew over completely after 13 - 17 days, leaving behind a superficial scar which is still clearly visible after 4 months. A more or less severe feeling of illness existed in all persons for the first few days. There were no secondary infections. The one case of swollen glands mentioned eased after 2 days. In 2 test subjects, a very unpleasant dermatitis (severe swelling and reddening of the skin with intense itching) remained on the treated area of skin for some weeks, which was unaffected by powder, ointment and moist dressings and only finally healed after a zinc/sulphur shaking mixture was used.

Prescription.
Precipitated sulphur 10.0g
Zinc oxide 40.0g
Talcum 40.0g
Glycerol 55.0g
Distilled water 55.0g

Experiment 4. In order to rule out the possibility (which was suspected by non-specialists) that the boot leather could somehow affect the substance, a control experiment was also carried out as follows: A palm-sized piece of woollen sock was placed on the skin of a test subject and covered with a corresponding piece of old boot leather. 1 cm3 of fluid was dripped slowly onto the leather; after 1 ½ minutes it had completely soaked in. Exposure time 2 hours, result as in Experiment 3, only to a reduced extent; only a few smaller blisters appeared, which healed completely in 9 days with the treatment described.

- Chemical tests:

Although the hypothesis that the leather caused a decisive change in the fluid was disproved by the described experiments, especially by Experiment 4, another chemical test was carried out in this respect at the Chemisch-Physikalischen Versuchsanstalt der Marine (Navy Research Institute for Chemistry and Physics). The tests carried out there gave no indication of a chemical change in the fluid after contact with leather (for example by tannic acid or old boot grease).

- Chemical analysis:

There was no indication of a chemical change in the fluid after contact with leather (for example by tannic acid or old boot grease).

Experiments 5 -11:

Experiment 5: As expected, no symptoms in any of the test subjects at any time.

Experiment 6: Except for a slight reddening of the skin, which disappeared after a few days, no symptoms.

Experiment 7 and 8: No symptoms occurred.

Experiment 9: Except for a slight feeling of heat while rubbing in, no subjective or objective symptoms.

Experiment 10: During the exposure a slight feeling of heat, no other symptoms or after-effects at all.

Experiment 11: No symptoms at all either during the exposure or later.

Experiment 12. Within 24 hours, all participants exhibited swelling and reddening of varying severity as well as itching of the treated area of skin. The symptoms abated completely after 2 - 3 days without treatment.

Experiment 13. Within 24 hours, painful reddening and swelling of the skin developed, which in some cases was considerable and of a strangely mushy appearance. Blister formation did not occur in any case (see Fig. 2).

The injuries healed completely in 3 - 5 days, in some cases without treatment, in some cases with zinc/sulphur shaking mixture.

Experiment 14. During the exposure the usual feeling of heat or burning. After the exposure a very painful inflammation of the skin occurred within 15 - 20 hours, with reddening, swelling and blister formation of varying severity (see Fig. 3 and 4).

Healing without complications following treatment with removal of the larger blisters, sterile dressings until drying out, finally cod liver oil ointment. The skin grew back completely after a total of 7 - 13 days.

One case produced unusual results in this experiment and is therefore discussed separately below: One test subject (the author himself) felt severe burning pain in the skin immediately after applying the swab, this increased rapidly in such a manner that the swab had to be removed after 3 minutes. The pain and the initially present reddening of the skin soon decreased slightly, then increased again after a few hours, until the formation of a blister the size of a small apple occurred after a total of 18 hours (see Fig. 5 and 6).

This blister formation was associated with very severe pain. When the blister was lanced, 21 cm3 of clear, amber-yellow fluid drained out, which coagulated rapidly after drainage.

After the fluid was drained the pain increased so that it was initially decided not to remove the blister.

The blister soon refilled after the incision was blocked by coagulation (see Fig. 6) and was only drained again when the tension became too great. In total, 245 cm3 of secretion was collected in this manner within the first 3 days (it being necessary to disregard the amounts which for example seeped into the dressing overnight); then the blister was removed, as the pain had in the meantime decreased a great deal and the secretion was much less.

Another unusual observation was made. When the blister appeared (on the right arm), a severe dermatitis with reddening, swelling and itching developed in all areas of the right and left arm which had come into contact with the original fluid or the ethylene dibromide over the past months. Furthermore, a moderately severe, painful swelling of the glands in the left armpit occurred.

Whereas on the first day of the illness a slight oedema was only present in the immediate surroundings of the blister, on the second day of illness an extensive oedema of the entire right forearm and hand developed suddenly in the afternoon. The oedema developed so quickly that the wedding ring could only be pulled off with difficulty (see Fig. 7).

In the first few days, there was a pronounced feeling of illness with a slight increase in temperature (up to 38.3° measured rectally). After 8 days of treatment with immobilisation and sterile dressings the wound dried out, skin grew over completely after a total of 17 days with cod liver oil ointment, leaving behind a superficial, unpleasant scar.

Experiment 15. Reddening, swelling and blister formation as in Experiment 3 (see Fig. 8).

An acute over-sensitivity was observed in experiment 13, possibly acquired because of the previous 13 experiments. The author himself was the test subject and was the only one to have participated in all the experiments without exception, whereas all the others had been absent to a greater or lesser extent (for external reasons). The author was therefore more severely injured than the other test subjects owing to the particular frequency of the injuries experienced.

RESULT OF CASE REPORT:
The worker accidently exposed to the fluid had spilled some of the sealing fluid from the device onto both of his navy boots. He did not pay any attention to this situation, as on the fluid is labelled harmless by the manufacturer, and people had already often touched it with their bare hands without suffering any injury. During the following night burning pain started in both feet, particularly the left. The ship’s doctor recorded the findings of the case.
The patient was reported to have:
"Normal temperature. Normal general condition. The entire instep of the left foot and the spaces between the toes are reddened, the skin is raised in a blistered manner between the proximal phalanx of the first and second toes and further proximally; the blisters do not contain any fluid in the manner of a burn blister, they consist of a mushy mass. The instep of the right foot is only slightly affected; there is only a mushy-feeling blister above the proximal phalanx of the first toe. The inflamed skin is very sensitive to pressure; vascular disorders and neurogenic injury cannot be found."

Treatment was carried using a Volkmann's splint, boric ointment and cod liver oil ointment dressings and soap baths; for the pain Eukodal was administrated initially, later Veramon. With good healing, skin had grown completely over the injured areas after 14 days.
Inspection of the navy boots did not produce anything of interest. The leather was apparently unaffected by the fluid.
Confounding factors:
No specific test confounding factors were reported in the test, however it is possible that due to methodological deficiencies such as the application of aneasthetic to some test individuals that not all results were reported.
Strengths and weaknesses:
Due to the results observed dermal irritation is considered to be clearly indicated. The age and depth of reporting are considered to be less than optimal, however are sufficient for assessment of the reliability of the study.

Applicant's summary and conclusion

Conclusions:
Irritation and blisters were observed in almost all cases where the registered substance was applied dermally to humans. This is considered to be evidence of irritation via the dermal route.
Executive summary:

Following a skin injury to a worker caused by the fluid from a remote water level indicator, systematic tests were carried out on human skin with this fluid. The said fluid, a mixture of ethylene dibromide, tetrachloroethane, paraffin oil and a trace of Sudan Red B, is to be considered harmless if uncovered areas of skin are sprayed with it, according to the present studies. If, however, items of clothing which are soaked in the fluid come into contact with the skin, then very severe local irritation symptoms, severe inflammation and blister formation are always observed with a sufficiently long exposure time. The type of clothing does not matter, it is the same whether it consists of leather, wool or cotton fabric. It was found that only the ethylene dibromide contained in the fluid must be made responsible for the skin damage, whereas the other constituents are without skin-irritating properties under the present experimental conditions. While the skin damage was observed in all test subjects with application on items of clothing, severe general damage of a resorptive nature was triggered in one test subject. In this case violent general symptoms of illness developed only 3 minutes after exposure, after 14 experiments had been carried out on the skin many days previously; there must therefore have been an acquired over-sensitivity in this case.