Registration Dossier

Administrative data

Endpoint:
health surveillance data
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
Not specified
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Taken from publically available data, and is considered accurate based on the registrants experience of the substance.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1986

Materials and methods

Study type:
medical screening
Endpoint addressed:
other: General health effects
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
See "details on study design" listed below.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
not specified
Details on test material:
Not specified

Method

Type of population:
occupational
Ethical approval:
confirmed, but no further information available
Details on study design:
STUDY SUBJECTS: A group of 29 white, male refrigeration repair workers were identified for inclusion in the study. Twenty four were employed at the time of the study in the company for whom the referral case had worked. Five other refrigeration repair workers who had been part of the preliminary study in 1979 were also included. Of this group of 29, 27 participated, including eight from the original study. Of the original ten, one had moved out of state whereas one other refused to participate but was still employed as a refrigeration worker and apparently healthy. The referral case was also examined and his results are presented separately.
A reference group was selected to compare results of the medical questionnaire and the electroneurophysiological studies. The reference subjects were selected from one of two local unions of plumbers and pipe fitters or insulation workers. Potential reference subjects were randomly selected from five year age groups to match the age distribution of the study subjects. Potential reference subjects were excluded if they had prior neurological impairment, a history of low back injury, or if they had been exposed to fluorocarbons within the previous 12 months. A total of 32 white, male, non-refrigeration repair workers were contacted. Seven declined to participate, six had a history of prior back injury, sciatic neuropathy, or other neurological problems, and three had worked in the refrigeration trade within the past 12 months. This left 16 potential unexposed subjects of whom 14 participated. This number of reference subjects resulted in an 80% power to detect a difference of 3 metres per second in nerve conduction velocities with alpha set at 5% for a two tailed t test.
MEDICAL LABORATORY TESTING: Medical history, physical examinations, and testing were performed by physicians at the University of Utah Medical Center at least 16 hours after the last work exposure. A questionnaire was administered to determine the presence of symptoms related to the neurological, cardiovascular, and respiratory systems. Chronological occupational histories and information on alcohol consumption were obtained from each study subject. Respiratory function was assessed with the forced vital capacity manoeuvre. The forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were obtained according to the American Thoracic Society standards using an Ohio-Med 822 rolling dry seal spirometer and a Spirotech microprocessor. The forced expiratory manoeuvre was repeated until at least two tests were within 5% of each other and within 5% of the best test-that is, at least three acceptable tests. All the results were corrected to standard pressure and body temperature. The best FVC and FEV, were used for interpretation and the results were evaluated as a percentage of predicted normals as measured by Knudson et al. Chest radiographs and standard 12-lead electrocardiograms at rest were obtained. Blood was analysed for complete blood counts with differential, albumin, total protein, glucose, calcium, phosphorus, uric acid, urea nitrogen, creatinine, lactic dehydrogenase, alkaline phosphatase, serum aspartate and alanine aminotransferase, bilirubin, triglycerides, cholesterol, electrolytes, and zinc protoporphyrin. Routine urine analysis was performed. Reference subjects received an identical evaluation and tests except for pulmonary function tests, electrocardiograms, and chest radiographs.
ELECTRONEUROPHYSIOLOGICAL TESTING: Nerve conduction speeds were determined at room temperature on a TE 42 Electromyograph using surface electrodes on all study and reference subjects. The following nerves were tested bilaterally using supramaximal stimuli: ulnar motor, ulnar sensory, median motor, median sensory, tibial, peroneal, and sural. All nerve conduction velocities were measured orthodromically, except the sural nerve, which was measured antidromically. Distal latencies were measured on the median and ulnar motor, peroneal, and tibial nerves. Sensory action potentials were measured for the ulnar sensory, median sensory, and sural nerves. Skin temperature was greater than 30°C at the site of recording for all tests.

Results and discussion

Results:
STUDY FINDINGS: Among the 27 refrigeration repair workers studied, no additional cases of peripheral neuropathy were identified and the chest radiographs, pulmonary function tests, electrocardiograms, and blood and urine test results were all within normal limits.
The mean age of the 27 refrigeration repair workers was 32 and of the 14 reference subjects, 35. The mean number of symptoms (out of 34) among the exposed was 5•8 compared with 4•1 in the reference group. There were similar numbers of drinkers, ex-drinkers, and non-drinkers of alcohol in the two groups.
Lightheadedness was reported by 18 workers (67%); tiring easily by 12 (44%); and breathing trouble, headaches, and pressure in the chest were each reported by nine workers (33%). Seven workers (26%) reported palpitations, numbness in fingers, irritability, or trouble remembering. Perspiring easily and eye irritation were each reported by six workers (22%). Two symptoms, lightheadedness and palpitations, were reported significantly more often by the refrigeration repair workers. Twelve of the 18 workers reporting lightheadedness named fluorocarbons as the cause and four of nine experiencing trouble breathing named soldering or welding. Other reported symptoms were not so closely associated with particular workplace exposures.
The mean nerve conduction velocities of the refrigeration repair workers were standardised to the age distribution of the reference group. The refrigeration repair workers had mean nerve conduction velocities essentially the same as the unexposed reference group for all nerves studied. Sural nerve conduction velocities for both groups were, on average, at the lower limits of normal. Sensory action potentials of the ulnar and median sensory and the sural nerves were normal, as were distal latencies of the tibial, peroneal, median motor, and ulnar motor nerves.
The average nerve conduction velocities for the ulnar and median sensory nerves increased during this period. No change in working conditions could account for this increase and the differences were not large by comparison with the measurement variability.

Any other information on results incl. tables

CASE REPORT: The referral case was a 33 year old white man who entered the refrigeration repair trade in 1971. In 1976 he began to notice loss ofweight, difficulty in concentration, depression, and weakness. In the summer of 1978, while repairing a leak in a refrigeration system, the pipe broke releasing fluorocarbons into the workarea. He became nauseated, vomited, and complained of generalised weakness and abdominal cramps. He left work and remained off work for several weeks. In July1978 his nerve conduction velocities in his left leg were as follows: peroneal nerve, 40m/sec (normal > 40m/sec); tibial nerve, 23m/sec (normal > 35m/sec); and sural nerve 21m/sec (normal > 37 .5 m/sec).

InOctober 1978 hewasadmittedtohospitalfor further evaluation of his distalaxonopathy.Onphysical examination decreasedvibratoryandpositionsensesin the toes werenoted;touch sensationwasintact. His musclestrength, bulk,and tone were normal. Deep tendon reflexes weremildlydecreasedinthebicepsandtriceps bilaterally.Theremainder ofthe examinationgavenormal results.Laboratoryevaluation showednoabnormalities inalbumin,liverenzymes,bilirubin,glucosetolerance,vitaminB12,folate,sedimentation rate, urine analysis,cerebrospinal fluid, chestradiograph,orthyroid function. Serologicaltestresults forrheumatoid arthritis andsyphiliswerenegative.Urinarylead andmercuryconcentrationswerewell below theaccepted normallevel.The aetiology for his distal axonopathycouldnotbedetermined,butthehistorysuggestedapossiblelinkwithexposureatwork. Hereturnedtorefrigeration repair work for11monthsandwasre-examined in1981 with the other refrigeration repairworkers in thisstudy.Atthat timehisphysicalconditionwasunchanged,with persistentsensorydeficits in the feetand hands. Thenerveconduction velocities hadconsiderablyimproved: left peronealnerve,46.5m/sec; left tibialnerve45.6m/sec;and left suralnerve,34.9 m/sec.

Applicant's summary and conclusion

Conclusions:
The report concludes that at general exposure levels in the refrigeration repair trade fluorocarbons CFC-12 does not impair the peripheral nervous system. This can be extrapolated to general exposures; however due to the removal of CFC-12 from general use in accordance with the Montreal Protocol, significant exposure can be precluded.
Executive summary:

This study is reported as supporting information only to present the results of an assessment on humans from the use of CFC-12 as a refrigerant material. It should be noted that because of their environmental impact, it was decided in the Montreal Protocol that CFC’s such as CFC-12 will be replaced.  As such, exposure to CFC-12 as a refrigerant material is no longer applicable.

Use of the substance for the registrants application is covered by a derogation to Regulation (EC) No 2037/2000 in accordance with Regulation (EC) No 1005/2009 that allows for use of the substance as a processing agent.  As such, there is no exposure. However, the data presented here is considered useful in the context of supporting confirmation that the substance is not harmful to humans following exposure. The experimental details are as follows.

This cross sectional study showed a significant increase in lightheadedness and palpitations in refrigeration repair workers intermittently exposed to fluorocarbons compared with a reference group of unexposed workers. No objective evidence of peripheral nerve dysfunction was found in the refrigeration repair workers and no decrement in nerve conduction velocities was found in eight refrigeration repair workers followed up over three years of continuous employment. 

Azar et al exposed volunteers to 10000ppm FC12 for 2.5 hours and found no untoward reactions or cardiac arrhythmias. Stewart et al exposed volunteers to 1000ppm FC12 for eight hours a day, five days a week, for four weeks. No untoward effects, electroencephalographical abnormalities, or cardiac arrhythmias were shown.

 

Lightheadedness and palpitations are difficult symptoms to evaluate, as they are often found in people with no underlying pathology. On the other hand, these symptoms are frequently associated with various cardiac arrhythmias including ventricular tachycardia. Lightheadedness may also represent a direct effect on the central nervous system.In the light of our findings and those of Speizer et al further evaluation of these symptoms in refrigeration repair workers using continuous ambulatory electrocardiographic monitoring appears to be indicated.

 

No association was found between refrigeration repair work and peripheral neuropathy. Some potential sources of bias may contribute towards finding no association between exposure and disease inoccupational studies. One important potential source of bias is the "healthy worker effect." The study discounts this effect in three ways.

 

Firstly, early in the course of distalaxonopathy an individual may experience few or no symptoms and it would, therefore, be an unlikely cause for that individual to leave his place of employment.

 

Secondly, a reference group of workers was used to compare results of electroneurophysiological testing, rather than the general population norms.

 

Finally, eight workers were followed up for three years and were found to have no deterioration in their electroneurophysiological tests.

 

The level of exposure to fluorocarbon experienced by the group of refrigeration repair workers in the study appears to be low. Repairs of large leaks is no longer anticipated following the banning of the substance in general refrigerant uses. The report concludes that at general exposure levels in the refrigeration repair trade fluorocarbons CFC-12 does not impair the peripheral nervous system.