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Diss Factsheets

Toxicological information

Exposure related observations in humans: other data

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Administrative data

exposure-related observations in humans: other data
Type of information:
experimental study
Adequacy of study:
other information
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference Type:
Methylene dianiline: assessment of exposure and cancer morbidity in power generator workers
Anders Seldén et al
Bibliographic source:
Int Arch Occup Environ Health (1 992) 63:403-408

Materials and methods

Endpoint addressed:
Test guideline
no guideline required
Principles of method if other than guideline:
A study of the cancer morbidity in a cohort of workers with different exposure patterns to MDA was performed. The current MDA exposure was also assessed.
GLP compliance:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:


Ethical approval:
confirmed and informed consent free of coercion received
Details on study design:
Material: The present formula contained about 35 % MDA and 50 % other condensation products of aniline and formaldehyde with dibutyl phtalate ( 15 %) as a solvent. According to the manufacturer, the composition had remained constant over the
course of the study period.
Air samples: The vapour pressure of MDA is only 1 mm Hg at 197 °C, but mixture with epoxy resin leads to an exothermal reaction. In the autumn of 1987, orientation air samples for assessment of MDA levels were obtained during maintenance work with a stator from a nuclear power station generator. Two personal and six stationary samples, out of which three came from the interior of a curing tent for the stator heated to a maximum of 65 °C, were collected. An impinger technique with 0 4 M HCI as adsorbent and an air flow of 11/min was used. The samples were analysed with high pressure liquid chromatography and, in addition to MDA, free aniline was measured.
Urine samples: For the analysis of urinary MDA metabolites (UMDA), eight male coil winders engaged in the work with the stator provided urine samples during 2 days of consecutive exposure. Samples were collected in 500-mL polyethylene bottles and included all urine for each voiding opportunity. A final sample was obtained 2.5 unexposed days later. The total number of samples varied between subjects from 8 to 13. The samples were acidified with 5 mL 6 M HCI and stored at 20 °C until analysis about 1 year later using a method based on capillary gas chromatography and selected ion monitoring. The results were then adjusted for the total urine volume for each subject. During the exposed shifts, independent observers recorded the number of instances of skin contact with epoxy and each change of gloves among the workers involved. Besides nitrile rubber gloves, the workers used cotton overalls covered by a PVC apron.
Dapsone test: In order to elucidate the impact of individual acetylator phenotype on U-MDA levels, seven of the eight workers also agreed to participate in a dapsone test. Three hours after oral intake of 100 mg dapsone, a structural analogue to MDA, serum was collected for determination of the quotient between acetylated and unacetylated dapsone. Slow and fast acetylators were separated by a quotient of 0 30. This part of the study was approved by the research ethics committee of the Orebro Medical Center Hospital.

Exposure assessment:
Details on exposure:
Cohort study: Company records were used to identify a cohort of coil winders believed to be the group of workers most heavily exposed to epoxy. Current employees were recorded by the company, whereas former employees coded as coil winders were identified from pay rolls available from each December since 1969. Employing this approach, the exposure period 1963-1968 was not covered, but the company archives were considered too extensive to justify a complete search. The records contained no information on individual MDA exposure
However, each individual in the cohort was retrospectively classified with regard to the probability of exposure to epoxy by experienced management and union representatives Thus, the cohort was subdivided into three categories: ( 1) exposed, ( 2) possibly exposed, and ( 3) unexposed to epoxy. Epoxy exposure was assumed to have entailed MDA exposure The local trade union confirmed the completeness of the cohort.
Among the 613 individuals in the cohort 595 were employed before 1986 and thus of interest for this report. The personal identification number of each individual, based on a unique ten-digit code, was checked in the national population register and corrected if necessary. From this central register, other local population registers and the company records, information was also obtained on vital status, place of residence, nationality and date of leaving the country. The number of subjects who left Sweden was unusually high ( 8 6 %), reflecting the international background of the cohort: 29 % of the cohort members were citizens of a foreign country. The mean age (standard deviation) in 1985 for resident males was 42.9 ± 11 6 years (n = 482).
Information on the cancer incidence in the cohort was obtained by computerised matching with the national cancer register for the period 1964-1985. Expected numbers of total and bladder cancer, respectively, were calculated by multiplying the number of person years under observation (to death, leaving the country or end of the study period, whichever applied) by age, sex, calendar year, and cause-specific local and regional (both ad hoc) and national incidence rates Standardised incidence ratios (SIR) were derived from the ratio of the observed to the expected number of cases, and the 95 % confidence interval (CI) for the SIR was calculated assuming a Poisson distribution.

Results and discussion

Any other information on results incl. tables

Air samples: The air levels of MDA during work with the stator were very low concordant with the low vapour pressure of MDA at the prevailing temperature range. The highest air level of MDA reached about 0.05 % of a suggested US American threshold limit value of 800 g/m3.The levels of free aniline were also very low, but there was considerable intersample variation in the proportions between MDA and aniline levels, possibly reflecting analytical imprecision at these low concentrations.

Urine samples: Considering the low concentration of MDA in the airand the use of protective clothing, U-MDA in mostworkers was unexpectedly high. After correctionfor the total urine volume, U-MDA levels of more than400 µg/L were recorded in several samples. In the samplestaken 2.5 days after the unexposed work shifts, the concentrationof MDA metabolites had decreased considerably,but it returned to the same levelas immediately before the first exposed shift (approximately 50 µg/L). In six out of the eight workers the levelsin these "pre-exposure" samples were influenced byMDA exposure during the week preceding the samplingperiod. No details were available, however, withregard to this previous exposure.

Neither the recorded instances of skin contact with epoxy nor the acetylator phenotype determined in the dapsone test seemed (by visual inspection) to correlate with the U-MDA excretion profiles of the workers involved.

Cohort study: The numbers of expected cancer cases were almost identical regardless of the population basis used for their calculation. In the male population of the cohort the overall SIR was only 0.52 ( 95 % CI 0.16-1.21) based on five observed cases. A single male bladder cancer case appeared in the unexposed subgroup of coil winders. In the definitely exposed subgroup of 192 male coil winders no single cancer case appeared over the observation period, whereas almost three cases had been expected. Two additional cancer cases were identified, none of them in the urinary bladder, among the 45 female workers, whereas 2.7 cases had been expected from the national rates. The females of the cohort provided only 710 person years of observation and are not further discussed here.

Applicant's summary and conclusion