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epidemiological data
Type of information:
experimental study
Adequacy of study:
key study
1 (reliable without restriction)

Data source

Reference Type:
study report
Report date:

Materials and methods

Study type:
cohort study (retrospective)
Endpoint addressed:
repeated dose toxicity: inhalation
other: human long term systemic and local inhalation toxicity
Test guideline
no guideline available
GLP compliance:

Test material

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


Details on study design:
HYPOTHESIS TESTED (if cohort or case control study):

- Type: Job history data, Exposure data, Medical history data
- Details:
Job history data:
The activity profile for the study participants comprised the beginning and end of an activity with the corresponding beginning and ending date, the type of activity and the plant in which the activity was performed. Any existing prior exposure of the study participants, e.g. work in the chemical industry, was recorded.
Exposure data:
All available concentration measurements were collected. A total of 188 usable measurement values were available for modeling the measurement data for three production sites.
Measurements from areas without RPE-requirements and above the detection limit: n=67;
Measurements from areas with RPE-requirements and where values behind the mask of 0.003 mg/m³ was used: n=64;
Measurements from areas without RPE-requirements and below the detection limit: n=57.

Medical History data:
The main response of this study was lung function. Data on lung function, age, smoking behavior, country of origin, and basic biometric data such as body weight and height were recorded. Several study participants received a blood test in addition to another lung function test to determine sensitization parameters.

The data was collected in three sites of Evonik cyanuric chloride prodution facilities. In the first site the recruitment period for the former male employees of this site was limited to the period from 1974 to 2007. In the second site, production ran from 1977 to 2009. In the third site, cyanuric chloride was produced from 1970 until the end of 2007. The study group includes study participants, who where active at one of the three sites until the end of 2007, and historical study participants, who had been active in the past at one of the three cyanuric chloride sites but where no longer active at the start of the study. The follow-up of the participants ran to the end of 2007.

STUDY PERIOD: 1958 to 2007

- Total no. of subjects: 394 male employees (221 active and 173 historical study participants)
- Selection criteria: only male participants, working period in cyanuric chloride production facilities: at least 12 month
- Sex/age/race: male/ average age: 47.5 /predominant causasian
- Smoker/nonsmoker: 160 active smoker, 78 ex-smoker, 149 non-smoker

Lung function parameter: FEV1, VC or FVC, FEV1%FVC
Sensitization parameters: specific IGE value, total IGE value
Exposure assessment:
Details on exposure:
TYPE OF EXPOSURE: respiratory exposure (gaseous and dusty Cyanuric chloride)

TYPE OF EXPOSURE MEASUREMENT: Area air sampling and Personal sampling

EXPOSURE LEVELS: personal average concentration: 0.019 mg/m³ (min=0.003, max= 0.044) by mean over all years, cumulative total exposure by mean: 0.20 mg/m³(min=0.005, max=0.941); mean Cyanuric chloride concentration per exposure year: 0.020 mg/m³ (min=0.003, max= 0.051)

EXPOSURE PERIOD: duration of exposure by mean: 11.3 years (min=0.58, max=34)

forming similar exposure groups (SEGs) by definition of:
four job categories, ten measurement locations, and six activity profiles. Also taking into account the use of protective masks.
Statistical methods:
Refer to any other information on materials and methods inc. tables below.

Results and discussion

A mean cumulative total Cyanuric chloride exposure of 0.2 mg/m³-year could be determined. Lung diseases were not relevant to the study. Only a certain sensitization to Cyanuric chloride, without an effect on lung funtion values, could be proven. The individual model analysis revealed no effect with regard to symptoms or diseases such as the later stages of chronic obstructive pulmonary disease (COPD). Some evidence of sensitization through Cyanuric chloride in the sense of increase specific IGE values, but without proof of respiratory sensitization (allergization of respiratory passages) were found.
The multi-model approach (sensitivity analyses for linear regression models for FEV1 and VCmax, as well as all exposure variants, allowing for interaction cross-sectionally and longitudinally, meta-analytical approach with precicion-weighted summary estimates from the multi-model approach) yielded a wide variability of findings with infrequent significance. No clear effect of cyanuric chloride exposure, but a possible negative effect in the central lung function parameters VCmax and FEV1, were able to prove. The lung function parameters, therefore, proved to be the most sensitive end points.

The detailed analysis, which were calculated with typical individual models, revealed that the lung function losses with current mid-range exposure to cyanuric chloride were harmless in the remaining manufacturing site. However, according to Hockey-Stick-models a long term treshold of 0.3 mg/m³-year was calculated for the cumulative Cyanuric chloride exposition. Taking into consideration mean exposure period of 11.2 years, a tolarable additional loss of lung function of 10% of the age typical loss and a factor of two for the conversion of long term values into an occupational exposure limit a TWA (time weighted average, 8h) of 0.06 mg/m³ was calculated.
Confounding factors:
Confounding from concomitant other exposure like rotation among various other chemicals production units at the site and any existing prior exposure were taking into account to determine the health impact of long-term exposure to Cyanuric chloride on the lung function. These potential confounders revealed no important impact on the lung.
Strengths and weaknesses:
- lack of sufficient case numbers.
- The follow up period of the acitve study population was to short.

Applicant's summary and conclusion

The study comprises the worldwide most extensive data base regarding the effect of long term Cyanuric chloride exposure for human health. In relation to external pulmonary reference values the results indicated no abnormalities of lung function parameters. When considering models with maximum estimates of pulmonary function loss, a long-term treshold value for cumulative exposure could be identified.

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