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epidemiological data
Type of information:
experimental study
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions

Data source

Reference Type:
Effect of Occupational Exposure to Cyanuric Chloride on Respiratory Morbidity Cross-Sectional Analyses of Respiratory Symptoms and Longitudinal Analyses of Lung Function Parameters
Morfeld and Yong
Bibliographic source:
Journal of Occupational and Environmental Medicine, (JAN 2019) Vol. 61, No. 1, pp. E1-E11

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:


Type of population:
Details on study design:
This study was designed as a retrospective cohort study including all active and former employees of three cyanuric chloride plants. Medical data and job activity profiles for the study subjects, as well as exposure data from the beginning of the production to the end of the study in 2007 were recorded.

Study population:
Employees from three cyanuric chloride production sites. 394 male employees who were employed at least 12 months in one of the cyanuric chloride production sites were included in the study. The follow-up of the study ended in 2007. While the final medical examinations were performed in early 2008.

During the occupational career, a continuous health surveillance program, including physical examination, lung function tests were provided to identify impairment of lung function. The following response variables for measuring lung function were selected for the study: Vmax, FVC, VC, FEV1, FEV1%VC

COPD stages Ia and IIa as well as further diseases such as asthma, shortness of breath, chronic bronchitis, and other COPD stages were studied as categorized dependent variables in cross-sectional analyses.
Exposure assessment:
Details on exposure:
TYPE OF EXPOSURE: respiratory exposure (gaseous and dusty Cyanuric chloride)

Exposure Assessment: Four job categories, ten measuring places, and six job activities (with or without wearing mask) were standardized across the study sites. The level of cyanuric chloride exposure at all three sites depends on the areas, time, and activity. Working areas are divided into mask obligatory and those not. The employees were exposed to cyanuric chloride only for a given period.
Statistical methods:
In cross-sectional analyses, linear regression models were used for continuous dependent variables, and logistic regression models for categorized variables. In longitudinal analyses, generalized estimation equation (GEE) was used to account the longitudinal changes of lung function. GEE model takes the correlation of the repeated intraindividual measurements into account. Also used second-degree fractional polynomials to analyze the progression of age with best model fitting,14 for the purpose to exclude a distortion of estimate of cyanuric chloride exposure in the previous non-linear regression models.

Results and discussion

From a cross-sectional perspective, the average lung function parameters of the study group were unexceptional; minor respiratory symptoms and diseases were reported to a limited extent; respectively 9.46% of COPD-Stage Ia and 4.60% of COPD-Stage IIa was found in the crosssectional analysis. None of the manifest COPD (higher stages pathological findings) was reported in all study participant.

The single model analysis (linear and logistic regression models without interaction terms for the central exposure variants and all endpoints of interest) revealed no effect with regard to symptoms or diseases such as the later stages of COPD. We found some hints of sensitization
due to cyanuric chloride by means of increased specific IgE values, especially for the open space facility in Münchmünster, but without evidence of respiratory sensitization.
The multi-model approach yielded no apparently negative impact of cyanuric chloride exposure was observed, while there was a potentially unfavorable effect on the lung function parameters VCmax and FEV1.
With the existing mid-range exposure to cyanuric chloride and the current way of handling cyanuric chloride exposures in Wesseling—even with extrapolation to 40 years—the lung function losses of -8% (estimate of maximum loss) and -3% (estimate of average loss) were tolerable in comparison with the age-related regression.
The detailed analysis, in which we selected and calculated single models, determined threshold values and a derived OEL (typical = characteristic for the results of the multi-model analysis), revealed that the decline of lung function with current mid-range exposure to cyanuric chloride
in Wesseling can be considered unexceptional. By means of hockey-stick models, we determined a long-term threshold for the cumulative exposure to cyanuric chloride at approximately 0.3 mg/m3·years. Provided this long-term threshold, an average exposure duration of 11.2 years, and a tolerable additional 10% decline of lung function due to aging, as well as conversion of long-term values to a time-weighted average (TWA) of 8-h shift with a factor of 2, we recommend a shift reference value of 0.06 mg/m3.

As a central result of this study, therefore, we can recommend an occupational exposure threshold (TWA 8h, “time weighted average” 8h) of 0.06 mg/m3 as a maximum shift value for cyanuric chloride.
Confounding factors:
Potential confounding factors, such as age, body height, weight, different plants, different lung function measuring devices, smoking status, rotation patterns, and duration of prior exposure to chemicals are adjusted for.
Strengths and weaknesses:
some of the medical responses were only available in a cross-section; extending the follow-up of the study would be valuable

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. A shift reference value (time-weighted average, 8 hours) of 0.06 mg/m³ was derived.
Executive summary:

A sensitisation to cyanuric chloride, without an effect on lung function, has been observed. For the total cohort, both the single models and the multimodel analyses provided hints of lung function loss resulting from long-term exposure to cyanuric chloride. With respect to the estimated average loss from a represenative model, cumulative exposure of 0.3 mg/m³-years yielded the best model fit. A shift reference value (time-weighted average, 8 hours) of 0.06 mg/m³ could be derived.