Registration Dossier

Administrative data

Endpoint:
epidemiological data
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented publication which meets basic scientific principles

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2000
Report Date:
2000

Materials and methods

Study type:
cohort study (retrospective)
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The cohort follow-up began on January 1, 1981, and conntinued until the termination of employment or through the end of the study on December 31, 1998. the analysis employed a Cox proportional hazard model to compare the probability of developing an obstructive pulmonary pattern among the exposed and the unexposed, which used the date of a first abnormal PFT as the estimated time of onset for all "incident cases". The cohiert analysis included only persons who were employed after 1981 and thereby had been monitored since the very beginning of their employment.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Method

Type of population:
occupational
Ethical approval:
confirmed, but no further information available
Details on study design:
The cohort follow-up began on January 1, 1981, and conntinued until the termination of employment or through the end of the study on December 31, 1998. the analysis employed a Cox proportional hazard model to compare the probability of developing an obstructive pulmonary pattern among the exposed and the unexposed, which used the date of a first abnormal PFT as the estimated time of onset for all "incident cases". The cohiert analysis included only persons who were employed after 1981 and thereby had been monitored since the very beginning of their employment. The resluts of the cohort analysis were reported numerically as risk ratios (RR).
The case-control portion of the study involved 2 outcomes of interest:
1. "suspected" cases of pulmonary obstruction
2. upper airway symptoms (rhinitis/sinusitis) or conjunctivitis cases
The study was conducted at an adhesive production facility in Puerto rico. The study population included all men and women employed between 1981 and 1998. All of these persons underwent routine annual (production workers) or biennial (nonproduction workers) physical examinations that included pulmonary function tests (PFTs).
The following data were abstracted:
- Birth date, sex, race
- Dates of visits with the on-site occupational physican - including data on diagnoses and treatments from visits related to any respiratory illnesse s, allergies, or dermatologic conditions.
- Information from a self-administerd questionnaire regarding rashes, allergies, and smoking status. This instrument was first used by the facility i n 1989 as a preemplyment questionnaire, but it was also given to workers employed prior to this period during their closest medical exam.
- Information from each pulmonary function test, including date of PFT; smoking status; Age, weight, and height at the time of the PFT; and FVC (force d vital capacity, the volume of air that can be max. forcefully exhaled), FVC % predicted, FEV1 (forced expiratory volume 1, the volume of air that is fo rcefully exhaled in 1 s), FEV1 % predicted, % FEV1, % FEV1 predicted, FEF25-75% (forced expiratory flow, the average forced expiratory flow during th e mid (25-75%) portion of the FVC), FEF25-75% predicted, PEF (peak expiratory flow rate, the peak flow rate during expiration), and PEF % predicted.
All study participants were initially classified as either "ever exposed" or "unexposed". The "ever exposed" category included all workers who ever emplyed as monomer manufactures, mixers, bottlers/packagers, or waste handlers.

Results and discussion

Results:
The cohort analysis showed that the risk of developing pulmonary obstruction was not higher among workers exposed to cyanoacrylates than among workers who were unexposed. Unfortunately, the small sample size of the cohort study did not allow further stratification of the exposure categories. In contrast, the case-control analysis had a larger sample size and therefore permitted further stratification of exposure. Regardless of the exposure assignment method, the results demonstrated no signs of an association between a person ever having pulmonary obstruction and his exposure to cyanoacrylates.
More details of the results see in the tables below.

Any other information on results incl. tables

Characteristics of he Total Cohort at the End of Follow-Up on December 31, 1998

 

n(%)

Person-years (%)

Outcome distribution

 

 

Suspected casesa

61 (13.6%)

663.0 (15.7%)

Incident casesb

26 (6.1%)

163.7 (3.9%)

Noncases

389 (86.4%)

3548.6 (84.3%)

Exposure distribution

 

 

Unexposed

215 (47.8%)

1912.2 (45.4%)

Ever exposedc

235 (52.2%)

2299.4 (54.6%)

Peak

 

 

High peak (max 1.5 ppm)

44 (18.7%)

706.4 (30.7%)

Low peak (max 0.11 ppm)

191 (81.3%)

1593.0 (69.3%)

Cumulatived

 

 

Low (≤ 17 ppm-d)

79 (33.8%)

378.6 (16.5%)

Moderate (> 17, ≤ 67 ppm-d)

76 (32.4%)

510.5 (22.2%)

High (> 67 ppm-d)

79 (33.8%)

1410.2 (61.3%)

Gender distribution

 

 

Male

309 (68.7%)

3381.7 (80.3%)

Female

141 (31.3%)

829.9 (19.7%)

Smoking status

 

 

Current

70 (15.6%)

728.5 (17.3%)

Never

340 (75.6%)

2955.1 (70.2%)

Former

40 (8.9%)

528.0 (12.5%)

aDefined as persons whose PFTs ever showed an obstructive pattern as reflected in an FEV1/FEV ratio <70%.

bDefined as person whose PFTs were normal initially, but then showed an obstructive pattern (FEV1/FEV ratio <70%).

cDefined as persons ever employed in monomer production, mixing, bottling and packaging, or waste handling.

dOne exposed cohort member was lacking a cumulative exposure score due to missing hire date.

Comparison of Exposed and Unexposed According to Outcome and demographic Characteristics

 

Exposed,

n(%)

Unexposed,

n(%)

Pulmonary obstruction

 

 

Suspected casesa

32 (13.6%)

29 (13.5%)

Incident casesb

11 (4.6%)

15 (7.0%)

Noncases

203 (86.3%)

186 (86.5%)

 

 

 

Rhinitis/conjunctivitis

 

 

Casesc

25 (10.6%)

14 (6.5%)

Noncases

210 (89.4%)

201 93.5%)

 

 

 

Gender distribution

 

 

Male

170 (72.3%)

139 (64.6%)

Female

65 (27.7%)

76 (35.4%)

 

 

 

Age distribution

 

 

<35

50 (21.3%)

58 (27.0%)

35-50

114 (48.5%)

91 (42.3%)

>50

71 (30.2%)

66 (30.7%)

 

 

 

Smoking status

 

 

Current

41 (17.5%)

29 (13.5%)

Never

173 (73.6%)

167 (77.7%)

Former

21 (8.9%)

19 (8.8%)

aDefined as persons whose PFTs ever showed an obstructive pattern as reflected in an FEV1/FEV ratio <70%.

bDefined as person whose PFTs were normal initially, but then showed an obstructive pattern (FEV1/FEV ratio <70%).

cDefined as persons whose routine medical evaluation records ever mentioned any of the following diagnosis: rhinitis, sinusitis, or conjunctivitis.

Cohort Proportional Hazard Modeling Result for Incident Cases

 

 

95 % Confidence interval

Variables

Risk Ratio

Lower Limit

Upper Limit

Exposure to cyanoacrylates

0.66

0.29

1.50

Male

0.51

0.22

1.18

Former smoker

2.05

0.59

7.13

Current smoker

1.27

0.45

3.62

Age (continuous variable)

0.91

0.85

0.96

 

Case-Control Analysis for “suspected” Pulmonary Obstruction Cases

 

 

 

Odds ratio

 

Cases

Noncases

Crude (95% CI)

Adjusteda(95% CI)

Cyanoacrylate exposure

 

 

 

 

Never exposed

29

186

1.00

1.00

Ever exposed

32

203

1.01 (0.59-1.74)

0.99 (0.57-1.75)

Peak exposure

 

 

 

 

Never exposed

29

186

1.00

1.0

High peak (max 1.5 ppm)

6

38

1.01 (0.39-2.61)

0.53 (0.17-1.48)

Low peak (max 0.11 ppm)

26

165

1.01 (0.57-1.79)

1.14 (0.62-2.08)

Cumulative exposure

 

 

 

 

Never exposed

29

187

1.00

1.00

Low (≤ 17 ppm-d)

8

71

0.73 (0.32-1.66)

0.97 (0.39-2.22)

Moderate (> 17, ≤ 67 ppm-d)

10

66

0.98 (0.45-2.12)

0.94 (0.40-2.05)

High (> 67 ppm-d)

14

65

1.39 (0.69-2.79)

1.05 (0.47-2.27)

aAdjusted for age, smoking, gender, and rhinitis/conjunctivitis

Case-Control Analysis of Persons with at least one reported episode of rhinitis/sinusitis or conjunctivitis

 

 

 

Odds ratio

 

Cases

Noncases

Crude (95% CI)

Adjusteda(95% CI)

Cyanoacrylate exposure

 

 

 

 

Never exposed

14

201

1.00

1.00

Ever exposed

25

210

1.71 (0.87-3.36)

1.61 (0.82-3.29)

Peak exposure

 

 

 

 

Never exposed

14

201

1.00

1.0

High peak (max 1.5 ppm)

7

37

2.72 (1.06-6.98)

1.06 (0.32-3.19)

Low peak (max 0.11 ppm)

18

173

1.49 (0.72-3.08)

1.85 (0.86-4.08)

Cumulative exposure

 

 

 

 

Never exposed

14

202

1.00

1.00

Low (≤ 17 ppm-d)

5

74

0.98 (0.34-2.81)

1.32 (0.40-3.74)

Moderate (> 17, ≤ 67 ppm-d)

8

68

1.70 (0.69-4.19)

1.55 (0.58-3.90)

High (> 67 ppm-d)

12

67

2.58 (1.16-5.74)

1.93 (0.74-4.98)

aAdjusted for age, smoking, gender, and rhinitis/conjunctivitis

Applicant's summary and conclusion

Conclusions:
This study failed to detect any evidence that exposure to MCA or ECA may be associated with occupational asthma. these results allow the conclusion that workers routinely exposed to the peak concentrations of at least 1.5ppm/d, (with occasional higher concentrations during accidents or spills) and those exposed to a short-term average concentrations of about 0.5 ppm or less are not at increased risk of developing pulmonary obstrcution compared with those unexpossed to MCA or ECA.
Executive summary:
The association between pulmonary obstruction (e.g., asthma) and occupational exposure to methyl cyanoacrylate (MCA) and ethyl cyanoacrylate (ECA) was examined in an occupational cohort of 450 persons at an adhesive production facility in Puerto Rico. Employee medical records containing information on physical examinations and pulmonary function tests (PFTs), as well as occupational histories, on each employee over a period of about 17 years and industrial hygiene measurements were evaluated. The cohort analysis was based on a Cox proportional hazards model. Workers exposed to ECA or MCA were compared to workers unexposed to these chemicals with respect to their risk of becoming an ''incident case. An ''incident case was defined as any per son whose PFTs were normal at the time of employment, but later demonstrated an obstructive pattern, which was defined as a decline in the ratio of forced expiratory volume exhaled in 1 s to forced vital capacity (FEV /FVC) below 70%. A separate casecontrol analysis was also conducted that compared ''suspected cases, defined as all those whose PFTs ever demonstrated an obstructive pattern (e.g., asthma), to persons whose PFTs remained within normal limits throughout their employment with respect to their past peak and cumulative exposures to cyanoacrylates. All of these analyses showed no evidence that exposure to average short-term concentrations of ECA or MCA of less than 0.5 ppm and occasional daily peak exposures of at least 1.5 ppm (usually 10 min or less), with occasional higher concentrations during spills, were associated with an increased risk of pulmonary obstruction. However, the study suggested that persons occupationally exposed to cyanoacrylates were more likely to have some reversible eye or upper airway irritation than persons who were unexposed.