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Exposure related observations in humans: other data

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Endpoint:
exposure-related observations in humans: other data
Type of information:
experimental study
Adequacy of study:
other information
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Test procedure in accordance with generally accepted scientific standards and described in sufficient details

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2008

Materials and methods

Type of study / information:
Exposure chamber study of possible chemosensory effects of e-caprolactam in the low concentration range relevant to indoor environmental conditions.
Endpoint addressed:
respiratory irritation
Principles of method if other than guideline:
Twenty healthy subjects (10 male, 10 female) aged from 21 to 38 years were exposed for 6 h, respectively, to 0, 0.15, 0.5 and 5 mg/m3 e-caprolactam (CAP) vapors in a randomized and double-blind method. As a measure of trigeminal stimulation of the eye, blink frequency was video-recorded four times per day and evaluated by using a new semi-automatic, computer-assisted method compared to baseline recording and manual counting. Digital slit lamp photographs were taken at the same time to examine conjunctival hyperaemia. A standardized ophthalmologic grading scale was used to measure redness of the eyes objectively. Active anterior rhinomanometry compared nasal resistance before and after exposure. Subjective ratings of discomfort and mental orientation were assessed using the German version of the Swedish Performance Evaluation system (SPES). As a measure of personality traits, positive and negative affectivity was determined (PANAS).

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): e-Caprolactam

Method

Details on study design:
- The study was conducted, taking into account the Declaration of Helsinki (2000 version). It was authorized by the local Institutional Review Board (IRB) of the Medical Faculty of Heidelberg.
- Volunteer cohort: On the basis of pre-selection by telephone and subsequent preliminary examinations, 10 healthy women and 10 healthy men between 21 and 38 years were selected.
-Exclusion criteria: possible allergic disposition and acute infection, acute or chronic disorders of the skin, the upper respiratory tract, the lungs and the heart, known contact with caprolactam in the past and smokers.
- an ECG was recorded before and immediately after each exposure week and the laboratory chemistry parameters creatinine, GOT. GPT, gamma-GT activities and the blood count were determined.
- The examinations were carried out on four consecutive days in an exposure chamber (30 m2). The exposure time was 6 h plus 15 min preliminary and follow-up examinations in each case.
- During exposure, a standardized examination program included slit lamp photo documentation of the bulbar conjunctiva, measurement of the blink frequency and questionnaires at the beginning of exposure and after 1, 3 and 6 h (four times per day).
- The individual concentration levels of 0, 0.15, 0.5 and 5 mg/m3 (German MAK value) were adjusted in a randomized sequence.
A double-blind design was selected for the study, i.e. neither the investigator nor the volunteers were aware of the exposure level on each specific day.
- The environment variables, i.e. temperature and humidity, were measured and documented every 50 min with a thermohygrometer (Bioblock scientific, model 93353). Air turnover in the chamber was constant, using an air conditioner. It was possible to keep variables within a range of 10% of the intended level (temperature 22°C, humidity 60%).
Exposure assessment:
measured
Details on exposure:
TYPE OF EXPOSURE:
CAP was dissolved in 50 ml distilled water. Subsequently, the dissolved CAP was drawn up into a 50 ml perfusor syringe and pumped into a glass dish in the chamber using a Braun Melsungen AG (type 871 702/8) perfusor system.
On the day of zero exposure, only distilled water was dripped into the dish. The glass dish was heated at 150°C using a hotplate so that CAP could evaporate into the atmosphere. Several fans were used to distribute CAP homogenously in the chamber. Any influence on the ocular membranes caused by the air flow in the chamber could be ruled out by anemometer measurements (air flow 0 m/s) taken during the preliminary tests.

TYPE OF EXPOSURE MEASUREMENT:
Preliminary measurements at six different sites in the chamber yielded a comparable CAP concentration (range of variation ±10%). Therefore, the concentration in the air was determined at one monitoring point during exposure. To monitor the concentrations, air samples were taken every 50 min and the concentrations subsequently determined by means of High Pressure Liquid Chromatography (HPLC).

Results and discussion

Results:
All persons were in good health condition. No abnormal findings were obtained in the detailed baseline physical examination. The follow-up examinations at the end of each day of exposure showed no abnormal health effects, nor were there any changes from the findings of the preliminary examinations. Closing examinations also did not reveal any diagnostic findings.

Any other information on results incl. tables

The results of other study parameters:

1. Blink frequency:

The light source for generating the control and measurement strips to examine the blink frequency had no significant influence on the absolute blink frequency.

Table 1 shows the results of the blink frequency in relation to increasing CAP concentrations and in relation to the exposure period. The blink frequency shows considerable interindividual variations but no statistically significant effects on the level of the blink frequency were observed in the concentrations used when compared with the zero exposure.

2. Conjunctival redness:

There were no statistically significant differences in the individual assessments of the available digital photographs with regard to a possible conjunctival irritation induced by CAP. The concentrations of e-caprolactam used had no detectable influence on redness of the conjunctiva (data not shown).

3. Nasal resistance:

The differences of total nasal resistance before and after exposure in anterior rhinomanometry in relation to the specific CAP concentration did not reveal any significant differences with regard to a possible concentration–response relationship. Even though there was a concentration-dependent increase in the difference of the total nasal resistance. This means that the resistance of nasal breathing increases with increasing CAP concentrations in the air. However, it is only a trend without any statistical significance (data not shown).

4. Symptoms and complaints (SPES):

All 29 acute symptoms had been summarized to a total daily score. The total symptom score significantly increased up to the highest CAP concentration of 5 mg/m3 (data not shown). In the low concentration range up to 0.5 mg/m3, the total scores did not statistically, nor significantly differ from each other. No statistically significant increase or decrease in the total symptom score was observed in the course of the day. The results do not indicate any adaptation or habituation processes in the course of the 6 h exposure.

The symptoms of possible irritation to the eyes or nose are summarized in a total score of “irritation” (Table 2). Neither for total irritation nor for the subscores of ocular or nasal irritation was significant concentration–response relationships observed. There were also no significant differences in the assessments of total irritation in the course of the individual exposure days.

Regarding olfactory perception, a statistically significant unpleasant odor perception was obvious even in the low dose range of 0.15 mg/m3 (P < 0.01). There was no significant increase at 0.5 mg/m3. At a concentration of 5 mg/m3, odor nuisance was highly significantly more pronounced than at zero exposure (P < 0.001).

Table 1. Average blink frequency in relation to CAP concentrations and intraday variations of the blink frequency (means, standard deviation, median and range)

Measurements

CAP concentrations (mg/m3)

ANOVA

0

0.15

0.5

5.0

0 min

21.9±14.4

20.5 (1-68)

25.2±24.2

17.5 (1-107)

23.8±20.4

19.5 (2-98)

28.4±20.6

27 (2-85)

P>0.05

1 h

18.0±10.5 14

 (2-39)

25.5±25.3

20.5 (0-113)

22.8±14.6

19 (4-63)

29.7±25.8

21.5 (1-100)

P>0.05

3 h

21.5±21.0

15.5 (0-102)

19.4±14.9

17.5 (0-60)

18.2±13.0

16.5 (2-45)

29.1±25.0

22.5 (5-96)

P>0.05

6 h

16.5±11.4

14.5 (0-37)

21.2±19.7

 16 (0-77)

18.9±18.1

13 (1-71)

25.9±21.8

15.5 (4-87)

P>0.05

Average blink frequency (per 90 s)

19.5±10.8

20.5 (0.8-46.8)

22.8±19.9

18.4 (0.3-89.3)

20.9±15.2

15.8 (2.5-58.0)

28.2±21.0

23.3 (3.0-81.8)

P>0.05

 

Table 2. Total symptom scores for chemosensory irritation and breakdown into effector organs (means, standard deviation, median and range).

 

CAP concentrations (mg/m3)

ANOVA

0

0.15

0.5

5.0

Total irritation

0.19±0.21

0.16(0.00-0.70)

0.25±0.36

0.18(0.00-1.54)

0.27±0.29

0.18(0.00-1.08)

0.32±0.33

0.25(0.00-1.27)

P>0.05

Irritation to the eyes

0.23±0.26

0.13(0.00-0.86)

0.32±0.47

0.16(0.00-1.93)

0.35±0.41

0.25(0.00-1.75)

0.38±0.40

0.25(0.00-1.54)

P>0.05

Irritation to the nose

0.16±0.20

0.05(0.00-0.55)

0.17±0.27

0.10(0.00-1.55)

0.18±0.24

0.13(0.00-1.00)

0.26±0.29

0.18(0.00-1.00)

P>0.05

 

Applicant's summary and conclusion