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Toxicological information

Exposure related observations in humans: other data

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Administrative data

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: In full accordance to Good Clinical Practice guidelines.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2016

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
The aim of this study was to examine symptoms and objective effects which occur on the mucous membranes of the eyes and the upper respiratory tract of human volunteers.
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
ε-caprolactam
EC Number:
203-313-2
EC Name:
ε-caprolactam
Cas Number:
105-60-2
Molecular formula:
C6H11NO
IUPAC Name:
azepan-2-one
Specific details on test material used for the study:
epsilon-caprolactam (Merck Schuchardt, Hohenbrunn, Germany)

Method

Ethical approval:
other: The study was conducted in full accordance to the principles of the Declaration of Helsinki and was approved by the Ethics Committee of the Medical Faculty of Heidelberg University (Reference: S-090/2013).
Details on study design:
A total of 52 healthy volunteers (26 women and 26 men) were assessed.
Human volunteers were aged between 19 and 50 with an average of 32 ±11 years.
Exclusion criteria for volunteers included pregnancy, allergies such as hay fever/asthma, severe disorders, smoking, occupational contact with caprolactam, untreated severe visual disorders and eye blinking frequency greater than 20 blinks/minute.
Exposures were random to caprolactam concentrations of 0, 0.05, 0.5 and 5 mg/m3 for six hours on four consecutive days.

Assessment parameters included n-butanol odor threshold, rhinomanometry,
eye blinking frequency, tear film break-up time, eye redness, nasal flows and resistance, olfactory function as well as total protein and interleukin-8 in nasal lavage fluid.
In addition SPES and PNAS questionnaires were used to record both subjective symptoms and personality factors.
Parameters were determined daily before, during and after exposure. Eye blinking frequency and SPES questionnaire were also recorded after three hours of exposure and shortly before leaving the exposure chamber. PNAS questionaires were only evaluated at the end of the study.
Examination of olfactory function including n-butanol odor threshold, odor discrimination and odor identification (Sniffin' Sticks, Burghart Messtechnik, Wedel, Germany) was carried out before first exposure and after last exposure.
Details on exposure:
Exposure occurred in a chamber (volume 30 m ).
Exposures were randomized and blinded using a cross-over design (neither volunteers nor researchers were informed about the airborne concentrations).
Room temperature and humidity were determined and documented eight times per day.
--> Evaluated mean values (±SD) for temperature and humidity were 28.1 °C (±2.0) and 63% (±5), respectively.

For generation of exposure atmospheres, caprolactam was dissolved in distilled water. The solution dripped into a glass dish using an infusion system (Perfusor Compact, Braun, Melsungen, Germany). The dish was heated to 150 °C with a hotplate. Pretests were carried out to determine the drip rate required to achieve the desired caprolactam concentrations. Distilled water was used for control condition.
Air samples were taken at a defined site in the chamber by means of a hose and pump (model HFS-513A, Gilian, Clearwater, USA). The air was passed through an OVS-7 sampling tube (Xad-7 Sorbent Tube, SKC, Eighty Four, USA). The air samples were taken for 50 minutes in each case, ensuring that a total of eight measurements could be taken during the six-hour exposure period.
After sampling, the Xad-7 sorbent was removed from the tube and mixed with water, methanol and the internal standard (capryllactam). An aliquot of the
eluate was injected into the HPLC apparatus (1200 Infinity Series, Agilent Technologies, Waldbronn, Germany; Column: SupelcosilTM LC-18-DB, Supelco Sigma Aldrich Chemie GmbH, Buchs, Germany). Caprolactam and capryllactam were separated and then measured with an UV detector (Wavelength: 210 nm).
--> The airborne concentrations averaged for all exposures and for 13 weeks were found to differ only slightly from the target values with a maximum deviation of 5%.

Results and discussion

Any other information on results incl. tables

There were no significant differences comparing the results before and after the daily exposures.

Statistical analysis yielded no evidence of concentration-response relationships.

Evaluation of olfactory symptoms showed that the duration of stay in the chamber and not the test substance concentration was decisive for the perception of “impure air”. Personality factors had no significant influence on the reported symptoms.

Exposure to the test substance concentrations of 5 mg/m3 at maximum for six hours at for consequtive days did not cause chemosensory effects on the upper respiratory tract or eyes of healthy volunteers. Therefore, the concentration of 5 mg/m3 corresponds to the NOEC (No Observed Effect Concentration).

Applicant's summary and conclusion

Conclusions:
There were no significant differences comparing the results before and after the daily exposures.
Statistical analysis yielded no evidence of concentration-response relationships.
Evaluation of olfactory symptoms showed that the duration of stay in the chamber and not the test substance concentration was decisive for the perception of “impure air”. Personality factors had no significant influence on the reported symptoms.

Exposure to the test substance concentrations of 5 mg/m3 at maximum for six hours at for consequtive days did not cause chemosensory effects on the upper respiratory tract or eyes of healthy volunteers. Therefore, the concentration of 5 mg/m3 corresponds to the NOEC (No Observed Effect Concentration).
Executive summary:

The aim of this study was to examine symptoms and objective effects which occur on the mucous membranes of the eyes and the upper respiratory tract of human volunteers. A total of 52 healthy volunteers (26 women and 26 men) were assessed. Human volunteers were aged between 19 and 50 with an average of 32 ±11 years. Exclusion criteria for volunteers included pregnancy, allergies such as hay fever/asthma, severe disorders, smoking, occupational contact with caprolactam, untreated severe visual disorders and eye blinking frequency greater than 20 blinks/minute. Exposures were random to caprolactam concentrations of 0, 0.05, 0.5 and 5 mg/m3 for six hours on four consecutive days. Exposure occurred in a chamber (volume 30 m ). Exposures  were randomized and blinded using a cross-over design (neither volunteers nor researchers were informed about the airborne concentrations). Room temperature and humidity were determined and documented eight times per day.

There were no significant differences comparing the results before and after the daily exposures. Statistical analysis yielded no evidence of concentration-response relationships. Evaluation of olfactory symptoms showed that the duration of stay in the chamber and not the test substance concentration was decisive for the perception of “impure air”. Personality factors had no significant influence on the reported symptoms.

Exposure to the test substance concentrations of 5 mg/m3 at maximum for six hours at for consequtive days did not cause chemosensory effects on the upper respiratory tract or eyes of healthy volunteers. Therefore, the concentration of 5 mg/m3 corresponds to the NOEC (No Observed Effect Concentration).