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Endpoint:
direct observations: clinical cases, poisoning incidents and other
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Chemosensory effects during acute exposure to N-methyl-2-pyrrolidone (NMP)
Author:
van Thriel C, Blaszkewicz M, Schäper M, Juran SA, Kleinbeck S, Kiesswetter E, Wrbitzky R, Stache J, Golka K, Bader M
Year:
2007
Bibliographic source:
Toxicol. Lett. 175:44-56. Epub 2007 Sep 29.

Materials and methods

Study type:
study with volunteers
Endpoint addressed:
acute toxicity: inhalation
respiratory irritation
Test guideline
Qualifier:
no guideline required
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
1-methyl-2-pyrrolidone
EC Number:
212-828-1
EC Name:
1-methyl-2-pyrrolidone
Cas Number:
872-50-4
Molecular formula:
C5H9NO
IUPAC Name:
1-methylpyrrolidin-2-one
Test material form:
liquid

Method

Type of population:
general
Subjects:
- Number of subjects exposed: 15
- Sex: male
- Age: 26.5 (±2.4 years)
- Race: not specified
- Known diseases: non-smoking
Ethical approval:
confirmed, but no further information available
Remarks:
ethics committee of the Leibniz Research Centre for Working Environment and Human Factors at the University of Dortmund approved the study protocol
Route of exposure:
inhalation
Reason of exposure:
intentional, occupational
Exposure assessment:
measured
Details on exposure:
TYPE OF EXPOSURE: Vapor
- heater platform precisely vaporized defined amounts of liquid NMP (provided by BASF, Germany) and vapor brought into the inlet airflow
- conditioned air was dispersed throughout the entire chamber by a branched pipe system on the floor of the lab
- NMP vapor exhausted from the lab by four outlets, located at the ceiling
- leakage-avoidance: chamber was maintained at a negative pressure between 20 and 30 Pa
- average air exchange rate = 300m3/h
- exposure chamber, a secluded room built of glass and stainless steel with spatial dimensions of 4.80m×2.65m×2.27m (≈29m3)
- four subjects exposed simultaneously

TYPE OF EXPOSURE MEASUREMENT: Area air sampling
- four sampling devices for online monitoring of the airborne concentration at the ceiling of the chamber
- air samples were taken quasicontinuously (every 80 s)
- analyzed by photo acoustic IR spectrometry (INNOVA, 1412 Photo Acoustic Field Gas-Monitor)

EXPOSURE LEVELS: The exposure scenarios varied with respect to concentration and workload.
- 10, 40, 80, and 25/160 mg/m3 conditions
- three time-weighted average concentrations (CTWA) with targeted CTWAs of 10, 40, and 80 mg/m3
- 10, 40 mg/m3: constant time course of concentration in time (steadystate)
- 80 mg/m3: generated either as a steady-state or as a fluctuating concentration with a basis concentration of 25 mg/m3 and exposure peaks of 160 mg/m3

EXPOSURE PERIOD:
- 10, 40, 80 mg/m3: 2 x 4 h, exposure-free lunch break of 30 min
- 25/160 mg/m3: 4 x 15 min, 1h 24 mg/m3 between successive peaks
- at least 1 exposure free week between two subsequent sessions

DESCRIPTION OF EXPOSURE GROUPS / CATEGORIES:
- all conditions were investigated with and without additional physical workload
- 10, 40, 80, and 25/160 mg/m3 condition groups
Examinations:
- Lung function parameters: breathing frequency
- Chemosensory irritation: individual sensations, rhinomanometry, eye blink rate
- Acute Toxicity: Acute symptoms by Swedish Performance Evaluation System (SPES)
Medical treatment:
Medical treatment was not necessary.

Results and discussion

Clinical signs:
- in concentrations as high as current European OELs and STELs (DFG, 2006) NMP caused predominantly odor effects
- magnitudes of these olfactory mediated effects were relatively weak and during simulated work shifts adaptation to the odor of NMP occurred
- intensity ratings of trigeminally mediated sensations were not systematically elevated
- the two sensations pungent and sharp, physiologically transmitted by myelinated delta-fibers, were at least occasionally different from baseline (preexposure ratings)
- none of the subjective signs of sensory irritations were elicit concentration dependent
- physiological measures assessing ocular and intranasal irritations were not significantly affected
- results of the Akesson and Paulsson study (1997), where no sensory irritation were revealed during acute experimental exposures to 50 mg/m3 of NMP could be replicated and expanded to even higher concentrations
Results of examinations:
Lung function parameters:
- no effect of the CTWA condition, either as a main effect or in interaction with any of the other factors used in this statistical model
- average: the breathing rates were slightly higher during the measurements obtained in the exposure sessions with 75W physical workload
- across a test day, the breathing rates of the subjects increased from about 15.5 to 16.7 breaths per minute
- within the 25-min periods of the measurements the breathing rates decreased
- effects were statistically significant the sizes of the changes of breathing rates were relatively small and physiologically irrelevant
Outcome of incidence:
Ther were no serious or adverse effects observed during the study. Further information are given in 'Any other information on results incl. tables'.

Any other information on results incl. tables

Acute symptoms by Swedish Performance Evaluation System (SPES):

- almost no acute health symptoms were reported during the eight exposures

- Page’s trend tests revealed no significant differences for ratings of unspecific/ prenarcotic, taste, respiratory symptoms, general irritations, nasal irritation or eye irritation

- for olfactory symptoms Page’s trend tests indicated significant differences between the ratings given during the four CTWA steps for exposures with mental (L = 412, p < 0.001) and physical workload (L = 395, p < 0.05); mental workload conditions: trend confirmed by significant pairwise comparisons; physical workload condition yielded insignificant differences

- six other symptom subscales: final comparisons of the two workload alternatives within the four CTWA steps revealed no significant differences for ratings of acute olfactory mediated health symptoms

Ratings of chemosensory sensations:

- only very weak intensities of chemosensory sensations were reported

- including exposure peaks of 160 mg/m3 of NMP several, especially trigeminal mediated sensations were barely detectable

- no effect due to physical or mental workload

- odor of NMP seemed to be detectable during all conditions and together with annoyance this sensation increased almost dose-dependent

- dose-dependency was not observed for nose and eye irritations

- non-parametric analyses: no significant effect for the five sensations nauseous, prickling, burning, “sneeze”, and tickling

- overall ANOVA – including the 25/160 mg/m3 condition: odor intensity differed significantly in relation to exposure condition (F(3,42) = 16.98, p < 0.001) and measuring time (F(5,70) = 13.90, p < 0.001)

Rhinomanometry, eye blink rate, and breathing frequency:

- nasal flow of the participants was significantly lower after the exposures (F = 6.653, p = 0.02)

- ANOVA: decreasing flow was neither affected by the CTWA condition, nor by the different types of workload

- respective flow changes of the four exposure conditions: DeltaFlow=−42 ml/s at 10 mg/m3, −37 ml/s at 40 mg/m3, −36 ml/s at 80 mg/m3, and −10 ml/s at 25/160 mg/m3

- eye blink rates: not affected by the factor exposure conditions

- exposure peaks did not affect the blinking rates

- ANOVA: one significant main effect of the four repetitions of this (psycho) physiological measurement (F = 3.04, p = 0.04)

- average: the mean eye blink rates increase from 16.0 min−1 (1st measurement), to 17.2 min−1 (2nd), to 17.3 min−1 (3rd), and finally 17.7 min−1 (4th) at the end

of the test day

- breathing frequency ANOVA: three significant main effects of

      - (a) the two workload conditions (F = 5.14, p = 0.04)

      - (b) the four repetitions of this (psycho)physiological measurement within a session (F = 13.51, p < 0.01)

      - (c) the two sections at the first and last 5 min of each 25-min assessment period (F = 24.86, p < 0.01)

- no effect of the CTWA condition, either as a main effect or in interaction with any of the other factors used in this statistical model

- average: the breathing rates were slightly higher during the measurements obtained in the exposure sessions with 75W physical workload

- across a test day, the breathing rates of the subjects increased from about 15.5 to 16.7 breaths per minute

- within the 25-min periods of the measurements the breathing rates decreased

- effects were statistically significant the sizes of the changes of breathing rates were relatively small and physiologically irrelevant

Applicant's summary and conclusion

Conclusions:
The results of the present study provide first evidence that acute NMP concentrations up to 160 mg/m3 do not cause severe sensory irritation.
The weak olfactory effects that we reported in our experimental exposure study might be an overestimation of the chemosensory effects of acute NMP exposures in workers increasing the margin of safety for disease prevention.
Moreover, even if exposure peaks of 160 mg/m3 were used during the varying exposure scenarios the blinking frequency, a very sensitive marker of exposure peaks, was affected by the previous experience of a malodor in a controlled chamber with two successive sessions.

Due to the consistency of our data with the results of a previous environmental chamber study (Akesson and Paulsson, 1997), the higher degree of controlling for co-variables, the usage of physiological measures (e.g. rhinomanometry) for the assessment of sensory irritations and the proven validity of the rating techniques, the present study allowed the conclusion that NMP caused no adverse sensory irritation in concentrations covered by current OEL values (DFG, 2006).
Executive summary:

In a human experimental study chemosensory effects of NMP under controlled conditions were examined. Fifteen healthy males were investigated in a cross-over study. NMP vapor concentrations were 10, 40 and 80 mg/m3 for 2×4 h with an exposure-free lunch break of 30 min. To maximize chemosensory effects a peak exposure scenario (25 mg/m3 baseline, 160 mg/m3 peaks 4×15 min, time-weighted average: 72 mg/m3) was tested.

The four different conditions were conducted with and without moderate physical workload. Chemosensory effects were measured physiologically by anterior rhinomanometry, eye blink rate and breathing frequency. Subjectively, ratings of acute health symptoms and intensity of olfactory and trigeminal sensations were collected repeatedly throughout the exposures. All physiological variables were unaffected by the different NMP concentrations and even the peak exposures were non-effective on these measures. Olfactory mediated health symptoms increased dose-dependently. For these symptoms a strong adaptation was observable, especially during the first 4 h of the exposures. Other acute symptoms were not significantly affected. Comparable to the symptoms, only olfactory sensations increased dose-dependently. Trigeminal sensations (e.g. eye and nose irritations) were evaluated as being barely detectable during the different exposures, only during 160 mg/m3 exposure peak weak and transient eye irritation were reported.

The results clearly suggest that NMP concentrations of up to 160 mg/m3 caused no adverse sensory irritation or undue annoyance.