Registration Dossier

Toxicological information

Exposure related observations in humans: other data

Administrative data

Endpoint:
exposure-related observations in humans: other data
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
Mutiple short exposures over a maximum 12-hour period
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted according to generally accepted methodology for this type of study.

Data source

Reference
Reference Type:
publication
Title:
Can we trust odor databases? Example of t- and n-butyl acetate
Author:
Cain WS and Schmidt R
Year:
2009
Bibliographic source:
Atmospheric Environment 43: 2591-2601

Materials and methods

Type of study / information:
This study investigated the chemosensory properties of tertiary butyl acetate. In one study, volunteer subjects were asked to detect the odor of tertiary butyl acetate. In the second study, subjects were asked to detect the presence of vapor with the eye via chemesthesis (sensory irritation) in 10 second exposures.
Endpoint addressed:
eye irritation
Test guideline
Qualifier:
no guideline followed
Deviations:
not applicable
Principles of method if other than guideline:
Study 1: Odor Detection

Twenty three young adult male and female subjects (average age of 22 years) participated in the study. The test was conducted over a period of 12 hours, generally in 6-hr blocks broken in halves with a lunch break. A block would provide at least 240 judgments. Each exposure lasted about 2 seconds/sniff so total exposure over a 6-hr period was about 8 minutes. Test chemical was diluted with nitrogen and different test vapor concentrations were delivered to a series of sampling cones. Test subjects sampled the cones and rated their ability to detect the odor of tertiary butyl acetate on a scale from 1 (very low) to 5 (very high).

Study 2: Ocular Detection

This study compared the concentration of tertiary butyl acetate necessary to cause sensory irritation with the odor recognition threshold in Study 1. Twenty four young adult male and female subjects (average age 22 years) participated in the study. The test covered a period of 6 hours which included at least 180 trials, 30 cycles for six concentrations. Complete testing equaled 15 min per eye. A series of vapor generating stations delivered vapors over the range 21-670 ppm. Polyethylene cyclinders delivered the test material to the eyes at a flow rate of 10 L/min and a linear air speed of 8.6 cm/s. Each station had two cylinders, one for each eye. For each exposure cycle, test vapor was randomly delivered to one eye while the other eye was exposed to blank air. Each exposure was for a maximum of 10 seconds with a 30-sec time-out between exposures. Subjects terminated exposure early if sensation was detected in less than 10 seconds.

In both series of tests, values were determined for concentrations that gave 50% detection for the test subjects.
GLP compliance:
no
Remarks:
Human studies are not subject to GLP compliance.

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
-Name of test material (as used in publication): t-butyl acetate
-Source: Acros Organics, Fair Lawn NJ USA
-Lot #: A0196138001
-Purity: > 99%

Method

Ethical approval:
confirmed and informed consent free of coercion received
Details on study design:
Study 1: Odor Detection

Twenty three young adult male and female subjects (average age of 22 years) participated in the study. The test was conducted over a period of 12 hours, generally in 6-hr blocks broken in halves with a lunch break. A block would provide at least 240 judgments. Each exposure lasted about 2 seconds/sniff so total exposure over a 6-hr period was about 8 minutes. Test chemical was diluted with nitrogen and different test vapor concentrations were delivered to a series of sampling cones. Test subjects sampled the cones and rated their ability to detect the odor of tertiary butyl acetate on a scale from 1 (very low) to 5 (very high).

Study 2: Ocular Detection

This study compared the concentration of tertiary butyl acetate necessary to cause sensory irritation with the odor recognition threshold in Study 1. Twenty four young adult male and female subjects (average age 22 years) participated in the study. The test covered a period of 6 hours which included at least 180 trials, 30 cycles for six concentrations. Complete testing equaled 15 min per eye. A series of vapor generating stations delivered vapors over the range 21-670 ppm. Polyethylene cyclinders delivered the test material to the eyes at a flow rate of 10 L/min and a linear air speed of 8.6 cm/s. Each station had two cylinders, one for each eye. For each exposure cycle, test vapor was randomly delivered to one eye while the other eye was exposed to blank air. Each exposure was for a maximum of 10 seconds with a 30-sec time-out between exposures. Subjects terminated exposure early if sensation was detected in less than 10 seconds.

In both series of tests, values were determined for concentrations that gave 50% detection for the test subjects.
Exposure assessment:
measured
Details on exposure:
For Study 1, an eight-station vapor delivery device was used to present the test concentrations ranging from 0.5 to 66 ppb. Test chemical was diluted with nitrogen to achieve desired concentrations. Test concentrations were measured by gas chromatography with flame ionization detector. For each cycle, a computerized voice directed test subjects to sample sequential glass cones at 5-second intervals. The test subject indicated which cone appeared to deliver odorant and the confidence in the choice on a scale of 1 (very low) to 5 (very high). There was a 15-second time-out between each of the eight trials and a 5-10 min period between cycles.

For Study 2, the same delivery system was used with some modifications: (1) only six stations were used and the test concentrations ranged from 21-670 ppm and (2) polyethylene cylinders instead of glass cones delivered the vapor concentrations to the eyes. For each trial, the test subjects placed the cyclinders to their closed eyes and when directed by a computerized voice, opened their eyes for a 10-second exposure. After exposures, subjects were directed to move to the next station where a 30-second time-out occurred before the next exposure.

Results and discussion

Results:
For odor threshold, the mean values for % correct detection were similar for males and females. Using the 50% criterion, the odor threshold for tertiary butyl acetate for the test subjects in this study was 8 ppb with a geometric standard deviation of 2.47. Most subjects showed less than threefold variation from the mean.

For chemesthesis (sensory eye irritation), the mean values for % correct detection were similar for males and females. Using the 50% criterion, the threshold for ocular irritation for tertiary butyl acetate for the test subjects in this study was 177 ppm with a geometric standard deviation of 1.6. Most subjects showed less than twofold variation from the mean.

These data can also be used to calculate a Reference Concentration (RfC) for tertiary butyl acetate. The short-term (10 second) threshold for ocular irritation (trigeminal nerve stimulation) in humans was 177 ppm for typical individuals. The psychometric function for ocular detection (Z = 3.13 log Cppm – 7.22) can be used to calculate the concentration at which no detection would occur (Z = -2 at 47 ppm). Therefore, the LOAEL for typical humans was 177 ppm and the NOAEL was 47 ppm. The NOAEL to LOAEL uncertainty factor for irritation was 3.77.

Based on the psychometric function for cumulative performance, at 47 ppm, even the most sensitive individual would not feel the presence of vapor 50% of the time. Using 47 ppm as the LOAEL for sensitive groups and the psychometric function for eye irritation, a NOAEL of 11 ppm can be calculated for this group (Z = -4).

Applicant's summary and conclusion

Conclusions:
There are numerous published studies and databases that have been used to set safety thresholds for chemical exposure based on odor potency. These data may differ by several orders of magnitude for the same chemical. In a study designed to compare the odor threshold for tertiary butyl acetate with the vapor concentration needed to detect vapor with the eye via chemesthesis (sensory irritation), the level needed to cause chemesthesis (177 ppm) was more than 10,000 times above that for odor detection (8 ppb).

The psychometric function for ocular detection was used to calculate the concentration at which no detection would occur. The LOAEL for typical humans (50% detection) was 177 ppm and the NOAEL was 47 ppm. Based on this information, at 47 ppm, even the most sensitive individual would not feel the presence of vapor 50% of the time. Then, using 47 ppm as the LOAEL for the sensitive group, a NOAEL of 11 ppm could be calculated for this group.
Executive summary:

In a study to investigate the chemosensory properties of tertiary butyl acetate, male and female test subjects were exposed to analytically verified vapor concentrations of the test material in a controlled setting and asked to judge odor and sensory irritation. Data values were reported as the points of 50% detection above chance. For tertiary butyl acetate, the odor threshold occurred at 8 ppb. For sensory irritation, detection at 50% occurred at 177 ppm. There were no significant differences in response between male and female test subjects for either odor detection threshold or sensory irritation threshold. The LOAEL for sensory irritation for typical test subjects was 177 ppm and the NOAEL was 47 ppm. The LOAEL for sensitive individuals was considered to be 47 ppm and the NOAEL 11 ppm.