Methyl isothiocyanate

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:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

other: Regulatory review

Title:

Human Studies Review Board: Weight of Evidence Discussion for Methyl isothiocyanate (MITC).

Author:

Lowit A

Year:

2006

Bibliographic source:

United States Environmental Protection Agency Washington, D.C. 20460. Office of Prevention Pesticides and Toxic Substances

Report date:

2006

Materials and methods

Type of study / information:

Human Eye Irritation and Odor Threshold

Endpoint addressed:

eye irritation

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Methyl isothiocyanate

EC Number:

209-132-5

EC Name:

Methyl isothiocyanate

Cas Number:

556-61-6

Molecular formula:

C2H3NS

IUPAC Name:

isothiocyanatomethane

Method

Ethical approval:

confirmed and informed consent free of coercion received

Exposure assessment:

measured

Details on exposure:

EXPOSURE LEVELS: 0, 0.22, 0.6, 0.8, 1.9, 3.3 ppm

Results and discussion

Results:

• For a one-minute exposure, the NOAEL for eye irritation is 3.3 ppm due to a lack of response in any parameter tested.
• For exposures 4-14 minutes, the NOAEL for eye irritation is 0.6 ppm based on responses on the Likert subjective scale at 1.9 ppm.
• For exposures of 1-8 hours, based on the statistically significant subjective (Likert scale) responses at 0.8 ppm MITC at 1-4 hours and the statistically significant eyeblink responses at 2 and 3 hours, 0.22 ppm was designated as the NOAEL for this study.

Any other information on results incl. tables

Subjective (Likert scale) responses. Exposure to 0.8 ppm (800 ppb) MITC resulted in a statistically significant positive response based on averaging the subjective assessments by the subjects using the Likert scale methodology (Table 2). In that test, as many as 8 out of 9 subjects showed a positive response at 1 and 2 hours, the first two time points examined. (Note: judgement of a positive response is itself somewhat subjective in light of the variability observed among control subjects.) Mean responses at those times, expressed as the percentage of the full Likert scale indicated by the subject, were 25%±14% and 26%±14%, respectively, compared to 2%±2% in zero-time untreated controls (a judgement of 50% was stated to be equivalent to the irritation one might expect from the cutting of a single mild onion). One-hour and 2-hour air-only controls exhibited responses of 6%±9% and 5%±8%, respectively. By 3 and 4 hours, all 9 subjects at 0.8 ppm appeared to respond positively, with mean responses of 39%±19% and 39%±26%, respectively. Air-only controls at the latter 2 times were 5%±6% and 4%±6%, respectively. Exposure to 0.22 ppm (220 ppb) did not result in a statistically significant mean Likert scale response when compared against air-only controls. Despite the fact that statistical significance was achieved at 1 hour when compared against zero-time controls (13%±15% vs. 4%±8% among zero-time controls), the lack of statistical significance when compared against air-only controls (which registered 6%±9%) resulted in a judgement of no response.

Shorter exposures to 0.6 ppm (600 ppb) did not result in statistically significant Likert scale changes, though 1 of 9 individuals appeared to respond at 4 and 14 minutes. Exposure to 1.9 ppm (1900 ppb) or 3.3 ppm (3300 ppb) MITC for 4 or 14 minutes resulted in positive subjective responses at 4 and 14 minutes. At 1 minute of exposure, levels as high as 3.3 ppm did not evoke a statistically significant positive response.

Eyeblink responses. Mean blink rate determinations at 0.8 ppm were statistically significantly increased at the 2- and 3-hour time points compared both to air-only and zero-time controls (Table 3), with 7 of 9 subjects responding positively. Mean blinks per minute (minus the zero-time rate) were 16±11 and 14±13 at those times. Air-only control rates at 2 and 3 hours were 3±9 and 3±8 blinks per minute, respectively. Statistical significance was not achieved at 1 and 4 hours, though a positive response was indicated in several individuals. The blink response to 0.6 ppm and 1.9 ppm at 1, 4 and 14 minutes did not indicate positivity. At 3.3 ppm, statistical significance was achieved at 4 and 14 minutes. A strong suggestion of a response was also present at 1 minute, though it was not statistically significant.

Tearing, ocular morphology, and visual acuity. No statistically positive tearing responses were observed. However, 2 of 9 individuals exposed to 3.3 ppm MITC showed apparently positive responses at 14 minutes (longer exposures were not evaluated at this concentration). With respect to the possibility that there were changes in ocular morphology or visual acuity, the following passage is quoted from the study report (page 39): “Preliminary analysis of the photographs of test subjects’ eyes indicated that no notable, exposure related changes were observable in the large majority of tests. In a few tests in which minimal increases in redness and swelling were observed, it appeared that they were more likely to occur in exposures to air than in exposures to MITC. A few individuals evinced a degree of mild edema at the highest level of MITC exposure, but this tended to be canceled out by other subjects who evinced some native edema and redness, pre-exposure in the early morning. Changes in subjects’ visual acuity were also few and apparently random. Accordingly the results of the photographic and acuity tests were not considered to provide any meaningful information on chemical exposure. Results from these tests are retained in study records.” Recovery. Rates of recovery from irritating MITC exposures were not evaluated directly. The comments of the test subjects indicated that recovery began immediately upon removal of the masks, and was complete within 20 minutes at the highest concentration tested, and sooner at lower concentrations.

Applicant's summary and conclusion

Executive summary:

In order to determine the no-observed-adverse-effect-level (NOAEL) for human eye irritation produced by MITC vapors, as well as its odor threshold, human volunteers were exposed to air concentrations of MITC in a laboratory setting at different times of exposure. A specialized olfactometer was used which permitted the operator to dispense the test material through a manifold system. The odor threshold was determined to be 1.7 ppm (5 mg/m3). The olfactometer was adjusted to include a goggle system; this was then used to deliver MITC during the eye irritation portion of the study. Five parameters were used to ascertain an irritation response: 1. the subjects’ subjective estimation of irritation (using the “Likert” scale); 2. photographs of the subjects’ eyes prior to and after exposure; 3. blink rate as measured by electromyography; 4. effect upon visual acuity; 5. tear production. Both a positive control (acetic acid) and a negative control (air) were employed. Baseline responses for each of the assessment parameters were determined under pre-exposure conditions (“zero-time controls”) and upon exposure to the negative control (“air-only controls”) for the prescribed period. A positive irritation response was based on three criteria: 1. the average response must be quantitatively greater than the pre-exposure response; 2. the average response must be greater than pre-exposure and greater than could be expected statistically from individual to individual differences within the group; 3. the average treated response must be greater than the air-only group’s response and greater than could be expected from individual differences observed within the group.

Concerning the ethical conduct of this study, informed consent was asserted in the odor threshold study but not mentioned in the eye irritation study; copies of the actual informed consent forms are not provided in the study report. The study also asserts approval through an ethical review but provides no documentation to support the statement. A detailed consideration of the ethical conduct of this study is provided in a separate memo by J. Carley (1/23/04). The odor threshold was determined to be 1.7 ppm (5 mg/m3). Conclusions from the eye irritation portion of the study include:

• For a one-minute exposure, the NOAEL for eye irritation is 3.3 ppm due to a lack of response in any parameter tested.

• For exposures 4-14 minutes, the NOAEL for eye irritation is 0.6 ppm based on responses on the Likert subjective scale at 1.9 ppm.

• For exposures of 1-8 hours, based on the statistically significant subjective (Likert scale) responses at 0.8 ppm MITC at 1-4 hours and the statistically significant eyeblink responses at 2 and 3 hours, 0.22 ppm was designated as the NOAEL for this study