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Toxicological information

Specific investigations: other studies

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Administrative data

Endpoint:
specific investigations: other studies
Type of information:
experimental study
Adequacy of study:
key study
Study period:
9 - 13 September 2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Followed the spirit of GCP ICH Topic E6.1 "Note for guidance on Good Clinical Practices (CPMP/ICW/35/95)" - ICH Harmonized Tripartite Guideline for Good Clinical Practices having reached Step 5 of the ICH Process at the ICH Steering Committee meeting on 1 May 1996.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008
Report Date:
2008

Materials and methods

Test guideline
Qualifier:
no guideline available
GLP compliance:
no
Remarks:
A Quality Control reviewer conducted a 100% review of all study-related documents. The protocol, the medical screening forms and informed consent documents and the regulatory binder were reviewed. The study report accurately reflects the data.
Type of method:
in vivo

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: clear colorless liquid
Details on test material:
100 ppm 2-Methyl-4-isothiazoline-3-one in Buffered Physiological Saline was used.

Test animals

Species:
human
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
A sufficient number of subjects were enrolled in order to provide 12 to 15 completed subjects.

Administration / exposure

Route of administration:
other: eye
Vehicle:
physiological saline
Details on exposure:
Product Application Procedure
An Eppendorf repeater pipette with sterile tips was prepared for the study material and the study material control as allocated for treatment of each eye. The sterile tips were changed for each subject to ensure asepsis, and the pipette tip did not touch the subject during the instillation process. If the tip came in contact with any surface during the procedure it was replaced. The subject reclined sufficiently to permit easy instillation of the study products into the conjunctival sac inside the lower eyelid. Using the repeater pipette, a single dose of 10 μL of the assigned product or control was instilled into the right eye first, followed immediately by a single dose of 10 μL into the left eye of the assigned product or control not instilled into the right eye. All instillations were performed by the same clinical staff member, as far as possible, using a uniform standard technique.

Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Not applicable
Duration of treatment / exposure:
4 applications
Frequency of treatment:
daily
Post exposure period:
No data
Doses / concentrations
Remarks:
Doses / Concentrations:
100 ppm
Basis:
nominal in water
No. of animals per sex per dose:
12 individuals completed the study
Control animals:
yes, concurrent vehicle
Details on study design:
Outline of Study Procedures
Prior to enrollment in the study subjects completed an informed consent and medical history, and was examined by the ophthalmologist. Upon enrollment subjects received a unique randomization number identifying which eye received the study product and which received the control product (buffered physiological saline). There were 2 types of assessment performed in this study, namely the ophthalmologist performed eye exams while subjects subjectively rated the irritation. The ophthalmologist performed eye examinations prior to product instillation, at 30 to 60 seconds and 1 hour after instillation. At each examination, the investigator assigned ordinal scores for severity of lacrimation, and bulbar and palpebral conjunctival irritation. Subjects assessed irritation prior to product instillation at 30 to 60 seconds, 3 minutes and 60 minutes post-instillation. They rated the severity of stinging/burning/pain and compared the severity of stinging/burning/pain between the 2 eyes. At the 3 minute time-point if the stinging/burning/pain were still present each subject was given 2 stopwatches, with the faces covered with tape, one for each eye. The subject was instructed to depress the appropriate stopwatch at the point when their stinging/burning had disappeared completely. Prior to product instillation at approximately 1-hour post instillation, a visual acuity test was performed followed by the one hour evaluation as a routine follow-up examination in the interest of subject safety. Subjects returned to the study site on Days 2, 3, and 4 to have 1 drop of the study product and the buffered physiological saline control instilled in the eye. A visual acuity test was performed 10 minutes after the instillation. On Day 5 the subjects returned to the study site to receive the study product and control product. Additionally, the ophthalmologist performed eye exams and visual acuity and the subjects subjectively rated the irritation. The ophthalmologist performed eye examinations prior to the instillation, and at 30 to 60 seconds and 1 hour after instillation. At each examination, the investigator assigned ordinal scores for severity of lacrimation, and bulbar and palpebral conjunctival irritation. Subjects assessed irritation at 30 to 60 seconds, 3 minutes and 60 minutes post-instillation. They rated the severity of stinging/burning/pain and compared the severity of stinging/burning/pain between the 2 eyes. At the 3 minute time-point if burning/stinging/pain were still present each subject was given 2 stopwatches, with the faces covered with tape, one for each eye. The subject was instructed to depress the appropriate stopwatch at the point when their stinging/burning had disappeared completely.

Examinations

Examinations:
Stinging/Burning Evaluation
Ophthalmologist Evaluations
Prior to product instillation between 30 and 60 seconds following instillation, the eyes were examined and scored by the ophthalmologist investigator. Eyes were examined and scored again after 1 hour. The investigator assessed lacrimation using the following 4-point scale:
0 = within normal limits
1 = slight (excessive wetness)
2 = moderate (a few formed tears)
3 = severe (intense tearing)

The investigator assessed irritation of the bulbar conjunctiva and palpebral conjunctiva using the following 4-point scale:
0 = within normal limits
1 = mildly pink
2 = moderately pink - some dilation
3 = intense red vessels dilated

Slit-lamp examinations were conducted at the 60-minute interval to assess the health of the corneal epithelium. The following scale was used:
0 = normal
1 = trace abnormality
2 = mild abnormality
3 = moderate abnormality
4 = severe abnormality

Subjects underwent a visual acuity test conducted by a trained TKL staffer 1 hour post-instillation.

Subjective Evaluations
Prior to product instillation between 30 to 60 seconds, 3 minute and 60 minute evaluation intervals, each subject was asked to rate the subjective perception of stinging/burning. Stinging was defined as any stinging, burning and/or sensation of pain. The severity of the sensation was rated as
0 = no stinging/burning/pain
1 = slight/mild/stinging/burning/pain
2 = moderate stinging/burning/pain
3 = severe/stinging/burning/pain

At all evaluations, subjects were asked to identify which of their 2 eyes feels more irritated (right, left, or neither) at that moment. A positive response to the question resulted in the subject being asked to rate the degree of difference in irritation in the more irritated eye as being:
a) slightly more irritated
b) much more irritated
c) very much more irritated

At the 3 minute evaluation, 2 stopwatches with their faces covered over with tape was started. One (1) was labeled for the left eye and 1 for the right. If the subject was still perceiving stinging/burning at the 3 minute evaluation, they were instructed to depress the appropriate stopwatch when the sensation had completely disappeared. If either eye was no longer experiencing stinging/burning at the 3 minute evaluation, the stopwatch was eliminated and appropriately documented on the case report form.

All subjects were dismissed at the end of the 1-hour evaluation period. However, if irritation was apparent, the subject was asked to return the following day to check for any residual effects.
Positive control:
Not applicable

Results and discussion

Details on results:
SUBJECT DISPOSITION
Thirteen (13) subjects were enrolled and 12 completed the study.

SUBJECT DEMOGRAPHICS AND BACKGROUND CHARACTERISTICS
Subject ages ranged from 23 to 61 years, with a mean age of 45.8 years. Enrolled were 10/77% females, and 3/23% males. The majority of subjects were white (11/85%) and 2 (15%) were Black.

Visual Assessments
At the Visit 1 30-60 second post-instillation evaluation there was no more than mild pink at the bulbar and palperbral conjunctiva and slight lacrimation for the study product. The control product also exhibited mild pink at the bulbar conjunctiva, however, there was normal irritation at the palperbral conjunctiva and normal lacrimation. There were no reaction to the active product at 60 minutes post-instillation at Visit 1, as there was only 1 subject with mild pink at the bulbar conjunctiva for the control product. All other readings that this time point were normal. At Visit 5 30-60 seconds post-instillation both the active and control products had 1 subject with moderate pink at the bulbar and palpebral conjunctiva and 1 subject with slight lacrimation. At the 60 minute postinstillation evaluation there was no more than mild pink reported for the active and control products at the bulbar conjunctiva. There were no other reactions at this time point.

Other Assessments
No more than slight/mild stinging/burning/pain were reported for both the active product and the control product. Additionally there was no statistically significant difference between the product at Visit 1 (P=0.063) or at Visit 5 (P=1.000).

ADVERSE EVENTS
There were 3 adverse events reported by 2 subjects. Subject No. 1 experienced mild bilateral ocular discharge and stinging, which were possibly related to the study product. Subject stated she was going to the eye doctor and will bring a report. She was contacted numerous times but never responded and was lost to follow-up. Subject No. 2 reported mild bilateral ocular discharge which was unlikely related to the study product.

Any other information on results incl. tables

Table 1: Summary of Visual Assessments All Enrolled Subjects Visit 5

   Active (N=13)  Control (N=13)
 30-60 Seconds Post-instillation    
 Bulbar Conjunctival Irritation    
 Normal (0) - n (%)  8 (66.7)  9 (25.0)
 Mildly Pink (1) - n(%)  3 (25.0)  2 (16.7)
 Moderately Pink (2) - n (%)  1 (8.3)  1 (8.3)
 Intense Red (3) - n (%)  0 (0.0)  0 (0.0)
 Palpebral Conjunctival Irritation    
 Normal (0) - n (%)  11 (91.7)  11 (91.7)
 Mildly Pink (1) - n(%)  0 (0.0)  0 (0.0)
 Moderately Pink (2) - n (%)  1 (8.3)  1 (8.3)
 Intense Red (3) - n (%)  0 (0.0)  0 (0.0)
 Lacrimation    
 Normal (0) - n (%)  11 (91.7)  11 (91.7)
 Slight (1) - n (%)  1 (8.3)  1 (8.3)
 Moderate (2) - n (%)  0 (0.0)  0 (0.0)
 Severe (3) - n (%)  0 (0.0)  0 (0.0)

 Objective Irritation Score (Sum of

Conjunctival Irritation Scores and

Lacrimation Score)

   
 N  12  12
 Mean  0.7  0.6
 Standard Deviation  1.4  1.4
 P value  1.000   

Applicant's summary and conclusion

Conclusions:
Under the conditions employed in this study, there was no statistically significant difference in stinging and/or irritation potential of 100 ppm 2-Methy-4-isothiazolin-3-one in buffered physiological saline to the buffered physiological saline control. The product was safe and well tolerated by this subject panel.
Executive summary:

This was a single-center study to evaluate and compare the stinging and/or irritation potential of Neolone 2-Methyl-4- isothiazolin-3-one in buffered physiological saline. A sufficient number of males and females, 18 years of age or older, were enrolled in order to provide 12 to 15 completed subjects. The subjects were instructed to report to the study site on Days 1, 2, 3, 4, and 5 to have 1 drop [10μl] of the study product and the buffered physiological saline control instilled in the eye. The ophthalmologist performed eye examinations and the subjects subjectively rated the irritation.

Thirteen (13) subjects were enrolled and 12 completed the study. Subject ages ranged from 23 to 61 years, with a mean age of 46 years. Enrolled were 10/77% females, and 3/23% males. The majority of subjects were white (11/85%) and 2 (15%) were Black.

At the Visit 1 30-60 second post-instillation evaluation there was no more than mild pink at the bulbar and palperbral conjunctiva and slight lacrimation for the study product. The control product also exhibited mild pink at the bulbar conjunctiva, however, there was normal irritation at the palperbral conjunctiva and normal lacrimation. There were no reaction to the active product at 60 minutes post-instillation at Visit 1, as there was only 1 subject with mild pink at the bulbar conjunctiva for the control product. All other readings that this time point were normal. At Visit 5 30-60 seconds postinstillation both the active and control products had 1 subject with moderate pink at the bulbar and palpebral conjunctiva and 1 subject with slight lacrimation. At the 60 minute postinstillation evaluation there was no more than mild pink reported for the active and control products at the bulbar conjunctiva. There were no other reactions at this time point.

No more than slight/mild stinging/burning/pain were reported for both the active product and the control product. Additionally there was no statistically significant difference between the product at Visit 1 (P=0.063) or at Visit 5 (P=1.000).

There were 3 adverse events reported by 2 subjects. Subject No. 1 experienced mild bilateral ocular discharge and stinging, which were possibly related to the study product. Subject No. 2 reported mild bilateral ocular discharge which was unlikely related to the study product. Adverse events are presented in Data Listing 5.

Under the conditions employed in this study, there was no statistically significant difference in stinging and/or irritation potential of 100 ppm 2-Methy-4-isothiazolin-3-one in buffered physiological saline to the buffered physiological saline control. The product was safe and well tolerated by this subject panel.