Registration Dossier

Toxicological information

Eye irritation

Currently viewing:

Administrative data

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
2-methylpropan-1-ol /Isobutyl alcohol/ is both reagents used in the manufacture of Reaction mass of 2-methylpropan-1-ol and sodium O-isobutyl dithiocarbonate and sodium hydroxide . Therefore, 2-methylpropan-1-ol /Isobutyl alcohol/ need to be considered in the assessment of Reaction mass of 2-methylpropan-1-ol and sodium O-isobutyl dithiocarbonate and sodium hydroxide

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OTS 798.4500 (Acute Eye Irritation)
Deviations:
no
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: compact
Details on test material:
2-methylpropan-1-ol /Isobutyl alcohol/ is both reagents used in the manufacture of Reaction mass of 2-methylpropan-1-ol and sodium O-isobutyl dithiocarbonate and sodium hydroxide . Therefore, 2-methylpropan-1-ol /Isobutyl alcohol/ need to be considered in the assessment of Reaction mass of 2-methylpropan-1-ol and sodium O-isobutyl dithiocarbonate and sodium hydroxide
- Name of test material (as cited in study report):Isobutanol
Isobutanol (99.9% purity by capillary GC, GC/MS and NMR used to confirm identity).

Test animals / tissue source

Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
Male and female New Zealand White rabbits were received from Hazleton Research Products, Inc. (Denver, PA). The strain and species were selected because of their availability and existing historical data. Rabbits were ordered to be between 2.0 and 2.3 kg (designated by the supplier to be approximately 12 to 14 weeks of age). The females were nulliparous and nonpregnant.

Periodically, a Clinical Veterinarian examined rabbits for any signs of health deficiencies. Within 1 or 2 days of receipt, all animals were assigned a unique number which was marked on the animal cage card. The rabbit number was also marked in indelible ink on 1 ear at the time of dosing.

The rabbits were housed individually in cages with wire floors (approximately 61.0 x 46.0 x 36.0 cm.). DACBQ (Deotized Animal Cage Board; Shepherd Specialty Papers, Inc.) was placed under each cage and changed regularly. An automatic timer was set to provide fluorescent lighting for a 12-hour photoperiod (approximately 0500 to 1700 hours for the light phase). Temperature and relative humidity were recorded (Cole-Parmer Hygrothermograph Seven-Day Continuous Recorder, Model No. 8368-00, Cole-Parmer Instrument Co., Chicago, IL). Temperature was routinely maintained at 61-70°F during the test period; relative humidity was routinely maintained at 40-70%. Any minor exceptions to these specified ranges were noted in the raw data.
Tap water (Municipal Authority of Westmoreland County, Greensburg, PA) was available ad libitum (except during dosing) and was delivered by an automatic watering system with demand control valves mounted on each rack. Water analyses were provided by the supplier, Halliburton NUS Environmental Laboratories, Materials Engineering & Testing Company, and Lancaster Laboratories, Inc. at regular intervals. EPA standards for maximum levels of contaminants were not exceeded. As available, water analysis reports were reviewed by the Study Director. AGWAYe PROLABe Animal Diet High Fiber Rabbit (Agway Inc.) was available ad libitum except during the actual dosing period. No analyses of chemical composition and possible contaminants of the feed were conducted by the supplier.

Animal Acclimation
The animals were acclimated for at least 5 days before dosing. Detailed clinical observations were conducted twice, at the time of receipt and during animal identification and/or dosing. In addition, rabbits were examined and weighed twice prior to dosing. Cage-side observations and mortality checks were conducted at least once daily. Animals considered unacceptable for the study, based on the clinical signs or body weights (rabbits), were rejected for use on this study.
Study Organization
The animals were weighed and inspected for health on the day of the test. Only those exhibiting a healthy state were used. Healthy animals appeared alert, active and well groomed, with no evidence of discharge, diarrhea, breathing difficulties or locomotor abnormalities. A BRRC veterinarian was available for consultation regarding any animal health concerns. Animals were randomly assigned to cages and were designated for dosing according to need and availability.

Test system

Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
Initial study
0.1 ml

Follow up study
0.01 ml
Duration of treatment / exposure:
24 hours
Observation period (in vivo):
Initial study
1, 24, 48, 52.5 hours and at 7, 9, 14, 15 and 21 days following instillation.
Follow up study
1, 24, 48 and 72 hours and at 7, 10 and 14 days
Number of animals or in vitro replicates:
Initial study
1 male and 1 female

Follow up study
2 males and 2 females
Details on study design:
Both eyes of each rabbit to be dosed were examined, using fluorescein stain, within 24 hours before application. If any preexisting eye injury was
apparent, the rabbit was rejected for use in the test. A volume of 0.1 ml of test substance was placed into the conjunctival sac of 1 eye/rabbit. The other eye of each animal served as the control.

A total of 2 rabbits (1 male and 1 female) were first dosed because of the potential for the test substance to produce severe ocular irritation. Eye examinations were made at 1, 24, 48, 52.5 hours and at 7, 9, 14, 15 and 21 days following instillation. Readings were not made at 72 hours because of a lost workday resulting from severe weather conditions. However, in anticipation of the lost workday, an additional reading was made in the afternoon of the second day following dose administration. Fluorescein staining was performed at 1 day and each subsequent examination day. Grading and scoring were performed by the system of Draize (1959). All rabbits were sacrificed by ear vein injection (Euthanasia-6 Solution) at 21 days.

Because severe ocular irritancy resulted from a dose of 0.1 ml, an additional 4 rabbits (2 males, 2 females) were dosed with 0.01 ml for comparison. These rabbits were dosed as described above except the dose was applied directly onto the cornea. Eye examinations were made at 1, 24, 48 and 72 hours and at 7, 10 and 14 days (Draize, 1959). All 4 animals were sacrificed at 14 days (ear vein injection using Euthanasia-6 Solution).

Reference
Draize, J. H. (1959). The Appraisal of Chemicals in Foods, Drugs and Cosmetics. Tbe Association of Food and Drug Officials of the United States.

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 21 days
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0.7
Max. score:
1
Reversibility:
fully reversible within: 21 days
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
2.3
Max. score:
3
Reversibility:
not fully reversible within: 21 days
Remarks on result:
other: Minor conjunctival redness was still evident at 21 days.
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24, 48, 72 hours
Score:
1.8
Max. score:
3
Reversibility:
fully reversible within: 21 days
Irritant / corrosive response data:
A volume of 0.1 ml of test substance instilled into rabbit eyes produced minor to moderate corneal injury in 2 of 2 rabbits. Iritis and severe conjunctival irritation were also apparent in both rabbits. One rabbit developed severe conjunctival swelling within 1 hour. At 24 hours, both rabbits had hemorrhages of the nictitating membrane. One animal also had a purulent ocular discharge. Within 7 days, corneal vascularization developed on 1 rabbit. Except for alopecia, 1 rabbit had a normal ocular appearance at 9 through 15 days. Minor conjunctival redness was again evident in this animal at 21 days. Minor conjunctival redness persisted in the other rabbit at this time.

Following the application of 0.01 ml of isobutanol onto 4 rabbit eyes, minor corneal injury was observed in 2. Iritis and moderate to severe conjunctival irritation were apparent in all 4 rabbit eyes. At 48 and 72 hours, 2 rabbits had hemorrhages of the nictitating membrane and/or sclera. One rabbit had a normal ocular appearance at 72 hours and another 2 rabbit eyes were healed at 7 days. All 4 rabbits had a normal ocular appearance by 14 days.
Other effects:
Both animals dosed with 0.1 ml had alopecia of the periocular area (with a small scab on 1) by 9 days.

Applicant's summary and conclusion

Interpretation of results:
irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Instillation of 0.1 ml of isobutanol into rabbit eyes produced severe ocular irritation. Minor conjunctival redness was still evident at 21 days. MinorModerate to severe irritation was produced from the application of 0.01 ml.
Executive summary:

2-methylpropan-1-ol /Isobutyl alcohol/ is both reagents used in the manufacture of Reaction mass of 2-methylpropan-1-ol and sodium O-isobutyl dithiocarbonate and sodium hydroxide . Therefore, 2-methylpropan-1-ol /Isobutyl alcohol/ need to be considered in the assessment of Reaction mass of 2-methylpropan-1-ol and sodium O-isobutyl dithiocarbonate and sodium hydroxide.

The eye irritation potential of isobutanol was examined in rabbits. Instillation of 0.1 ml of isobutanol into rabbit eyes produced severe ocular irritation. Minor conjunctival redness was still evident at 21 days. Moderate to severe irritation was produced from the application of 0.01 ml.