Document jNjQkbaDQVXYYJN6z658YbvMR

436 TRADE SECRET Study Title H-25357: Acute Eye Irritation Study in Rabbits Laboratory Project ID: DuPont-11111 DuPont-1l i l i Test Guidelines: U.S. EPA Health Effects Test Guidelines OPPTS 870.2400 (1998) OECD Guidelines for Testing of Chemicals Section 4: Health Effects, No. 405 (1987) Commission Directive 92/69/EEC EEC Method B.5 (1992) A uthor: Carol Finlay, B.A. Study Completed on: August 9,2002 Performing Laboratory: E.I. du Pont de Nemours and Company Haskell Laboratory for Health and Environmental Sciences Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 Page 1 of 17 Company Sanitized. Does not contain TSCA CBI H-25357: Acute Eye Irritation Study in Rabbits DuPont-11111 GOOD LABORATORY PRACTICE COM PLIANCE STATEM ENT This study was conducted in compliance with U.S. EPA TSCA (40 CFR part 792) Good Laboratory Practice Standards, which are consistent with the OECD Principles of Good Laboratory Practice (as revised in 1997) published in ENV/MC/CHEM(98)17, except for the item documented below. The item listed does not impact the validity of the study. The test substance was characterized by the sponsor prior to the initiation of this study. Although the characterization was not performed under Good Laboratory Practice Standards, the characterization was done by an ISO 9000 certified lab and the accuracy of the data is considered sufficient for the purposes of this study. Applicant / Sponsor: E.I. du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A. Study Director: t-AAbL i Cafri Finlay, ] A . Staff Toxicologist - &Ji 4 - D at? Applicant / Sponsor:_______________________________________ _________ DuPont Representative Date .Company Sanitized. Does not contain TSCA Cm H-25357: Acute Eye Irritation Study in Rabbits QUALITY ASSURANCE STATEM ENT Haskell Sample Number(s): 25357 Dates of Inspections: Protocol: June 24, 2002 Conduct: June 24, 2002 Records, Reports: August 1, 2002 Dates Findings Reported to: Study Director: August 2, 2002 Management: August 2,2002 Reported by: Quality Assurance Auditor D u P o n t-11111 Company Sanitized, Does not contain TSCA CEB H-25357: Acute Eye Irritation Study in Rabbits DuPont-11111 C E R T IF IC A T IO N We, the undersigned, declare that this report provides an accurate evaluation of the data obtained from this study. Reviewed by: f O h t f / w F llaammeessCC..ftetackay II Associate Scientist C -, 2#*- D ite Issued by Study Director: f (LAM - C api Finlay, B-ft. Staff Toxicologist 1 Datfr-" Company Sanitized. D oes not contain TSCA CB1 -4 - H-25357: Acute Eye Irritation Study in Rabbits STUDY INFORM ATION Substance Tested: 3 Synonyms/Codes: H-25357 Submitter's Notebook NumberCs Haskell Number: 25357 CAS Registry Number: Compositions Purity* * > Known Impurities: D u P o n t-11111 Physical Characteristics: Amber liquid Sponsor: E.I. du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A. Study Initiated/Completed: June 14, 2002 / (see report cover page) In-Life Initiated/Completed: June 24, 2002 / June 27, 2002 Company Sanitized, Does not contain TSCA C8S -5- H-25357: Acute Eye Irritation Study in Rabbits DuPont-11111 STUDY PERSONNEL Study Director: Carol Finlay, B.A. Management: Scott E. Loveless, Ph.D. Primary Technician: James C. Mackay II Toxicology Report Preparation: Sean M. Callaghan, B.A. Management: Nancy S. Selzer, M.S. Laboratory Veterinarian: William Singleton, D.V.M., A.C.L.A.M. .Company Sanitized. Does not eo1** -6 - rnt H-25357: Acute Eye Irritation Study in Rabbits DuPont-11111 SUM M ARY H-25357 was evaluated for acute eye irritation potential in 3 adult New Zealand White rabbits. An aliquot of 0.1 mL of test substance was administered to 1 eye of each test animal. The eyes remained unwashed following treatment. The conjunctiva, iris, and cornea of each treated eye were evaluated and scored according to a numerical scale approximately 1,24,48, and 72 hours following administration of the test substance. Two rabbits pawed the treated eye after instillation of the test substance. The test substance produced conjunctival redness (score of 1) in the treated eyes of two rabbits and discharge (score of 1) in the treated eyes of 2 rabbits. Fluorescein stain examinations were negative for corneal injury in the treated eyes of all rabbits. The treated eyes of the rabbits were normal by 24 or 48 hours after instillation of the test substance. No clinical signs were observed. Body weight loss of approximately 4% of initial weight occurred by study termination (72 hours) in one rabbit. Mean values were calculated for each animal separately by using numerical scores obtained from the quantitative evaluation of each ocular response observed in each rabbit approximately 24, 48, and 72 hours following treatment. These values are as follows: RABBIT NUMBER 35553 35502 35566 CORNEAL OPACITY 0.00 0.00 0.00 IRITIS 0.00 0.00 0.00 CONJUNCTIVAL REDNESS 0.33 0.00 0.00 CONJUNCTIVAL CHEMOSIS 0.00 0.00 0.00 In accordance with Directive 67/548/EEC, H-25357 is not classifiable as irritant. fem p anf .Sanitized. Does not contain TSCA CM H-25357: Acute Eye Irritation Study in Rabbits DuPont-11111 IN T R O D U C T IO N A. Objective The objective of this study was to evaluate the eye irritation potential and the reversibility of ocular effects of H-25357 following a single ocular application to albino rabbits. The results of the study were used to determine the appropriate toxicity classification and labeling requirements in accordance with EEC. B. Principles of the M ethodology Ocular effects are evaluated and scored approximately 1, 24, 48, and 72 hours after instillation of 0.1 mL of test substance (or a weight of not more than 100 mg of test substance) into the lower conjunctival sac of 1 eye of each of 3 rabbits. The reversibility of any effects is assessed for up to 21 days, if necessary. Ocular effects are scored according to the Draize Scale (Table 1). M ATERIALS AND M ETHODS A. Test Guidelines The study design complies with the following test guidelines: Office of Prevention, Pesticides and Toxic Substances (OPPTS) U.S. Environmental Protection Agency (EPA) (1998). OPPTS 870.2400 Acute Eye Irritation. Health Effects Test Guidelines. Organisation for Economic Co-Operation and Development (OECD) (1987). 405 Acute Eye Irritation/Corrosion. Guidelinefor Testing o f Chemicals. European Economic Communities (EEC) (1992). Directive 92/69/EEC Annex V, Part B.5, Acute Toxicity (Eye Irritation). Methodsfor the Determination o f Toxicity. B. Test Substance The test substance, H-25357, was supplied by the sponsor as an amber liquid. The test substance was inverted to mix before each amount for dosing was removed. The test substance appeared to be stable under the conditions of the study. No evidence of instability, such as a change in color or physical state, was observed. E gm pa p f Sanitized, Does not contain TSCA C S H-25357: Acute Eye Irritation Study in Rabbits D u P o n t-11111 C. Anim al H usbandry Adult HM:(NZW)fBR New Zealand White rabbits were received from Covance Research Products, Denver, Pennsylvania. The rabbits were housed singly in stainless steel, wire-mesh cages suspended above cage boards. Each rabbit was assigned a unique identification number which was recorded on a card affixed to the cage. The last 3 digits of the identification number were written on the inside of each rabbit's ear with a water insoluble marker. The rabbits were offered approximately 125 grams of PMI Nutrition International, LLC Certified High Fiber Rabbit LabDiet 5325 daily during the study. Water was available ad libitum. As specified in the Haskell Laboratory animal health and environmental monitoring program, the following procedures are performed periodically to ensure that contaminant levels are below those that would be expected to impact the scientific integrity of the study: * Water samples are analyzed for total bacterial counts, and the presence of coliforms, lead, and other contaminants. Feed samples are analyzed for total bacterial, spore, and fungal counts. Samples from freshly washed cages and cage racks are analyzed to ensure adequate sanitation by the cagewashers. Certified animal feed is used, guaranteed by the manufacturer to meet specified nutritional requirements and not to exceed stated maximum concentrations of key contaminants, including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The presence of these contaminants below the maximum concentration stated by the manufacturer would not be expected to impact the integrity of the study. The animal health and environmental monitoring program is administered by the attending laboratory animal veterinarian. Evaluation of these data did not indicate any conditions that affected the validity of the study. Rabbits were weighed and observed for general health during the 7-day quarantine period. Animal rooms were maintained on a timer-controlled, 12-hour light/12-hour dark cycle. Environmental conditions of the rooms were targeted for a temperature of 20C 1C and relative humidity of 50% 10%. Excursions outside these ranges were judged to have been of insufficient magnitude and/or duration to have adversely affected the validity of the study. D. Protocol On the day of treatment, the eyes of 3 male New Zealand White rabbits were examined using illumination, magnification, and fluorescein stain. Animals used on this study were free of pre existing corneal or conjunctival injury or irritation and were judged to be in good health. The rabbits weighed from 2082 to 2592 grams on the day of treatment. c mpa,ly Sanil* * <***. H-25357: Acute Eye Irritation Study in Rabbits DuPont-11111 An aliquot of 0.1 ml of H-25357 was introduced into the lower conjunctival sac of the right eye of each rabbit. The left eye of each rabbit was not treated with the test substance and served as a control. The treated and control eyes of all rabbits remained unwashed. Each rabbit was observed for approximately 30 to 60 seconds before being returned to its cage. Approximately 1, 24, 48, and 72 hours after H-25357 was administered, the rabbits were examined for evidence of eye irritation and for clinical signs of toxicity. At each of these observation periods, eyes were examined using illumination and magnification and scored for ocular reactions according to the Draize Scale (Table 1). Any other adverse ocular reactions, particularly those indicative of corrosive action, were also noted. Control eyes were not scored. These untreated eyes were used for comparison and were considered "normal" relative to the treated eye. Fluorescein stain examinations were conducted at the 24-hour and each subsequent evaluation. The rabbits were weighed on the day of treatment and at the last ocular evaluation. E. Data Analysis and Interpretation of Results For each animal, a mean value was calculated for each lesion (corneal opacity, iritis, conjunctival redness, and conjunctival chemosis) by averaging the scores obtained from the 24-, 48-, and 72hour observations. The results were interpreted according to Directive 67/548/EEC relative to the general classification and labeling requirements for dangerous substances. The test substance will be classified as "IRRITANT" and will require the symbol "Xi" and the indication of danger "IRRITANT" in accordance with the criteria below. In addition, the following risk (R) phrases will be assigned to substances classified "IRRITANTS" as applicable, according to the following criteria: R36 "IRRITATING TO EYES" The risk phrase, R36 "IRRITATING TO EYES", will be assigned if, when applied to the eye of the test animal, the test substance causes significant ocular lesions which occur within 72 hours after exposure and which persist for at least 24 hours. Ocular lesions are significant if the individual animal mean values of the 24-, 48-, and 72-hour evaluations in 2 or more animals comply with any of the following criteria: - corneal opacity - iridial lesion - conjunctival redness - conjunctival chemosis equal to or greater than 2.0, but less than 3.0 equal to or greater than 1.0, but less than 2.0 equal to or greater than 2.5 equal to or greater than 2.0 Company Sanitized. Does not contain TSCA CBI - 10- H-25357: Acute Eye Irritation Study in Rabbits DuPont-11111 R41 "RISK OF SERIOUS DAMAGE TO THE EYES" The risk phrase, R41 "RISK OF SERIOUS DAMAGE TO THE EYES", will be assigned if the test substance causes severe ocular lesions which occur within 72 hours after exposure and which persist for at least 24 hours. Ocular lesions are severe if the individual animal mean value of the 24-, 48-, and 72-hour evaluations in 2 or more animals comply with any of the following criteria: - corneal opacity equal to or greater than 3.0 - iridial lesion equal to 2.0 R41 "RISK OF SERIOUS DAMAGE TO THE EYES" risk phrase is also required if: - ocular lesions are still present 21 days following treatment - the test substance causes irreversible coloration of the eyes Company Sanitized. Does not contain TSCA CB H-25357: Acute Eye Irritation Study in Rabbits DuPont-11111 RESULTS AND DISCUSSION Two rabbits pawed the treated eye after instillation of the test substance. The test substance produced conjunctival redness (score of 1) in the treated eyes of two rabbits and discharge (score of 1) in the treated eyes of 2 rabbits. Fluorescein stain examinations were negative for corneal injury in the treated eyes of all rabbits. The treated eyes of the rabbits were normal by 24 or 48 hours after instillation of the test substance. No clinical signs were observed. Body weight loss of approximately 4% of initial weight occurred by study termination (72 hours) in one rabbit. The ocular scores from individual animals with respect to observation time are presented in Table 2. Mean ocular scores calculated in accordance with EEC are presented in Table 3. Individual body weights and clinical signs of toxicity are presented in Table 4. C O N C L U SIO N In accordance with Directive 1999/45/EEC, H-25357 is not classifiable as irritant. RECORDS AND SAMPLE STORAGE All data and records for analytical characterization conducted by the sponsor will be maintained at Chambers Works, Deepwater, New Jersey or at Iron Mountain Records Management, Wilmington, Delaware. Specimens (if applicable), raw data, and the final report will be retained at Haskell Laboratory, Newark, Delaware, or at Iron Mountain Records Management, Wilmington, Delaware. Company Sanitized. Does not contain TSCA c r t H-25357: Acute Eye Irritation Study in Rabbits DuPont-11111 TABLES fietnpany Sanitized. Does not contain TS6A CBs -13 - H-25357: Acute Eye Irritation Study in Rabbits DuPont-11111 TABLE 1 DRAIZE3SCALE FOR SCORING OCULAR LESIONS (1) Cornea (A) Opacity-degree o f density (area most dense takenfor reading) No opacity........................................................................................0 Scattered or diffuse area, details of iris clearly visible................... 1 Easily discernible translucent areas, details of iris slightly o b sc u red ..................................................................................... 2 Opalescent areas, no details of iris visible, size of pupil barely discernible............................................................... 3 Opaque, iris invisible........................................................................ 4 (B) Area o f cornea involved One quarter (or less) but not zero................................................. 1 Greater than one quarter, butless than half....................................... 2 Greater than one half, but less than three quarters......................... 3 Greater than three quarters, up to whole area............. 4 (2) Iris (A) Values Normal..................................................................................... 0 Folds above normal, congestion, swelling, circumcomeal injection (any or all of these or combination of any thereof) iris still reacting to light (sluggish reaction is positive)........... 1 No reaction to light, hemorrhage, gross destruction (any or all of these)..................................... 2 (3) Conjunctiva (A) Redness (refers topalpebral and bulbar conjunctiva excluding cornea and iris) Vessels normal................................................................................. 0 Vessels definitely injected above normal....................................... 1 More diffuse, deeper crimson red, individual vessels not easily discernible..................................................................................2 Diffuse beefy red............................................................................ 3 Company Sanitized. Does not contain TSCA CB1 H-25357: Acute Eye Irritation Study in Rabbits D u P o n t-11111 TABLE 1 (Continued) DRAKE SCALE FOR SCORING OCULAR LESIONS (B) Chemosis No swelling.................................................................................... 0 Any swelling above normal (includes nictitating membrane)........ 1 Obvious swelling with partial eversion of lids............................... 2 Swelling with lids about half closed.............................................. 3 Swelling with lids about half closed to completely closed............ 4 (C) Discharge No discharge.....................................................................................0 Any amount different from normal (does not include small amounts observed in inner canthus of normal animals)........... 1 Discharge with moistening of the lids and hairs just adjacent to lids............................................................................ 2 Discharge with moistening of the lids and hairs, and considerable area around the eye.............................................. 3 a Draize, J. H., "Dermal Toxicity." Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics. The Editorial Committee of the Association o f Food and Drug Officials o f the United States, Austin, Texas, 1959, pp. 46-59. 9m pany Sanitized. Does not eonf*H - 15- ) H-25357: Acute Eye Irritation Study in Rabbits ) ) DuPont-11111 TABLE 2 INDIVIDUAL RABBIT OCULAR IRRITATION SCORES FOLLOWING TREATMENT WITH H-25357 RABBIT READING NUMBER 35553 1 HOUR 35502 35566 35553 24 HOURS 35502 35566 35553 48 HOURS 35502 35566 35553 72 HOURS 35502 35566 CORNEA OPACITY AREA IRITIS 0 00 0 00 0 00 0 00 0 00 0 00 0 00 0 00 0 00 0 00 0 00 0 00 REDNESS 0 0 1 1 0 0 0 0 0 0 0 0 CONJUNCTIVA CHEMOSIS 0 0 0 0 0 0 0 0 0 0 0 0 DISCHARGE 1 1 0 1 0 0 0 0 0 0 0 0 FLUORESCEIN STAIN NA NA NA NEG NEG NEG NEG NEG NEG NEG NEG NEG NEG - negative for corneal injury .Company Sanitized, Does not contain TSCA CE -16- H-25357: Acute Eye Irritation Study in Rabbits DuPont-11111 TABLE 3 MEAN SCORES3FOR OCULAR RESPONSES FOR INDIVIDUAL RABBITS RABBIT NUMBER 35553 35502 35566 CORNEAL OPACITY 0.00 0.00 0.00 IRITIS 0.00 0.00 0.00 CONJUNCTIVAL REDNESS 0.33 0.00 0.00 CONJUNCTIVAL CHEMOSIS 0.00 0.00 0.00 a 24hr + 48hr + 72hr/3. Calculated according to EEC. TABLE 4 INDIVIDUAL BODY WEIGHTS OF RABBITS RABBIT INITIAL WEIGHT FINAL WEIGHT (72 HOURS) NUMBER SEX (R) (g) 35553 M 2082 1989 35502 M 2592 2604 35566 M 2110 2120 CLINICAL SIGNS OF TOXICITY OBSERVED IN RABBITS No clinical signs of toxicity were observed in any of the rabbits during the study. -17Does not contain tsc Ci