UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, 

### D.C. 20460

MEMORANDUM Date: January 12, 2016 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

SUBJECT: Fluridone: Updated executive summaries for 21-day dermal toxicity in rabbits and 90-day oral toxicity in dogs PC Code: 112900 Decision No.: 494948 Petition No.: NI A Risk Assessment Type: 

### N /A TXR No.: 0057340 MRID No.: 00103299, 00082344 DP Barcode: D431022 Registration No.: NIA Regulatory Action: N/A Case No.: NI A CAS No.: 59756-60-4 40 CFR: NIA
FROM: Austin Wray, Ph.D., Toxicologist 

# ,1

# ~ 1./r--z.c:::::::::.....---

- Risk Assessment Branch IV, 

# /t Health Effects Division (7509P)
THROUGH: Michael S. Metzger, Branch

# Chief**~** J /) {) Risk Assessment Branch V

### NII 

# A(f.av{ / Health Effects Division (7509P) ·
TO: Sarah Meadows, Risk Manager Reviewer Kathryn Montague, Risk Manager Herbicide Branch Registration Division (7505P)
I. CONCLUSIONS: The classification for the 90-day oral toxicity study in dogs was upgraded from Unacceptable/Guideline to Acceptable/Non-guideline. The LOAEL was not established in this study and the NOAEL was 200 mg/kg/day (HDT). The 2 1-day dermal toxicity study in rabbits (MRID 00103299) is classified Acceptable/Guideline. The LOAEL for systemic toxicity was not established
. The NOAEL for Page I of4systemic toxicity was 768 mg/kg/day
. The LOAEL for dermal toxicity was 192 mg/kg/day based on transient, slight erythema in 9/10 animals accompanied by slight desquamation. The NOAEL was not established. 

### II. ACTION REQUESTED: Revise executive summaries for DERs that are not up to date with current HED toxicology policies. 

### III.BACKGROUND: The executive summaries for the 21-day dermal study in rabbits and 90-day oral toxicity study in dogs were updated to make them more consistent with current HED toxicology polices regarding adverse effect identification and study classification. 

### IV. RESULTS/DISCUSSION: 870.3150 90-Day Oral Toxicity- Dog MRID 00082344 In a 90-day oral toxicity study (MRID No. 00082344), fluridone (98.6% a.i. Lot# 597-B29- 200C) was administered to 4 beagle dogs/sex/dose in capsules at doses of0, 50, 100, or 200 mg/kg/day. No adverse, treatment-related effects were observed on survival, clinical signs, body weight, body weight gain, food consumption, hematology, bone marrow analysis, urinalysis, organ weights, gross pathology, or microscopic pathology. 

### The LOAEL for fluridone in dogs is not established and the NOAEL is equal or greater than 200 mg/kg/day (HDT). This 90-day oral toxicity study is classified 

### Acceptable/Non-Guideline and does not satisfy the guideline requirements for a 90-day oral toxicity study in the dog [OCSPP 870.3150 (§82-1b)]. Although the results reported were valid for the doses tested, the study is classified non-guideline because no adverse effects were observed at the high dose (200 mg/kg/day). Dose selection for the 90-day study was based on a slight body weight reduction observed at 200 mg/kg/day in a range finding study. This minor body weight effect is not indicative of an adverse response to treatment and suggests the animals could have tolerated a higher dose in the 90-day study. However, another 90-day guideline non-rodent study is not required at this time because the toxicological data requirements are satisfied by the I-year feeding study in dogs (MRID No. 00103336). [NOTE: This study was classified as minimum (acceptable) in the previous review (TXR No
. 000824).] 

### COMPLIANCE: Signed and dated GLP, Quality Assurance, and Data Confidentiality statements were not provided; however, the study was conducted prior to the adoption ofGood Laboratory Practice standards. 

### COMMENTS: The classification ofthis study was changed from 

### Unacceptable/Guideline to 

### Acceptable/Non-guideline. According to current policy a study with no observed adverse Page 2 of4effects at the highest dose tested is considered acceptable ifthe study is conducted properly. However, the study did not meet the guideline requirements for dose selection (i.e. dogs could have tolerated a higher dose) and, as a result, is classified as a non-guideline study. 

### 870.3200 21128-Day Dermal Toxicity- Rabbit MRID 00103299 In a 21-day dermal toxicity study (MRID No
. 00103299) , groups ofNew Zealand white rabbits (5/sex/dose group) received Fluridone 4AS (Lot No.: #X-36339; purity: 44.5% a.i.) by dermal application at doses ofO, 192, 384 or 768 mg/kg/day for 21 days (6 hours/day and 5 days/week). No adverse, treatment-related effects were observed on survival, clinical signs, body weight, body weight gain, food consumption, hematology, clinical chemistry, organ weights, or gross or histological pathology. Localized dermal reactions included the following: Animals in the 192 mg/kg/day group (20% formulation) showed transient, slight erythema in 9/ 10 animals, accompanied by slight desquamation. Animals in the 384 mg/kg /day group (40% formulation) showed moderate, well-defined erythema, slight edema and mild desquamation, and epidermal fissures in 3/ 10 rabbits. Animals in the 768 mg/kg/day group (80% formulation) showed moderate to severe erythema with epidermal fissures in 8/ 10 rabbits , accompanied by slight edema. Differences in the dermal response between abraded and non-abraded skin were not statistically significant. 

### The LOAEL for systemic toxicity was not established. The NOAEL was 768 mg/kg/day. The LOAEL for dermal toxicity was 192 mg/kg/day based on transient, slight erythema in 9/10 animals accompanied by slight desquamation. The NOAEL for dermal toxicity was not established. This 21-day dermal toxicity study is classified 

### Acceptable/Guideline and satisfies the guideline requirement for a 21-day dermal toxicity study (82-2) in the rabbit. 

### COMPLIANCE: A signed and dated Quality Assurance statement was included in the study. Signed and dated GLP and Data Confidentiality statements were not provided; however, the study was conducted prior to the adoption ofGood Laboratory Practice standards
. 

### COMMENTS: The systemic NOAEL/LOAEL was updated to reflect current HED toxicology polices regarding identification ofadverse treatment-related effects. Previously the kidney effects were used to establish the LOAEL at 768 mg/kg /day. Re-evaluation ofthe study revealed a statistically significant but not biologically significant decreased in relative kidney weight (!15%) in high dose males. Furthermore, there were no concurrent effects in the histopathology Page 3 of4or clinical chemistry indicative ofkidney toxicity. Based on the lack ofcorroborating evidence for kidney toxicity, the decrease in relative kidney weight was considered not adverse. The LOAEL and NOAEL were revised to indicate no systemic toxicity occurred at dermal doses up to 768 mg/kg/day.

Page 4 of4Subchronic (2 1-da y) Dermal Toxicity Study (1981) I Page I of2 Fluridone / 1 12900 OCSPP 870.3200/ DACO 4.3.5/ OECD 410 

### EPA Reviewer: Austin 

### Wray, Ph.D. Signature: 

# ;l;:&::**~** Risk Assessment Branch IV, Health Effects Division (7509P) Date: 

### I

# $j 

# =, EPA Secondary Reviewer: Ronnie J. Bever Jr. , PhD, DABT 

### Signature: : · . Risk Assessment Branch VII, Health Effects Division (7509P) Date: 

# J TXR#: 0057340 

### DATA EVALUATION RECORD

- Supplemental See TXR # 004039 for root DER Template version 09/ 11



### STUDY TYPE: 21-Day Dermal Toxicity

- Rabbit; OCSPP 870.3200 [§82-2] ; OECD 410. 

### PC CODE: 112900 

### DP BARCODE: D431022 

### TEST MATERIAL (PURITY): Fluridone 4AS (44.5% a.i.) 

### SYNONYMS: EL-171; Compound 112371 

### CITATION: Pierson, C.; Probst, G.; Jordan, W. ; et al. (1981) Subchronic (Three Week) Dermal Toxicity Study in Rabbits with an Aqueous Suspension Containing 4 Pounds per Gallon Fluridone, Compound 112371. Lilly Research Laboratories, Greenfield, Indiana. Study B-7300
. June 10, 1982. MRID 00130299. Unpublished. 

### SPONSOR: Elanco 

### EXECUTIVE SUMMARY: In a 21-day dermal toxicity study (MRID No. 00103299) , groups ofNew Zealand white rabbits (5/sex/ dose group) received Fluridone 4AS (Lot No.: #X-36339; purity: 44.5% a.i.) by dermal application at doses of0, 192, 384 or 768 mg/kg/day for 21 days (6 hours/day and 5 days/week)
. No adverse, treatment-related effects were observed on survival, clinical signs, body weight, body weight gain, food consumption, hematology, clinical chemistry, organ weights, or gross or histological pathology. Localized dermal reactions included the following: Animals in the 192 mg/kg/day group (20% formulation) showed transient, slight eryt hema in 9/ 10 animals, accompanied by slight desquamation. Animals in the 384 mg/kg/day group (40% formulation) showed moderate, well-defined erythema, slight edema and mild desquamation, and epidermal fi ssures in 3/ 10 rabbits
. Animals in the 768 mg/kg/day group (8 0% formulation) showed moderate to severe erythema with epidermal fissures in 8/ 10 rabbits, accompanied by slight edema. Differences in the dermal response between abraded and non-abraded skin were not statisticallyFluridone / 112900 significant. Subchronic (21-da y) Denna! Toxicity Study (1981) I Page 2 of2

OCSPP 870.3200 / DACO 4.3.5/ OECD 410



### The LOAEL for systemic toxicity was not established. The NOAEL was 768 mg/kg/day. The LOAEL for dermal toxicity was 192 mg/kg/day based on transient, slight erythema in 9/10 animals accompanied by slight desquamation. The NOAEL for dermal toxicity was not established. This 21-day dermal toxicity study is classified 

### Acceptable/Guideline and satisfies the guideline requirement for a 21-day dermal toxicity study (82-2) in the rabbit. 

### COMPLIANCE: A signed and dated Quality Assurance statement was included in the study. Signed and dated GLP and Data Confidentiality statements were not provided; however, the study was conducted prior to the adoption ofGood Laboratory Practice standards
. 

### COMMENTS: The systemic NOAEL/LOAEL was updated to reflect current HED toxicology polices regarding identification ofadverse treatment-related effects. Previously the kidney effects were used to establish the LOAEL at 768 mg/kg/day. Re-evaluation ofthe study revealed a statistically significant but not biologically significant decreased in relative kidney weight (115%) in high dose males
. Furthermore, there were no concurrent effects in the histopathology or clinical chemistry indicative ofkidney toxicity
. Based on the lack ofcorroborating evidence for kidney toxicity, the decrease in relative kidney weight was considered not adverse
. The LOAEL and NOAEL were revised to indicate no systemic toxicity occurred at dermal doses up to 768 mg/kg/day.Subchronic (90-day) Oral Toxicity Study (non-rodents) (1978) I Page 1 of2 Fluridone / 112900 OCSPP 870.3150 / DACO 4.3.8/ OECD 409 

### EPA Reviewer: Austin Wrav. Ph.D. 

### Signature:

# ~**1J~** Risk Assessment Branch IV, Health Effects Division (7509P) Date: I**I~** 

## .!l EPA Secondary Reviewer: Ronnie J. Bever Jr., PhD, DABT 

### Signature:&

### ~-**.** 

## 'Bf»Pu11
. Risk Assessment Branch VII, Health Effects Division (7509P) Date:

### 1/j~46 Template version 09/11 TXR#: 0057340 

### DATA EVALUATION RECORD

- Supplemental See TXR # 000824 for root DER 

### STUDY TYPE: Subchronic Oral Toxicity [feeding]

- dog; OCSPP 870
.3150 (§ 82-1b] (nonrodent); OECD 409
. 

### PC CODE: 112900 

### DP BARCO DE: D431022 

### TEST MATERIAL (PURITY): Fluridone (98
.6% a.i.) 

### SYNONYMS: EL-171; Compound 112371 

### CITATION: Probst, G .S. ; Dietert, S.E
. ; Hoffman, D.F.; et al. (1978) A 3 -month Oral Toxicity Study ofEL-171 in Beagle Dogs. Lilly Research Laboratories, Greenfield, Indiana. Toxicology Report No. 9. August 21, 1978. MRID 00082344. Unpublished 

### SPONSOR: Elanco 

### EXECUTIVE SUMMARY: In a 90-day oral toxicity study (MRID No. 00082344) , fluridone (98.6% a.i. Lot # 597-B29- 200C) was administered to 4 beagle dogs/sex/dose in capsules at doses of0, 50, 100, or 200 mg/kg/day. No adverse, treatment-related effects were observed on survival, clinical signs, body weight, body weight gain, food consumption, hematology, bone marrow analysis, urinalysis, organ weights, gross pathology, or microscopic pathology. 

### The LOAEL for tluridone in dogs is not established and the NOAEL is equal or greater than 200 mg/kg/day (HDT). This 90-day oral toxicity study is classified 

### Acceptable/Non-Guideline and does not satisfy the guideline requirements for a 90-day oral toxicity study in the dog [OCSPP 870.3150 (§82-1 b)]. Although the results reported were valid for the doses tested, the study is classified non-guideline because no adverse effects were observed at the high dose (200 mg/kg/day). Dose selection for the 90-day study was based on a slight body weight reduction observed at 200 mg/kg/day in a range finding study. This minor body weight effect is not indicative ofan adverse response to treatment and suggests the animals could have tolerated a higher dose in the 90-day study. However, another 90-day guideline non-rodent study is not required at this time because the toxicological data requirements are satisfied by the I-year feeding study in dogs (MRID No. 00103336)
. [NOTE: This study was classified as minimum (acceptable) in the previous review (TXR No. 000824).]Fluridone/112900 Subchronic (90-day) Oral Toxicity Study (non-rodents) (1978) I Page 2 of2 OCSPP 870.3150/ DACO 4.3
.8/ OECD 409 COMPLIANCE : Signed and dated GLP, Quality Assurance, and Data Confidentiality statements were not provided; however, the study was conducted prior to the adoption ofGood Laboratory Practice standards
. COMMENTS : The classification ofthis study was changed from Unacceptable/Guideline to Acceptable/Non-guideline
. According to current policy a study with no observed adverse effects at the highest dose tested is considered acceptable ifthe study is conducted properly
. However, the study did not meet the guideline requirements for dose selection (i.e
. dogs could have tolerated a higher dose) and, as a result, is classified as a non-guideline study.