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 21-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 of4 

Page 1 of 8 Page 1 of 8
systemic 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 of 0, 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 (§82-1 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 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 of Good 

Laboratory Practice standards. 

COMMENTS: The classification of this study was changed from Unacceptable/Guideline to 

Acceptable/Non-guideline. According to current policy a study with no observed adverse 

Page 2 of4 

Page 2 of 8 Page 2 of 8
effects at the highest dose tested is considered acceptable if the 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 of Good Laboratory Practice standards. 

COMMENTS: The systemic NOAEL/LOAEL was updated to reflect current HED toxicology 

polices regarding identification of adverse treatment-related effects. Previously the kidney 

effects were used to establish the LOAEL at 768 mg/kg/day. Re-evaluation of the 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 of4 

Page 3 of 8 Page 3 of 8
or clinical chemistry indicative of kidney toxicity. Based on the lack of corroborating 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 of4 

Page 4 of 8 Page 4 of 8
Subchronic (21-day) Dermal Toxicity Study (1981) I Page I of2 

Fluridone/112900 OCSPP 870.3200/ DACO 4.3.5/ OECD 410 

EPA 

Risk Assessment 

Reviewer: 

Branch 

Austin 

IV, 

Wray, 

Health 

Ph.D. 

Effects Division (7509P) 

Signature: 

Date: I $j ;l;:&:: ~ = , 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 of 0, 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 

Page 5 of 8 Page 5 of 8
Fluridone/ 112900 

significant. 

Subchronic (21-day) Denna! Toxicity Study (1981) I Page 2 of 2 

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 of Good Laboratory Practice standards. 

COMMENTS: The systemic NOAEL/LOAEL was updated to reflect current HED toxicology 

polices regarding identification of adverse treatment-related effects. Previously the kidney 

effects were used to establish the LOAEL at 768 mg/kg/day. Re-evaluation of the 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 of kidney toxicity. Based on the lack of corroborating 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 6 of 8 Page 6 of 8
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 (§82-1 b] (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 of 0, 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 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).] 

Page 7 of 8 Page 7 of 8
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 of Good 

Laboratory Practice standards. 

COMMENTS: The classification of this 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 if the 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. 

Page 8 of 8 Page 8 of 8