UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

MEMORANDUM 

DA TE: July 20, 2015 

SUBJECT: Bromuconazole. Human Health Scoping Document in Support of Registration Review. 

PC Code: 120503 

Decision No.: 504955 

Petition No.: NA 

DP Barcode: D427265 

Registration No.: NA 

Regulatory Action: Registration Review 

Scoping Document 

Risk Assessment Type: NA 

TXRNo.: NA 

Case No.: 7035 

CAS No.: 116255-48-2 

MRID No.: NA 40 CFR: NA 

FROM: 

THROUGH: 

TO: 

Barry O'Keefe, Senior Biologist 

Vincent Chen, Toxicologist 

Risk Assessment Branch III (RAB3) 

Health Effects Division (7509P) 

Office of Pesticide Programs 

Christine Olinger, Branch Chief /J/ / ';// ' 

Risk Assessment Branch Ill (RAB~ f-/- (__ 

Health Effects Division (7509P) 

Office of Pesticide Programs 

James Parker, Chemical Review Manager 

Tom Moriarty, Team Leader 

Neil Anderson, Branch Chief 

Risk Management and Implementation Branch I (RMIB I) 

Pesticide Re-Evaluation Division (PRD) (7508P) 

Office of Pesticide Programs 

Executive Summa ry 

Following is the Health Effects Division's (HED's) human health scoping document for the 

fungicide bromuconazole to support Registration Review. To evaluate the scope of work 

necessary to support Registration Review, HED has considered previous risk assessments for 

bromuconazole: updates to its toxicity, exposure. and usage databases; and the latest Agency 

science policy and risk assessment methodologies. The only risk assessment for bromuconazole 

was conducted in 2002 (028 1745. J. Arthur. 09118/2002). That assessment was for occupational 

exposures, which are the only ru1ticipated exposures from the sole registered use of 

Page I of 18 
bromuconazole on roses, grown commercially in greenhouses, to control black spot growth. 

There are no residential uses. 

The toxicology database is adequate for risk assessment. In repeated dose studies the most 

consistently observed effects of bromuconazole across species, sexes, and treatment durations 

was liver toxicity. There is no evidence of increased susceptibity following in utero exposure in a 

dermal developmental toxicity study in rats or following oral exposure to rabbits. There is no 

evidence of increased susceptibity following pre/post-natal exposure to rats. There is no concern 

for the increased susceptibility seen following oral exposure to rabbits, since there are no fooduses and thus no potential for dietary exposure by humans. Bromuconazole is classified as " not 

likely to be carcinogenic to humans.'· Bromuconazole did not cause mutagenicity or 

genotoxicity. There arc no neurotoxicity or immunotoxicity concerns with respect to 

bromuconazole. Dermal absorption has not been determined. 

New occupational handler and post-application exposure and risk assessments will be needed 

during Registration Review because policies on body weights and unit exposure values and 

assumptions have changed since the initial assessment. Also, the label (EPA Reg. No. 264-548) 

needs to be amended to include a 12 hour re-entry interval (REI), based on the acute toxicity of 

the technical grade of the active ingredient bromuconazole. 

Introduction 

Bromuconazole, a triazole that belongs to the demethylation-inhibitor fungicide group, blocks 

black spot growth by disrupting membrane formation through inhibiting the sterol biosynthesis 

pathway at the enzyme erg I l/cyp5 I. There are no mammalian molecular data to specifically 

demonstrate a mode of action in test animals. There is only one registered end use product (EPA 

Reg. No. 264-548), an emulsifiable concentrate. The only human health risk assessment for 

bromuconazole was completed in 2002 (0281745, J. Arthur, 09/ 18/2002). That assessment was 

for occupational exposures, which arc the only anticipated exposures from the sole registered use 

of bromuconazole on roses in greenhouses. Refer to Attachment 1 (Table 1) for the chemical 

identity of bromuconazole. 

Hazard Identification/Toxicology 

The studies available for risk assessment include an acute toxicity battery; subchronic oral 

toxicity studies in rats, mice and dogs; a subchronic dermal toxicity study in rabbits; chronic 

toxicity studies in rats and dogs; carcinogenicity studies in rats and mice; prenatal developmental 

toxicity studies in rats and rabbits; a reproduction and fertility effects study in rats; a battery of 

mutagenicity and genotoxicity studies; and a metabolism and pharmacokinetic study in rats. 

Based on a metabolism studies in rats, bromuconazole is well absorbed, extensively metabolized, 

and rapidly eliminated. Following the administration of oral doses to rats for fourteen days, 95-

102% of bromuconazole was recovered. Females excreted higher levels than males via urine, 

but males excreted more in their feces. 

Page 2of 18 
The most consistently observed effects of bromuconazole across species, sexes, and treatment 

durations was liver toxicity. 

In the rat, mouse, and dog repeat dose oral toxicity studies, the liver effects were manifested by 

increased liver weight and increased incidences of liver pathology (i.e., hepatocytic fatty 

vacuolation and hepatocytic degeneration). Liver effects were also observed in the rat dermal 

prenatal developmental toxicity study (i.e., increased maternal liver weights) and the 

reproduction and ferti lity effects study (i.e., increased parental li ver weights and increased 

incidences of hepatocytic fatty vacuolation). 

The database contained an oral and a dermal developmental toxicity studies in rats. In the oral 

developmental study, there was evidence for increased susceptibility; developmental effects (i.e., 

additional cervical ribs and increased placental weights) occurred at a dose lower than the dose 

that caused maternal toxicity (i.e., decreased body weight gain, and increased liver weights). Jn 

the dermal developmental toxicity study, there was no evidence of increased susceptibility; 

developmental effects (i.e., additional ribs) occurred at the same dose as the dose that caused 

maternal toxicity (i.e., ungroomed and unkempt coat). In the rat reproduction and fertility effects 

study, offspring toxicity was manifest as decreased pup viability and decreased pup body weight 

gain at the same dose as parental toxicity (i.e., decreased body weight gain, increased liver 

weights, and increased incidences of hepatocytic fatty vacuolation). In rabbits, there were no 

indications of reproductive susceptibility in utero. Overall, there are no residual uncertainty for 

pre/post-natal toxicity; there is no concern for the increased susceptibility seen in the oral 

developmental study, since there are no food-use (i.e no tolerance established) and therefore no 

potential for human dietary exposure. 

Bromuconazole is classified as "not likely to be carcinogenic to humans" based on the lack of 

evidence for carcinogenicity in mice and rats. Bromuconazole did not cause mutagenicity or 

genotoxicity in in vitro and in vivo assays. 

In the rabbit prenatal developmental toxicity study, maternal animals expressed clinical signs of 

toxicity that may indicate neurobehavioral effects such as: lethargy/reluctance to move, increased 

respiration rate, ataxic/unsteady gait, aggression, lack of muscle tone and coordination, prone 

posture, and vocalization. However, the Agency waived the acute and subchronic neurotoxicity 

studies since there are no dietary or oral exposure scenarios (TXR0057274, 25 June 20 15). 

The Agency waived the subchronic inhalation study because the inhalation margin of exposure 

(MOE) is greater than the Agency's level of concern for inhalation waivers(> 1000) 

(TXR0057274, 25 June 2015). 

The Agency waived the immunotoxicity study for the following reasons: ( 1) there was no 

evidence of adverse effects on the immune system in mice. rats, or dogs in the data base for any 

of the conazole pesticides; (2) the liver, not the immune system. is generally the target organ for 

this chemical class, and hepatotoxicity or body weight changes are the primary toxicological 

endpoints of concern and were used in risk assessments; (3) the conazoles do not belong to a 

class of chemicals (e.g., the organotins, heavy metals, or halogenated aromatic hydrocarbons) 

that would be expected to be immunotoxic. There was no evidence of immunotoxicity with six 

Page 3of 18 
other structurally-related conazole fungicides, namely, flutriafol, metconazole, tebuconazole, 

tetraconazole, triadimefon, triflumizole, and triticonazole. In the immunotoxicity study for 

triflumi zole, the effects on the immune system occurred only at the highest dose tested. 

Immunotoxicity was demonstrated with difenoconazole, however it was observed in the presence 

of systemic toxicity and at a relatively high dose; and ( 4) PODs based on the most sensitive 

endpoints obtained via the appropriate routes of exposure in the most sensitive species are 

currently used for dietary and non-dietary risk assessments (TXR0057274, 25 June 201 5). 

Bromuconazole has low to moderate toxicity via the oral (Toxicity Category lI), dermal 

(Toxicity Category III), and inhalation (Toxicity Category IV) routes; is a slight eye irritant 

(Toxicity Category IJI) and is not a dermal iITitant (Toxicity Category IV); and is not a dem1al 

sensitizer. 

Please refer to Attachment 3 for a summary of the toxicity endpoints and PODs for 

bromuconazole, and to Attachment 4 for the complete toxicity profile tables for bromuconazole. 

Conclusions: The toxicology database for bromuconazole is adequate for risk assessment of the 

current uses. At the time of Registration Review or the next risk assessment, the Agency will 

update PODs and endpoints since they are based on toxicological effects that the Agency no 

longer considers adverse. Additionally, the uncerta inty factors will be re-assessed in the context 

of the updated PO Os and endpoints. 

Dietary Exposure 

Based on the sole use of bromuconazole on roses in greenhouses, di etary exposure is not 

expected, and therefore, does not need to be assessed during Registration Review. 

Residential Exposure 

Based on the sole use of bromuconazole on roses in greenhouses, residential exposures are not 

expected, and therefore, do not need to be assessed during Registration Review. Additionally, 

the potential for residential exposures from spray drift or bystander exposure are not expected, 

since the use is confined to greenhouses only. 

Aggregate Risk Assessment 

Aggregate assessments consider exposures from food, drinking water, and residential uses. 

Since there are no residential uses of bromuconazole, nor are there any uses that would result in 

exposures from food or drinking water, an aggregate risk assessment is not required during 

Registration Review. 

Occupational Exposure 

Bromuconazole is registered for use on roses grown in greenhouses. There is potential for short-

' intermediate-, and long-term occupational exposure to bromuconazole during handling (mixing, 

loading, and applying) and post-application activities in greenhouses. 

Page 4 of 18 
Occupational Handlers 

The registered bromuconazole label requires occupational handlers lo wear long-sleeved shirts, 

long pants, shoes, socks, and waterproof gloves. The previous occupational handler exposure 

and risk assessment (D281745, J. Arthur, 09/ 18/2002) was conducted at the maximum 

application rate and ass.urned the maximum area treated per day. The risk estimates from dermal 

and inhalation exposures were combined because the POD was the same for both routes and was 

based on the same toxicological effects (i.e., skeletal effects). The short- and intermediate-term 

risk estimates for dermal and inhalation exposures of occupational handlers at baseline attire did 

not exceed the level of concern (LOC) for a ll combined dermal and inhalation (i.e .. MO Es < 

100) scenarios. 

Occupational Post-Application 

Occupational post-application short- and intermediate-term dermal and inhalation exposures are 

possible for workers entering greenhouses to tend to or harvest treated roses. Chemical-specific 

post-application exposure data have not been submitted. 

The most recent post-application assessment for bromuconazole was completed in 2002 

(028 1745, J. Arthur, 09/18/2002) which used the default dislodgeable foliar residue (DFR) 

fraction of application rate (FAR) value (20%). At that time, the resulting MO Es ranged from 470 

to 4, l 00 for the currently registered use on roses at the maximum rate (0.02 lb ai/100 gallon at 

200 gallons of spray/A), and did not exceed HED's level of concern (LOC) of I 00 (MOE< 

LOC). The current default FAR value for post-application activities is 25%. With the use of the 

current FAR value, as well as updated transfer coefficient (TC) values and adult body weights, the 

resulting highest exposure risk estimate for post-application exposure from the application to 

roses at the maximum rate results in an MOE of 1,500. Since the highest estimated occupational 

post-application exposure using default DFR and TC values for bromuconazole is minimal in 

comparison to the level of concern (i.e., the calculated MOE is greater than 2 times higher than 

the level of concern, MOE >200 compared to the LOC of I 00), HED is not requiring the 40 CFR 

§ 158 DFR data. 

The CHIPCO® Bromuconazole label (EPA Reg. No. 264-548) does not currently have a 

restricted-entry interval (REI) listed on the label; instead it states as follows: "Do not enter or 

allow others to enter the treated area until sprays have dried:· The REI specified on the 

registered label should be based on the acute toxicity of the active ingredient bromuconazole. 

Bromuconazole is classified as Toxicity Category III via the dermal route and eye irritation, and 

Toxicity Category IV for skin irritation potential. It is not a skin sensitizer. Under 40 CFR 

156.208 (c) (2) (iii), active ingredients classified as Acute Toxicity Category III or JV for acute 

dermal, eye irritation and primary skin irritation are assigned a I 2-hour REI. Therefore, the [I 56 

subpart K] Worker Protection Statement (WPS) interim REI of I 2 hours is adequate to protect 

agricultural workers from post-application exposures to bromuconazole. 

Conclusions: There is sufficient information available to assess occupational handler and postapplication exposures of bromuconazole, so no additional data will be needed in registration 

review. During Registration Review a new assessment of occupational handler and postapplication exposures will be needed because the most recent assessment was conducted several 

Page 5of18 
years ago, and policies and data inputs and assumptions have changed. Also, HED has since 

updated its policy on body weights and updated unit exposure values, and other inputs (e.g., 

uncertainty factors, toxicity endpoints, or points of departure) for determining these risk 

estimates. These changes are not expected to result in risk estimates that would require 40 CFR 

§ 158 DFR data. Also, the label (EPA Reg. No. 264-548) needs to be amended to include a 12 

hour REL 

Public Health and Pesticide Epidemiology Data 

There were no incident cases reported for bromuconazole in both the OPP Incident Data System 

(IDS) and the Centers for Disease Control and Prevention/National Institute for Occupational 

Safety and Health (CDC/NIOSH) Sentinel Event Notification System for Occupational RiskPesti cidcs (SENSOR). There does not appear to be a concern at this time that would warrant 

further investigation. 

For the Main IDS, from January I, 2010 to February 5, 20 15, there were no incidents reported 

involving bromuconazole. 

In the Aggregate IDS, from January I, 2010 to February 5, 2015, there were no incidents 

reported involving bromuconazole. 

A query of the SENSOR-Pesticides database for 1998-2011 identifies no cases involving 

bromuconazole. 

The Agricultural Health Study (AHS) is a high quality, prospective epidemiology study 

evaluating the link between pesticide use and vari ous health outcomes, including cancer. The 

AHS includes private and commercial pesticide applicators and their spouses. Bromuconazole-is 

not included in the AHS, and therefore, this study does not provide information for this report. 

Conclusion: There were no incident cases reported for bromuconazole to either IDS or 

SENSOR-Pesticides; therefore, there does not appear to be a concern at this time that would 

warrant further investigation. The Agency will continue to monitor the incident inforn1ation and 

if a concern is triggered, additional analysis will be included in the risk assessment. 

Tolerance Assessment and International Harmonization 

There are no existing tolerances for bromuconazole, and therefore, no assessment is needed. 

Cumulative 

Bromuconazole is a member of the triazole-containing class of pesticides. Although conazoles 

act similarly in plants (fungi) by inhibiting ergosterol biosynthesis, there is not necessarily a 

relationship between their pesticidal activity and their mechanism of toxicity in mammals. 

Structural similarities do not constitute a common mechanism of toxicity. Evidence is needed to 

establish that the chemicals operate by the same, or essentially the same, sequence of major 

biochemical events. In conazoles, however, a variable pattern of toxicological responses is 

Page 6of18 
found; some are hepatotoxic and hepatocarcinogenic in mice. Some induce thyroid tumors in 

rats. Some induce developmental, reproductive. and neurological effects in rodents. 

Furthermore, the conazoles produce a diverse range of biochemical events including altered 

cholesterol levels, stress responses, and altered DNA methylation. It is not clearly understood 

whether these biochemical events are directly connected to their toxicological outcomes. Thus, 

there is currently no evidence to indicate that conazoles share common mechanisms of toxicity 

and EPA is not following a cumulative risk approach based on a common mechanism of toxicity 

for the conazoles. For information regarding EPA's procedures for cumulating effects from 

substances found to have a common mechanism of toxicity, see EPA's website at 

http://www.epa.gov/pesticides/cumulative. 

Human Studies 

The risk assessments which have been previously conducted for bromuconazole relied in part on 

data from studies in which adult human subjects were intentionally exposed to a pesticide to 

determine their dermal and inhalation exposure. Many such studies, involving exposure to many 

different pesticides, comprise generic pesticide exposure databases such as the Pesticide 

Handlers Exposure Database (PHED) and the Agricultural Reentry Task Force (ARTF) 

Database. EPA has reviewed all the studies supporting these multi-pesticide generic exposure 

databases, and has found no clear and convincing evidence that the conduct of any of them was 

either fundamentally unethical or significantly deficient relative to the ethical standards 

prevailing at the time the research was conducted. All applicable requirements of EPA 's Rule 

for the Protection of Human Subjects of Research ( 40 CFR Part 26) have been satisfied, and 

there is no regulatory barrier to continued reliance on these studies. 

Data Deficiencies 

None 

Page 7of18 
References 

Memoranda Relevant to Rel!istration Review of Cvcloate. 

Author OPffXR# Date Title 

Risk Assessment 

J. Arthur D28 1745 09118/2002 Bromuconazole: Occupational and Residential Risk Assessment of a 

New Fungicide for Use On Roses. 

Toxicology 

M. Bonner TXR 09/04/2003 BROMUCONAZOLE (PC Code 120503) - Toxicology Disciplinary 

0051892 Chapter for Registration Support Document for Use on Roses. 

U. Habiba TXR 08/13/2013 CONAZOLE FUNGICIDES: Summary of Hazard and Science Policy 

0056730 Council (HASPOC) Meeting on July 25, 2013: Recommendations on 

Data Requirement for lmmunotoxiciry Studies for Conazole 

Pesticides. 

U. Habiba TXR 06/25/2015 Summary of Hazard and Science Policy Council (HASPOC) Meeting 

0057274 of June 25, 20 15: Recommendations on the Need for a Subchronic 

Inhalation Toxicity Study and a Neurotoxiciry Banery (Acute and 

Subchronic). 

Incident Report 

S. Recore D427797 06/ 16/2015 Bromuconazole: Tier I Review of Human Incidents 

Attachments 

1. Chemical Identity Table 

2. Physicochemical Properties of Technical Grade Bromuconazole Table 

3. Endpoint Selection Table 

4. Toxicity Profile Tables 

5. Toxicology Data Requirements Table 

Page 8 of 18 
Attachment 1 

Chemical Identity Table 

Table 1. Bromuconazole Chemical Structure. -

Common Name (Abbreviation) Structure Chemical Name 

Bromuconazole 

1-[[ 4-bromo-2-(2,4-dich lorophenyl)tetrahydro-2- ·-<iV" 

furanyl]methyl]-1 H-1 ,2,4-triazole r 

( N'N 

N_J 

Page 9of 18 
Attachment 2 

Table 2. Phvsicochemical Properties of the Technical Grade Test Compound• 

Parameter Value 

Color White 

Physical State Solid 

Odor Slightly alcoholic 

Storage Stability Stable 

pll 5.3 

Melting Point 84°C 

Density 1.721?/ml 

LS850646 LS850647 

Acetone 31.86 g/100 ml 2 1.97 g/100 ml 

Dichloromethane 49.7 g/100 ml 35.37 g/ 100 ml 

Ethyl Acetate 23 .19 g/ 100 ml 17.30 g/100 ml 

N-1 lcxane 0. 165 g/100 ml 0. 192 g/100 ml 

Solubility Methanol 29.54 g/100 ml 18.85 g/100 ml 

1-0ctanol 6.14 g/100 ml 3.85 g/100 ml 

2-Propanol 5.74 g/100 ml 3.98 g/100 ml 

Toluene 21.72 g/100 ml 15.68 g/100 ml 

Water (Distilled) 60.9 mg/I 20.8 mg/I 

Water (pH 5) 52.3 mg/I 17.0 mg/I 

Water (pH 9) 59.4 ml!.11 22. 1 mg/I . . 1 Pcs11c1de Fact Sheet for Bromuconazolc, November 2002 . 

Page 10of 18 
Attachment 3 

Summary of Toxicity Endpoints and Points of Departure of Bromuconazole 

Table 3: Summary of Toxicological Doses and Endpoints for use in Occupational Human Health Risk Assessments 

Point of Uncertainty I RID, PAD, Level 

Exposure Scenario Departure (PoD) FQPA Safety of Concern for Study a nd Toxicological Effects 

Factors Risk Assessment 

Dermal Developmental UFA = lOx Occupational LOC Prenatal Develo[lmcntal Toxicitv -

Shon Term Dermal OAEL = UF11 = I Ox for MOE = 100 Rat 

( 1-30 days) 40 mg/kg/day Developmental Dermal LOA EL= 

133 mg/kg/day 

Intermediate Term Based on increased incidences of 

( 1-6 months) skeletal anomalies (i.e .. extra ribs). 

Inhalation Developmental UF" = !Ox Occupational LOC Prenatal Dcvelo[lmcntal Toxicitv -

Short Term NOAEL= UF11 = !Ox for MOE = 100 Rat 

( 1-30 days) 10 mg/kg Developmental LOAEL = 70 

mg/kg/day 

Intermediate Term Nole: Toxici1y via Based on increased incidences of 

(1-6 months) the i11halatio11 and additional cervical ribs. 

oral routes are 

assumed 10 be 

equivalent for this 

scenario. 

Cancer (oral. Classification: ·•Not Likely to be Carcinogenic to I lumans·· based on both the lack of carcinogenicity 

dermal. and in mice and rats. 

inhalation) 

Pomt of Departure (PoD) = A data point or an estimated pomt that rs derived from observed dose-response data and used to mark 

the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOA EL = no 

observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncenainty factor. UF" = extrapolation from 

animal to human (interspecies). UF11 = potential variation in sensitivity among members of the human population (intraspccics). 

FQPA SF = FQP J\ Safety Factor. MOE ... margin of exposure. LOC = level of concern. N/ A = not applicable. 

Page 11of18 
Attachment 4 

Toxicity Profile for Bromuconazole 

Table 4. 1. Acute Toxicity Data on Technical Bromuconazole. 

Guideline Study Type MRJD No.&% Results 

Toxicity 

No. Active lnl!r edient Catel!orv 

870.1100 Acute Oral - Rat 42937 12 1 LDso = 365 mg/kg (Males & Females, II 95.7% " combined) 

870. 1200 Acute Dermal - Rabbit 42937 122 LDso > 2000 mg/kg (Males & Females. 111 97.8 b combined) 

870. 1300 Acute Inha lation - Rat 42937123 LCso > 5.05 mg/L (Males & Females. IV 98.4% combined) 

870.2400 Primary Eye Irritation - Rabbit ·BOl8501 0. 1 ml. Mild Irritant 111 95.7% 

870.2500 Primary Skin Irritation - Rabbit 430 18502 Not an Irritant IV 95.7% 

430 18503 

870.2600 Dermal Sensitization Not a Dermal Sensiti zer. NA - Guinea Pig 95.7% 

• l3romucona1ole Tech. Used in these studies is also known as LS860263 which is made or 1wo isomers wi1h 1he ra1io of 55.5-56.5% LS850646 

& -12.9-43.5% LS850647. 

• Isomer ra1io 1101 provided in the records. 

Table4.2. Su bchrooic, Chronic a nd Other Toxicity Profiles for Bromuconazole. 

Guideline 

870.3100 

870.3150 

Study Type 

90-Day Oral 

Toxicity in 

Rodents 

(Rat) 

90-Day Oral 

Toxicity in NonRodcnts 

(Dog) 

MRJD (year) I Doses I 

C lassification 

42937131 (1990) 

Dietary Concentration (ppm): 

0.40. 200. 1000. 5000 

Dietary Dose (mg/kg/day): 

M: 0. 2. 72. 13.76. 68.1. 342.5 

F: 0, 3.0-1, 15.08. 74.5. 381.2 

Acceptable I Guideline 

-13018505 ( 1988) 

Capsule Doses (mg/kg/day): 

M: 0. 2.5. 25. 250 (-1 weeks) 

125 (After 4 weeks) 

F: 0. 2.5. 25. 250 (4 weeks) 

125 (After 4 weeks) 

Acceptable I Guide! inc 

Page 12of 18 

Results 

NOAEL (mg/kg/day): M = 13.8 F = 15. 1 

LO/\EL (mg/kg/day): M = 68.1 F = 74.5 

Based on decreased body \\eight gains in females. 

changes in hematology/blood chemistry parameters 

and in the incidence of microscopic lesions 

consisten1 with liver toxici1y. and increased liver 

wei!!ht in both sexes. 

NOAEL (mg/kg/day): M = 25 F = 2.5 

LOAEL (mg/kg/day): M = 125 F = 25 

M: Based on increased incidence of clinical signs 

(i.e .. crythema. feet swelling. conjunctivitis and eye 

discharge). changes in clinical chemistry and 

hematology parameters (i.e .. increased alanine 

aminotransferase. alkaline phosphatase. mean 

corpuscular volume. white blood cells. neutrophils. 

and platelet counts: and decreased blood cholesterol. 

calcium. albumen. haemoglobin. mean corpuscular 

haemoglobin conc..:ntrations and a lbumen/globulin 

ratio). increased adrenal wcigh1. and increased 

incidences of periacinar hcpatocytic degeneration. 

F: Based on decreased blood glucose concentration. 

At 125 mg/kg/day (i.e .. the dose-level above the 

LOEL). the fo llowing effects were also observed: 

decreased body weight. blood glucose. and urea 

conccntra1ion: and increas..:d kidney and liver 

wei!!hts. 
Table 4.2. Subcbronic, Chronic and Other Toxicity Profiles for Bromuconazole. . , . . 

Guideline Study Type 

MR.ID (year) I Doses I Results Classification . . - 870.3200 21/28-Day 43018504 (1993) Dermal Irritation 

Dermal Toxicity Dermal Dose (mg/kg/day): NOAEI. (mg/kg/day): M = NA f s NA 

(Rabbit) M: 0. I 00. 500. I 000 LOAEL (mg/kg/day): M = NA F = 'A 

F: 0. 100.500. 1000 

Unacceptable I Guideline Svstemic 

NOAEL (mg/kg/day): M = NA F = NA 

Note: This study is classified as LOA EL (mg/kg/day): M = NA r- = NA 

unacceptable because the applied 

test material did not cover I 0% of 

the body 's swface area. Under the 

conditions of this study. the dermal 

systemic toxicity and dermal 

irritation NOAEl-S cannot be 

determined. 

43018504 (1993) Dermal Irritation 

Dermal Dose (mg/kg/day): NOAEL (mg/kg/day): M = 1000 f = 1000 

M: 0. I 00. 500. I 000 LOAEL (mg/kg/day): M > 1000 F > 1000 

F: 0. I 00. 500. IOOO 

Acceptable I Guideline Systemic 

NOAEL (mg/kg/day): M = 1000 F = IOOO 

LOAEL (mafkg/day): M > 1000 F > IOOO 

870.3465 90-Day NA Study requirement waived (TXR0057274) 

Inhalation Toxicity 

870.3700 Prenatal 42937 127 (1990) Maternal 

Developmental Main Study 1 OAEL (mg/kg/day) 70 

Toxicity Study Gavagc Dose (mg/kg/day): LOAEL (mg/kg/day) = 500 

(Rat) F: 0. IO. 70. 500 Based on increased water consumption during the 

dosing period. decreased body weight gain during 

42937126 ( 1990) GD 6-10. and increased absolute and relative liver 

Range Pinding Study weights. Additionally. one dam was sacrificed after 

exhibiting neurotoxic cholincrgic-type clinical signs 

Acceptable I Guideline that had been previously observed in the range 

finding study 

Dcvclo12111cntal 

NOAEL (mg/kg/day) = 10 

LOAEL (mg/kg/day) = 70 

Based on increased placental weights and increased 

incidence of additional cervical ribs. 

43018508 (1991) Maternal 

Dermal Dose (mg/kg/day): NOAEL (mg/kg/day) = -1 0 

F: 0. 40. 133. 400 LOAEL (mg/kg/day) = 133 

Acceptable I Guideline Based on clinical signs (i.e .. ungroomed and 

unkempt coat). 

Devclo12mental 

NOA EL (mg/kg/day) = 40 

LOAEL (mg/kg/day)= 133 

Based on increased fetal and lillcr incidences of 

skeletal variations (i.e .. one extra rib or a pair of 

extra ribs). 

Page 13of 18 
Table4.2. Subchronic, Chronic and Other Toxicity Profiles for Bromuconazole. 

Guideline Study Type 

Prenatal 

Developmental 

Toxicity Study 

(Rabbit) 

870.3800 Reproduction and 

Fertility Effects 

(Rat) 

870.4 100 Chronic Toxicity 

(Dog) 

MRfD (year) I Doses I 

Classification 

42937129 ( 1990) 

Main Study 

Gavage Dose (mg/kg/day): 

F: 0. 12.S, SO, 200 

42937128 ( 1989) 

Range Finding Study 

Acec.:ptabk I Guideline 

42937130 (1989) 

43029901 (1990) 

Oiewry Concentration (ppm): 

0. 20.200. 2000 

Dietary Dose (mg/kg/day): 

Mo: 0. 1.3. 13.8. 141.2 

Fo: O. 1.6. 15.S, I S9.6 

Acceptable I Guideline 

42937124 (199 1) 

Capsule Dose (mg/kg/day): 

M: 0. 2.5. 25. 125 

F: 0. 2.S. 2S. 125 

Acceptable I Guideline 

Page 14of18 

Results 

Maternal 

NOAEL (mg/kg/day) = 12.5 

LOAEL {mg/kg/day) = SO 

Based on increased clinical signs (i.e .. 

lethargy/reluctance to move. increased respiration 

rate. ataxic/unsteady gait. aggression. lack of musck 

tone and coordination. prone posture. and 

vocalization). decreased body weight gain. and 

decreased food consumption. 

Developmental 

NOAEL (mg/kg/day) = 50 

LOAEL (mg/kg/day) = 200 

Based on decreased live fetuses. increased post 

implantation loss. and increased resorptions. 

Parental 

OAEL (mg/kg/day): M = 13.8 F = I S.S 

LOA EL (mg/kg/day): M = 141.2 f = I S9.6 

Based on decreased body weight gain. increased 

liver weights. and increased incidences of 

hepatocytic fatty vacuolation. 

Reproductive I Off..,pring 

NOAEL (mg/kg/day): M = 13.8 F = 15.S 

LOAEL (mg/kg/day): M = 141.2 F = 159.6 

Oased on decreased pup viabi lity in the first 

generation and decreased pup body weight gain 

during lactation in both generations. 

NOAEL {mg/kg/day): M = 25 F = 2.5 

LOAEL {mg/kg/day): M = 125 F = 25 

M: Based on swelling and 

acanthosis/hyperkcratosis/swl.!at gland hyperplasia 

and inflammation of the feet: increased incidence of 

reddened gum. adrenal cortical fatty cavuolation and 

zona fasciculata hypertrophy: increased white blood 

cell. lymphocyte. and platelet counts, alanine and 

aspartate amino-transfcrase activities. weights: 

decreased body weight. cholesterol. 

albumen/globulin ratio. albumen. and mean 

corpuscular haemoglobin concemrations and mean 

corpuscular haemoglobin. Increased incidence of 

renal cytoplasmic pigment in conicular epithelium. 

pancreatic exocrine cell degeneration. urine volume 

and paler appearance and decreased urine specific 

gravity. 

F: Based on increased incidence of adrenal cortical 

fatty vacuolation and decreased mean corpuscular 

haemoglobin concentration and mean corpuscular 

hcmoelobin. 
Table 4.2. Subcbronic, Chronic and Other Toxicity Profiles for Bromuconazole. 

Guideline Study Type MRJD (year) I Doses I Results Classification 

NA 7-Week Oral 42937125 (1989) Non-Liver Toxicitv 

Toxicity Range rinding Study NO/\EL (mg/kg/day): M = 220 F = 3 19 

(Mouse) Dietary Concentration (ppm): LOAEL (mg/kg/day): M = 637 F = 790 

0.250.650. 1600.4000. 10000 Based on increased spleen weight in both sexes. 

Dietary Dose (mg/kg/day): decreased brain weight in males. and decreased heart 

M: 0. 35.2. 91.7. 220. 1. 637.0. weight in females. 

1604.0 

F: 0. 48.95. 123.3. 3 19.0. 789.5. Liver Toxicitv 

2036.0 NOAEL (mg/kg/day): M < 35 F < 49 

Acceptable I Non-Guideline LOAEL (mg/kg/day): M = 35 F = 49 

Based on increased incidence of liver effects (i.e .. 

hepatic in nanm1ation. periacinar hepatocytic fatty 

vacuolation. and hepatocvtic hypertrophy), 

870.4200 Carcinogenicity 43018506 ( 199 1) NOAEL (mg/kg/day): M = 57.4 F = 60.8 

(Mouse) Dietary Concentration (ppm): LOAEL (mg/kg/day): M > 57.4 F > 60.8 

0.20. 100.500 

Dietary Dose (mg/kg/day): 

M: o. 2.27. 11.3. 57.4 

r: 0. 2.40. 12.3. 60.8 

Unacceptable I Guideline 

Note: This swdy is classified as 

unacceptable because the dose 

levels utili=ed were not adequate 

for assessing carci11oge11ic 

JJO/ential. 

43018507 ( 1993) NO/\EL (mg/kg/day): M = 10.8 F = 12.3 

Dietary Concentration (ppm): LOAEL (mg/kg/day): M = 11 2.9 F = 134.5 

0. I 00. IOOO. 3000 Based on decreased body weight gains. 

Dietary Dose (mg/kg/day): 

M: 0. 10.8. 11 2.9. 369.9 There is no increased risk of cancer in this study. 

F: 0. 12.3. 134.5. 428. 7 

Acceotable I Guidel ine 

870.4300 Combined Chronic 42937132 ( 1992) OAEL (mg/kg/day): M = 0.88 F = 1.09 

Toxicity I Dietary Concentration (ppm): LOAEL (mg/kg/day): M = 6.48 F = 8.27 

Carcinogenicity 0. 20. 150. I 000. 2000 Based on increased non-neoplastic liver lesions in 

(Rat) Dietary Dose (mg/kg/day): females. 

M: 0. 0.88. 6.48. 43.3. 87.2 

F: 0. 1.09. 8.27. 55.6. 114.2 TI1ere is no increased risk of cancer in this study. 

Acceotable I Guidel ine 

870.5100 Bacterial Reverse 43018509 ( 1988) There was no evidence of induced revcrtant colonies 

Mutation Test Applied Dose (μ g/platc): over background at any dose tested. either with or 

(Salmonella ±S9: 50. 158. 500. 1580. 5000 without S9. 

typhimuri11m) Acceptable I Guideline 

42937 133 (1989) There was no evidence of induced rcvertant colonies 

Applied Dose (~1glplate): over background at any dose tested. either with or 

±S9: 5. 16. so. 158. 500 without S9. 

Acceptable I Guideline 

Page 15of 18 
Table 4.2. Subchronic, Chronic a nd Other Toxicity Profiles for Bromuconazole. 

Guideline Study Ty pe MRlD (year) I Doses I 

Results Classification 

870.5300 in vilro 42937 134 ( 1990) There was no unequivocal evidence of induced 

Mammalian Cell Applied Dose (mg/ml.): forward mu1a1ion a1 the HGPRT locus over sol,·ent 

Gene Muta1ion -S9: IO. 15. 25. 35. 50. 75. 100. control values. 

Tes! 125 

(Chinese Hams1er +S9: 25. 50. 100. 200. 250. 350. 

V79 Cells) 500 

Unacceptable I Guideline 

.\'01e: The nega/il'e findings i111he 

presence of S9 mix miglu be 

accep1able 10 EPA if 1he 

inconsis1e111 res11/1s in cells exposed 

10 DMBA in the presence of S9 mix 

were clarified. Acceptable of !he 

11egG1ive resul1s in 1he absence of 

S9 mix would require 11ega1ive 

rernlrs in GI leas! one addi1iona/ 

c1ssay in which cells were lrea1ed 

wilh 1111eq11ivocal/y cy101oxic doses 

of LS860263 as well as a dose of 2 5 

Jlfd mL. 

870.5375 in vi1ro -12937136 ( 1990) In 1he absence of S9 mix. statis1ically significan1 

Mammalian Applied Dose (μglmL): increases were seen in the mean percem of 

Chromosome ±S9: 10,50, 100.250 me1aphascs with chromosomal aberra1ions at 10 and 

Aberration Test Acceptable I Guideline 50 μg/mL when gaps were excluded from the 

(Chinese Hamster de11.:m1ination. In the presence of S9 mix. 

Ovary (CHO-KI ) statistically significant increases were seen at I 0 and 

cells) 50 μg!mL whether gaps were included or excluded 

from the determination. While there were increases 

at I 00 μg/mL. both with and without S9 mix. the 

increases were not statistically significanL likely due 

to reduced bioavai lability oftest material as 

mentioned with respect to cytotoxicity. 

in vi1ro 42937135 (1989) No statistically significant increases were seen in the 

Mammalian Applied Dose (ppm): mean percent ofmetaphases with chromosomal 

Chromosome -S9: 6.25. 12.5. 25. 50 aberrations at any concentration of test material 

Aberration Test +S9: 25. 50. I 00. 125 evaluated. either with or without S9 mix or" hen 

(lluman Acceptable I Guidelim: gaps were included or excluded from the 

Lymphocytes) determination. 

43521101 ( 1994) There was no evidence of a clastogcnic response in 

Applied Dose (ppm): the absence of S9 activation. However. the S9-

-S9: 25. 50. 100 activated test material induced dose-related increases 

+S9: 50. 100. 200. 225 in the number and percentage of cells with structural 

Acceptable I Guideline aberrations over a concentration range of 100 10 225 

μg/ml. The response was significant (p<0.05) at 225 

μg!ml. We conclude. therefore. that the study 

provided acceptable evidence that S9-activated 

bromuconazole was clastogenic in human 

lymphocytes. 

870.5395 Mammalian 42937137 ( 1990) LS860263 was tested to an adequate top dose and 

E!)1hrocyte Gavage Dose (mg/kg): did not significantly increase the frequency of 

Micronuclcus Test 40.200. 1000 micronucleatcd polychromatic erythrocytes in mouse 

(Mouse) l\cceptabk I Guideline bone marrow at any dose or sampling time tested. 

Page 16of18 
Table 4.2. Subchronic, Chronic and Other Toxicity Profiles for Bromuconazole. 

Guideline Study Type MRID (year) I Doses I Results Classification 

870.SSSO Unscheduled DNA 43018SIO ( 1989) TI1ere was no evidence of UDS induction at any 

Synthesis in Applied Dose (μg/mL): tested concentration as measured by incorporation of 

Mammalian Cells Run I: 0.391. 1.24. 3.91. 12.4. 39. 1 tritiated thymidine into D A (using liquid 

in Culture Run 2: 0.39 1. 1.24. 3.91. 12.4. 39. 1. scintillation counting). 

(Rat Hepatocytes) 124 

Acceotablc I Guideline 

42937138 (1993) The mean net nuclear grain count was below zero for 

Applied Dose (~1g/mL): both doses at both treatment times indicating no 

189.7. 600 induction of UDS as tested in this study. There was a 

Acceptable I Guideline 2.S fold increase in the proponion of cells in S-phase 

in cultures from treated rats of both dosage groups 

sacri liced at 12-14 hours. Only slides from the 12-14 

hour time ooint were analyzed for S-ohasc synthesis. 

870.6200 Acute NA Study requirement waived (TXROOS7274) 

eurotoxicity 

Screening Battery 

90-Day NA Study requirement waived (TXROOS7274) 

Ncurotoxicity 

Screening Battery 

870.748S Metabolism and 43018S l I ( 1992) Under the conditions of the study [single oral high 

Pharmacokinetics Gavage Dose {mg/kg): dose ( 1 SO mg/kg). single oral low dose ( 15 mg/kg). 

(Rat) Single: 15. ISO and repeat ( 14 days) oral low dose ( 15 mg/kg) to 5-8 

Repeated: IS (14 Days) Fisher 344 rats/sex I. the mean recovery of radio label 

Acceptable I Guideline was - 9S% to I 02%. Pancrns of excretion of 

radiolabel were similar for all orally dosed groups. 

but there were significant difTercnces between the 

sexes. Females excreted higher levels [-43% to 

- 46% vs. - 30% to - 34%] of radio label via the urine. 

while males excreted higher levels [- 65% to - 73% 

vs. - 51 % to - 60%] via the feces. ll1e majority of the 

radiolabel excreted via both urine and feces occurred 

within the first 48 hours post dose. At all dose levels. 

low levels of radiolabel [0.04% at high dose: 0.02% 

at low dose (single and repeat)) were detected in 

tissues at 7 days post dose I both sexes]. 

Bromuconazolc was well absorbed. extensively 

metabolized. and rapidly eli minated. Approximately 

60 metabolites were detected. and S7 of these were 

assigned structures. Major routes of metabolism 

involved extensive modification of the 

tctrahydrofuran ring to give rise to LS 8020S0 [X24 j 

followed by various conjugations. which resulted in 

the X4 series of metabolites. I lydroxy metabolites of 

Bromuconazole were detected both free [X l 9A/B] 

and as sulphate ester conjugates. Although there was 

rapid and extensive metabolism. Bromuconazole was 

found in the urine and fecal extracts. and conjugated 

Bromuconazole diastereoisomers were found in the 

urine. 

870.7600 Dermal Penetration NA NA 

870.7800 1 mmunotoxicity NA Study requirement waived (TXROOS6730) 

Page l 7 of l 8 
Attachment 5 

Toxicology Data Requirements 

The requirements (40 CFR 158.500) for non-food uses are in the table below. Use of the new 

guideline numbers does not imply that the new ( 1998) guideline protocols were used. 

Table 5. Toxicoloey Data Requirements 

Guideline Study Type Required Submitted 

870. 11 00 Acute Oral Toxiciw Yes 

870.1200 Acute Dermal Toxic ity Yes 

870. 1300 Acute Inhalation Toxicity Yes 

870.2400 Acute Eye Irritation Yes 

870.2500 Acute Dermal Irritation Yes 

870.2600 Skin Sensitization Yes 

870.3100 90-Day Oral Toxicity in Rodents CR 

870.3 150 90-Day Oral Toxicity in Non-Rodents CR 

870.3200 2 1/28-Day Dermal Toxicity No 

870.3250 90-Day Dermal Toxicity Yes 

870.3465 90-Day Inhalation Toxicity CR 

870.3700 Prenatal Developmental Toxicity Study (Rat) Yes 

Prenatal Developmental Toxicity Study (Rabbit) Yes 

870.3800 Reproduction and Fertility EITects Yes 

870.4 100 Chronic Toxic ity (Rodent) CR 

870.4200 Carcinogenicity (Rat) CR 

Carcinogenicity (Mouse) CR 

870.5100 Bacterial Reverse Mutation Test Yes 

870.5300 in vitro Mammalian Cell Gene Mutation Test Yes1 

870.5375 i11 vitro Mammalian Chromosome Aberration Test 

870.5385 Mammalian Bone Marrow Chromosomal Aberration Test Ycs1 

870.5395 Mammalian Ervthrocytc Micronucleus Test 

870.6 100 Delayed Neurotoxicity of Organophosphorus Substances (Acute. 1 len) CR 

Delayed Neurotoxicity ofOrganophosphorus Substances (28-Day. Hen) CR 

870.6200 Neurotoxicity Screening Battery (Acute. Rat) Yes 

Neurotoxiciry Screenine Battery (90-0ay. Rat) Yes 

870.6300 Developmental Neurotoxicity Study CR 

870.7200 Companion Animal Safety CR 

870.7485 Metabolism and Pharmacokinetics CR 

870.7600 Dermal Penetration CR 

870.7800 lmmunotoxicity Yes 

CR Conditionally Required 

1A ot Applicable 

Either guideline study type may be used to satisfy the data requirement (e.g .. 870.5300 or 870.5375) 

Requirement waived (TXR0056730. 13 August 201 3) 

Requirement waived (TXR0057274. 25 June 20 15) 

Page 18of18 

Yes 

Yes 

Yes 

Y1.:s 

Yes 

Yes 

Yes 

Yes 

Yes 

No 

No 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

No 

Yes 

No 

No 

No 

No 

No 

No 

Yes 

No 

No 

Satisfied 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

NA 

Yes3 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

NA 

NA 

Yes3 

Yes3 

NA 

NA 

Yes 

NA 

Yes2