UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

Office of Prevention, Pesticides 

and 

Toxic Substances 

December 14, 2001 

TXR#: 0050379 

MEMORANDUM 

SUBJECT: Toxicology Chapter for DIQUAT DIBROMIDE 

PC Code: 032201 

DP Barcode: D279696 

Submission: S603025 

FROM: Linda L. Taylor, Ph.D. 

Reregistration Branch I 

Health Effects Division [7509C] 

THRU: Whang Phang, Ph.D., Senior Scientist 

Reregistration Branch I 

Health Effects Division (7509C) 

TO: Rebecca Daiss, Risk Assessor 

Reregistration Branch IV 

Health Effects Division [7509C] 

Action Requested: Revise Tox Chapter for Diquat dibromide. 

The toxicology chapter for Diquat dibromide is attached. 

1
DIQUAT DIBROMIDE 

PC Code: 032201

Toxicology Disciplinary Chapter for the Tolerance 

Reassessment Eligibility Decision (TRED) Document 

Date completed:

December 14, 2001

Health Effects Division

Office of Pesticide Programs

U.S. Environmental Protection Agency

Arlington, VA 22202

Prepared by:

Linda L. Taylor, Ph.D.

Reregistration Branch I

2
TABLE OF CONTENTS

1.0 HAZARD CHARACTERIZATION ........................................... 3

2.0 REQUIREMENTS ......................................................... 6

3.0 DATA GAP(S) ............................................................ 7

4.0 HAZARD ASSESSMENT .................................................. 7

4.1 Acute Toxicity ...................................................... 7

4.2 Subchronic Toxicity .................................................. 7

4.3 Chronic Toxicity ................................................... 10

4.4 Carcinogenicity .................................................... 12

4.5 Developmental Toxicity ............................................. 13

4.6 Reproductive Toxicity ............................................... 17

4.7 Neurotoxicity ...................................................... 19

4.8 Mutagenicity ...................................................... 21

4.9 Metabolism ....................................................... 22

5.0 TOXICITY ENDPOINT SELECTION ........................................ 23

5.1 See Section 9.2 for Endpoint Selection Table ............................. 23

5.2 Dermal Absorption.................................................. 23

5.3 Classification of Carcinogenic Potential ................................. 24

6.0 FQPA CONSIDERATIONS ................................................ 24

6.1 Special Sensitivity to Infants and Children ............................... 24

6.2 Recommendation for a Developmental Neurotoxicity Study ................. 24

7.0 REFERENCES .......................................................... 25

8.0 APPENDICES ........................................................... 28

8.1 Toxicity Profile Summary Tables ...................................... 29

9.1.1 Acute Toxicity Table

9.1.2 Subchronic Toxicity Table

9.1.3 Chronic Toxicity Table

9.1.4 Prenatal Developmental Toxicity Tables

9.1.5 Reproductive Toxicity Table

9.1.6 Other Tables

8.2 Summary of Toxicological Dose and Endpoints ........................... 34
1.0 HAZARD CHARACTERIZATION 

The toxicity data base for Diquat dibromide is adequate for the selection of endpoints for use in risk 

assessment. The Health Effects Division [HED] Hazard Identification Assessment Review Committee 

[HIARC] evaluated the acceptable studies available in the database and established an acute and a 

chronic reference dose [RfD], as well as doses and endpoints for incidental oral exposure, residential, 

and short-term, intermediate-term, and long-term dermal and inhalation exposure scenarios. The 

HIARC also evaluated available studies to determine if there is a special sensitivity for infants and 

children. 

Diquat dibromide is not acutely toxic via the oral [Toxicity Category III] and inhalation [Toxicity 

Category III] routes of exposure. 

Diquat dibromide is moderately to severely toxic via the dermal route of exposure, as evidenced by the 

acute dermal toxicity study [Toxicity Category II], as well as by the 21-day repeated dose dermal 

toxicity study in rats. Deaths and clinical signs of toxicity [hypothermia, hypoactivity, dyspnea, 

cyanosis, pale extremities, general poor condition, and emaciated appearance] were observed at the 

lowest observed adverse effect level [LOAEL] of 20 mg/kg/day following repeat dermal exposure. 

However, Diquat dibromide was not found to be a dermal irritant [Toxicity Category IV] or a dermal 

sensitizer. 

Diquat dibromide is toxic to the eye, as evidenced by the eye irritation study, which showed slight to 

severe eye irritation following acute exposure [Toxicity Category II]. Additionally, cataracts were 

observed in rats and dogs following repeated oral exposure [for 12 week and longer] to Diquat 

dibromide. 

In a repeat-dose [subchronic] inhalation study, Diquat dibromide was shown to be toxic via the 

inhalation route of exposure, as evidenced by increased lung weight, mottling and reddening of the 

lungs, and lung lesions [multifocal chronic interstitial pneumonia and alveolar macrophages] following 

a 3-week exposure period. 

Following repeat dermal exposure [6 hours/day, 7 days/week for 3 consecutive weeks] to rats, severe 

systemic toxicity was observed, as evidenced by high mortality and clinical signs [hypothermia, 

hypoactivity, dyspnea, cyanosis, pale extremities, general poor condition, and emaciated appearance]. 

These effects were attributed to the fact that the dermal barrier had been compromised. Dermal 

irritation [erythema, edema, and desquamation] and tissue destruction [necrosis and eschar formation] 

were observed at the application site at all dose levels. Sores, severe erythema, fissures, acute 

necrotizing purulent dermatitis, and degeneration of the hair follicles and sebaceous glands were 

observed at the application site in both sexes, and congestion of the lungs, liver, and kidneys were 

observed in both sexes. In a non-guideline repeat dermal toxicity study in rabbits [24-hour exposures 

for 20 consecutive days], moderate systemic toxicity was observed, as evidenced by loss of weight, 

unsteadiness, muscular weakness and inability to stand, and microscopic lesions in the kidneys [cell 

necrosis in the distal convoluted renal tubules]. Dermal irritation was observed at the site of application 

[erythema and scabbing].The data indicate that the rat is more sensitive following repeat dermal 

exposure than the rabbit. 

The chronic data provide evidence that the eyes [cataracts, extralenticular lesions (vitreous adhesions, 

4
retinal detachment and synechia)] are a target organ in both the rat and dog, the adrenal and 

epididymides are also target organs in male dogs, and the kidney is a target organ in mice, dogs, and 

rabbits. 

Developmental toxicity was observed in both the rat and rabbit, as evidenced by delayed skeletal 

ossification in the rat and an increased incidence of fetuses with friable and/or mottled livers and a 

higher incidence of skeletal alterations in the rabbit. Maternal toxicity was observed as decreased bodyweight gain and food consumption in both the rat and rabbit. At the highest dose tested, clinical signs 

[mortality (both species), piloerection (rat), subdued activity (both species), diarrhea (rabbit)] were 

observed. In the mouse, maternal toxicity was observed as increased incidence of deaths, clinical signs 

[piloerection, dyspnea, respiratory noise, abnormal posture (hunched or raised tail)], and decreased 

body-weight gain. The maternal effects in the mouse were attributed to poor dosing technique. 

Developmental toxicity was observed in the mouse, as evidenced by decreased fetal body weight and 

increased incidence of overall skeletal alterations. 

Reproductive toxicity was observed in the rat in both generations, as evidenced by decreased numbers 

of live F1 pups/litter and decreased pup body-weight gain [F1 and F2]. Parental toxicity was observed 

as increased incidences of clinical signs [piloerection, opaque eyes, and ulcers on the palate and tongue 

(F1)], ophthalmoscopic signs [eye opacity, partial or total lenticular cataracts, and iritis], and decreased 

body-weight gains and food consumption during the premating period. 

Although increased incidences of diarrhea, staining of the nose, piloerection, urinary incontinence, 

mouth staining, upward curvature of the spine, tip-toe gait, hunched posture, subdued behavior, and 

sides pinched in were observed in females following acute oral exposure in the acute neurotoxicity 

study, the Agency has concluded that these symptoms may not be due to direct neurotoxicity. Several 

of these [piloerection, hunched posture, and hypoactivity] and other clinical signs indicative of 

neurotoxicity [unsteadiness, muscular weakness, and inability to stand, hypothermia, dyspnea, cyanosis, 

pale extremities] were observed in pregnant rats and mice after oral administration during gestation and 

in rats following subchronic dermal exposure. However, no evidence of neurotoxicity was observed 

in the functional observational battery, motor activity measurement, or neurohistopathology 

examination in the subchronic neurotoxicity study in rats. Neuropathology was not observed in any 

study. 

The data provided no indication of increased sensitivity of rats, mice, or rabbits to in utero and/or early 

postnatal exposure to Diquat dibromide. The HED HIARC determined that a developmental 

neurotoxicity study was not required for Diquat dibromide based on the fact that (1) there is no 

indication of abnormalities in the development of the fetal nervous system in prenatal developmental 

toxicity studies in rats, mice, and rabbits at oral dose levels that were maternally toxic, (2) there was 

no evidence of neuropathology in either the acute or subchronic neurotoxicity study, (3) the clinical and 

FOB observations in the acute neurotoxicity study, which could not be unequivocally correlated to an 

effect on the nervous system, were not observed in the subchronic neurotoxicity study, and (4) no 

effects were observed in the brain weights or histopathology of the nervous system in the chronic 

toxicity studies with Diquat dibromide in several species. 

No effects were observed on the endocrine system in any of the available studies on Diquat dibromide. 

There was no evidence of increased tumor incidence in the carcinogenicity studies in rats and mice. The 

5
carcinogenic potential of Diquat dibromide was classified as Category E [evidence of noncarcinogenicity to humans] by the Health Effects Division Reference Dose (RfD)/Peer Review 

Committee. The mutagenic data indicated that there was no concern for mutagenicity. 

Diquat dibromide was poorly absorbed from the gastrointestinal tract following oral exposure [single 

and repeat], and it was eliminated mainly in the feces. Approximately 6% of the administered dose was 

found in the urine within 4 days after dosing. Only a small portion of the absorbed Diquat dibromide, 

which was rapidly eliminated in the urine, was metabolized to monopyridone and dipyridone analogs. 

Diquat dibromide did not accumulate in any tissue monitored. 

There are no data gaps at the present time. 

6
2.0 REQUIREMENTS 

(updated December 14, 2001) 

The requirements (CFR 158.135) for Food/Feed Use for Diquat dibromide are in Table 1. Use of the new 

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

Table 1. 

Test Technical 

Required Satisfied 

870.1100 Acute Oral Toxicity

870.1200 Acute Dermal Toxicity

870.1300 Acute Inhalation Toxicity

870.2400 Primary Eye Irritation 

870.2500 Primary Dermal Irritation 

870.2600 Dermal Sensitization 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.3100 Oral Subchronic (rodent)

870.3150 Oral Subchronic (nonrodent)

870.3200 21-Day Dermal 

870.3250 90-Day Dermal 

870.3465 90-Day Inhalation 

yes 

yes 

yes 

no 

no 

yes*

yes*

yes 

no 

yes/

870.3700a Developmental Toxicity (rodent)

870.3700b Developmental Toxicity (nonrodent)

870.3800 Reproduction 

yes 

yes 

yes 

yes 

yes 

yes 

870.4100a Chronic Toxicity (rodent)

870.4100b Chronic Toxicity (nonrodent)

870.4200a Carcinogenicity (rat)

870.4200b Carcinogenicity (mouse)

870.4300 ChronicToxicity/Carcinogenicity (rodent) 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.5100 Mutagenicity—Gene Mutation - bacterial 

870.5300 Mutagenicity—Gene Mutation - mammalian 

870.5xxx Mutagenicity—Structural Chromosomal Aberrations 

870.5xxx Mutagenicity—Other Genotoxic Effects 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.6100a Acute Delayed Neurotox. (hen)

870.6100b 90-Day Neurotoxicity (hen)

870.6200a Acute Neurotox. Screening Battery (rat)

870.6200b 90 Day Neuro. Screening Battery (rat)

870.6300 Develop. Neuro 

no 

no 

yes 

yes 

no 

-

-

yes 

yes 

no 

870.7485 General Metabolism 

870.7600 Dermal Penetration 

yes 

yes 

yes 

yes 

Special Studies for Ocular Effects 

Acute Oral (rat)

Subchronic Oral (rat)

Six-month Oral (dog) 

no 

* chronic toxicity study is available and satisfies this requirement; / 2 studies of 21-days duration available; although these studies 

do not satisfy the guideline requirement [OPPTS 870.3465; §82-4] for a subchronic [90-day] inhalation toxicity study, they provide 

useful information regarding repeated [21 days] inhalation exposure. At the present time, long-term inhalation exposure is not 

anticipated. However, if long-term inhalation exposure scenarios are identified in the future, this issue will need to be revisited. 

7
3.0 DATA GAP(S) 

There are no data gaps at this time. A developmental neurotoxicity study in rats [OPPTS 870.6300] may 

be required in the future. 

4.0 HAZARD ASSESSMENT 

(updated AUGUST, 2001) 

4.1 Acute Toxicity 

Adequacy of data base for acute toxicity: The database for acute toxicity is considered complete. No 

additional studies are required at this time. The acute toxicity data indicate that Diquat dibromide is not 

acutely toxic via the oral [Toxicity Category III] and inhalation [Toxicity Category III] routes of 

exposure, but it is moderately-to-severely toxic via the dermal [Toxicity Category II] route of exposure. 

Additionally, Diquat dibromide is not a skin irritant [Toxicity Category IV], but it is considered a 

moderate-to-severe eye irritant [Toxicity Category II]. Diquat dibromide is not a skin sensitizer. 

The acute toxicity data on Diquat dibromide are summarized below in Table 2. 

Table 2. Acute Toxicity Data on DIQUAT DIBROMIDE 

Guideline 

No. Study Type MRID #(S) Results Toxicity Category 

870.1100 acute oral - rat 

Diquat Water Weed Killer 

00081506 rat LD50 = 810 mg/kg %

rat LD50 = 600 mg/kg &

III 

870.1200 acute dermal - rat 

Diquat Water Weed Killer 

00100614 rabbits LD50 = 262 mg/kg %

rabbits LD50 = 315 mg/kg &

rabbits LD50 = 288.5 mg/kg %+&

II 

870.1300 acute inhalation - rat 

Diquat Water Weed Killer 

26385* rat LC50 = 0.80 mg/L %

rat LC50 = 1.09 mg/L &

rat LC50 = 0.97 mg/L %+&

III 

870.2400 primary eye irritation -

Diquat Water Weed Killer 

00081507 rabbit slight to severe eye irritant II 

870.2500 primary skin irritation -

Diquat Water Weed Killer 

00107903 slight irritation IV 

870.2600 Dermal Sensitization 00107903 not a dermal sensitizer N/A 

* Accession No.; With the exception of the dermal sensitization study, which was conducted with the technical diquat [Diquat Herbicide 

Concentrate], the above studies were conducted with the end-use products [Diquat Water Weed Killer and Diquat 2 Spray (eye irritation study only)] 

and not in terms of the Diquat ion. Because the only difference between the technical diquat and the end-use products is 2.15% of water, studies with 

the end-use products have been accepted to satisfy the generic data requirements for acute studies. The above LD and LC values are expressed in 

terms of the test material and not, as is commonly done with diquat, in terms of the diquat cation. 

4.2 Subchronic Toxicity 

Adequacy of data base for subchronic toxicity: The database for subchronic toxicity is considered 

complete. No additional studies are required at this time. The subchronic database provides evidence that 

Diquat dibromide is toxic mainly to the port of entry. Exposure via the dermal route resulted in mortality, 

clinical signs [loss of weight, unsteadiness, muscular weakness, inability to stand, hypothermia, 

hypoactivity, dyspnea, cyanosis, pale extremities, emaciated appearance], cell necrosis in the kidney, 

congestion in the kidney, lung, and liver, and dermal irritation [erythema, edema, atonia, desquamation] 

8
and tissue destruction [necrosis and eschar formation at all dose levels] at the application site, and sores, 

severe erythema, fissures, acute necrotizing purulent dermatitis and degeneration of the hair follicles and 

sebaceous glands at the site of application. Exposure via the inhalation route resulted in increased lung 

weights, mottling and reddening of the lungs, and lung lesions [multifocal chronic interstitial pneumonia 

and alveolar macrophages]. Although there is no acceptable oral subchronic toxicity study in either the dog 

or rat, a chronic oral toxicity study is available in both species, and a separate subchronic oral toxicity study is 

not required for either species. 

870.3100 Subchronic Oral Toxicity - Rat 

There is no subchronic oral toxicity study available on Diquat dibromide; however, the chronic oral toxicity 

study in rats satisfies this data requirement [see below under Chronic Toxicity]. The guideline subchronic oral 

toxicity study requirement is satisfied by the chronic toxicity guideline requirement [OPPTS 870. 4100]. 

870.3200 Repeated Dose Dermal – Rat 

In a repeated [21-day] dermal exposure study [MRID 40308101], 9-week old male and female Sprague-Dawley 

rats [6/sex/dose] were exposed dermally [intact skin; exposure site 2.5 cm x 1.5 cm, mid-dorsal surface] to 

Diquat dibromide [20.64% w/w cation] at dose levels of 0 [deionized, distilled water], 5, 20, 40, and 80 

mg/kg/day for 3 weeks [6 hours/day, 7 days/week]. Collars were worn throughout the treatment period to prevent 

ingestion of the test material. Additionally, following the daily [6-hour] exposure, the residual test material was 

rinsed from the skin with water, and the skin was wiped dry. 

Mortality occurred at the three highest dose levels. At 20 mg/kg/day, one female was sacrificed moribund on 

day 19. At 40 mg/kg/day, one male [day 19] and four females [days 9, 14, 18, and 22] died or were sacrificed 

moribund. At 80 mg/kg/day, five of the six males [days 7, 8, 10, 11, and 13] and all of the females [days 7, 7, 

8, 8, 12, 20] died or were sacrificed moribund. Clinical signs of toxicity [hypothermia, hypoactivity, dyspnea, 

cyanosis, pale extremities, anogenital staining, little or no stool, general poor condition, emaciated appearance] 

were observed in the rats that died. At the high-dose level, decreased body weights [by day 7, males 87%/female 

data not meaningful] and body-weight gains throughout study [negative gain by day 3 (both sexes)] were 

observed in both sexes, and these findings were consistent with the general poor condition of the rats in this 

group. Males at the other dose levels displayed slightly lower body weights than the control males throughout 

the study [91%-98% of control], and body-weight gains also were decreased in all groups compared to the 

control, but there was no dose response. Females at the other dose levels also displayed slightly lower body 

weights [90%-97% of control] than the control, and body-weight gains were decreased at 20 mg/kg/day [63% 

of control] and 40 mg/kg/day [51% of control]. There also was a decrease in food consumption that was 

associated with the decreased body-weight gains. 

Dermal irritation [erythema, edema, and desquamation] and tissue destruction [necrosis and eschar formation] 

were observed at all dose levels at the site of application. Additionally, sores, severe erythema, fissures, acute 

necrotizing purulent dermatitis, and degeneration of the hair follicles and sebaceous glands were observed at the 

site of application in one or both sexes at $20 mg/kg/day. The incidence and severity of the dermal effects were 

generally dose-related, but considerable animal-to-animal variability was noted. Most of the dermal effects were 

first observed on day 8 or 11 and were still evident at study termination. An acute necrotizing purulent dermatitis 

was the most prominent tissue alteration in the treated skin in the three highest dose groups [males 2/6, females 

4/5; males 5/6, females 6/6; and males 6/6, females 6/6 with increasing dose. The lesion was characterized by 

necrosis of the epidermis and papillary layer of the dermis with massive infiltrates of neutrophils. The viable 

epidermis was described as thick and hyperkeratotic. 

9
Alterations in clinical chemistry and organ weights can be attributed to the poor condition 

[malnutrition/starvation] of the highest dose level group [both sexes]. Histopathological examination of tissues 

other than the skin revealed congestion of the lungs, liver, and kidneys at the two highest dose levels [both sexes] 

and coagulation/necrosis of hepatocytes in the high-dose females. 

The systemic toxicity NOAEL was 5 mg/kg/day, based on mortality [earliest death by day 7] and clinical 

signs [hypothermia, hypoactivity, dyspnea, cyanosis, pale extremities, general poor condition, and 

emaciated appearance] at 20 mg/kg/day [LOAEL]. Dermal irritation [characterized by erythema, edema, 

and desquamation] and tissue destruction [characterized by necrosis and eschar formation] were observed 

at all dose levels in both sexes at the site of application. However, by day 21, necrosis and eschar formation 

were no longer observed at the low-dose level [5 mg/kg/day]. Additionally, sores, severe erythema, fissures, 

acute necrotizing purulent dermatitis, and degeneration of the hair follicles and sebaceous glands were 

observed at the site of application in both sexes at $20 mg/kg/day. 

This study is classified ACCEPTABLE/Guideline, and it satisfies the guideline requirement [OPPTS 870. 3200; 

§82-2] for a subchronic dermal toxicity study in rats. 

870.3265 Subchronic Inhalation Toxicity – Rat 

In a repeated [21-day] inhalation exposure study [MRID 40301701], male and female Fischer 344 rats 

[10/sex/dose] were exposed via inhalation [whole body] to respirable aerosols of Diquat Concentrate [23.5% w/w 

cation] at dose levels of 0 [distilled water], 0.49, 1.1, and 3.8 Fg/L for 3 weeks [6 hours/day, 5 days/week]. A 

satellite group of control and high-dose rats [10/sex/group] were treated similarly and were held for 3 weeks post 

dose for an assessment of reversibility of toxic effects. A subsequent study [MRID 40640801] in which male 

and female Fischer 344 rats [10/sex/dose] were exposed via inhalation [whole body] to respirable aerosols of 

Diquat Concentrate [23.5% w/w cation] at dose levels of 0 [distilled water] and 0.1 Fg/L for 3 weeks [6 

hours/day, 5 days/week] was performed to determine a NOAEL. 

There were no deaths. Clinical signs of toxicity [abnormal respiratory sounds (both sexes) and anogenital 

discharge (females)] were observed at the high-dose level, and the incidence increased over time. Only a few 

rats had abnormal respiratory sounds during the first week of exposure, but over the dosing period, 80% of the 

high-dose males and 65% of the high-dose females displayed this condition. The mean onset of anogenital 

discharge was 4 days and 80% of the high-dose females had this condition. At the high-dose level, a slight, but 

statistically-significant, decrease in body weight was observed in both sexes throughout the study [males 94%-

95%/females 94%-97%], and body-weight gains were decreased during the first week [males 41%/females 38% 

of control] and overall [males 79%/females 86% of control]. Decreased food consumption was observed 

throughout the study at the high-dose level [both sexes] and at the mid-dose level [males] during the first week 

of exposure. 

No adverse effects were observed on any of the hematology, clinical chemistry, or ophthalmological parameters 

monitored at termination only. There was a dose-related increase in lung weight in both sexes, with statisticallysignificant increases at all dose levels in males and at the mid- and high-dose levels in females. At necropsy, 

mottling and/or reddening of the lungs was observed at all dose levels in females and in the mid- and high-dose 

males. Microscopic lesions were observed in the anterior nasal tissues [epithelial dysplasia (mid- and high-dose), 

erosion (high dose), and rhinitis (high dose)] in both sexes and in the lungs [multifocal chronic interstitial 

pneumonia (all dose levels), alveolar edema (mid-dose females, high-dose both sexes), and alveolar macrophages 

(all dose levels)] of both sexes. No effects were observed in the single-dose [0.1 Fg/L] study. 

Following the 3-week recovery period, the clinical signs of toxicity [abnormal respiratory sounds and anogenital 

10
discharge] and microscopic lung and nasal lesions were no longer evident, and lung weights were comparable 

to the controls. The high-dose female body weight was comparable to the control female body weight following 

the recovery period, but the high-dose males continued to display a slight decrease in body weight [statistically 

significant] compared to the control. However, body-weight gains during the recovery period were comparable 

between the groups for both sexes. One rat/sex at the high-dose level displayed mottled lung and one male and 

two female high-dose rats displayed red lung following the recovery phase compared to none in the control 

groups. 

The NOAEL is 0.1 Fg/L [males 0.024 mg/kg/day; females 0.026 mg/kg/day], based on increased lung 

weights and microscopic lesions in the lungs at the LOAEL of 0.49 Fg/L [males 0.117 mg/kg/day; females 

0.128 mg/kg/day]. 

This repeated dose [21-day] inhalation toxicity study is classified Acceptable/non-guideline when considered 

along with the subsequent one-dose study. Although these studies do not satisfy the guideline requirement 

[OPPTS 870.3465; §82-4] for a subchronic [90-day] inhalation toxicity study, they provide useful information 

regarding repeated [21 days] inhalation exposure. At the present time, long-term inhalation exposure is not 

anticipated. However, if long-term inhalation exposure scenarios are identified in the future, this issue will need 

to be revisited. 

4.3 Chronic Toxicity 

Adequacy of data base for chronic toxicity: The data base for chronic toxicity is considered complete. 

No additional studies are required at this time. The chronic data provide evidence that the eyes [cataracts, 

extralenticular lesions (vitreous adhesions, retinal detachment and synechia)] are a target organ in rats and dogs, 

the adrenal and epididymides are also target organs in male dogs, and the kidney is a target organ in mice and 

rats. There was no treatment-related increase in the incidence of any tumor type in either the rat or mouse 

carcinogenicity study. The dose levels were considered adequate in the rat and mouse studies, based on 

moderate reductions in body-weight gain in both species and on histopathological changes [lens opacity, severe 

cataracts, and extralenticular lesions] in the eyes of the rats. 

870.4100 Chronic Feeding – Rat 

In a combined chronic toxicity/carcinogenicity study [MRID 00145855], male and female Sprague-Dawley rats 

[50/sex/dose] were fed diets containing 0, 5, 15, 75, and 375 ppm of Diquat dibromide [26.5% w/v cation; 

equivalent to 0, 0.19, 0.58, 2.91, and 14.88 mg/kg/day (males)/0, 0.24, 0.72, 3.64, and 19.44 mg/kg/day (females) 

of diquat cation; 26.5%] for 104 weeks. In addition, 10 rats/sex/dose were treated similarly and sacrificed at 12 

months. 

Treatment had no adverse effect on survival. With the exception of effects on the eye, there were no treatmentrelated clinical signs of toxicity. Changes in the eyes were observed at the two highest dose levels and consisted 

of an initial appearance of the eye being clearer and more transparent than usual. This was followed temporally 

by opacity, which first occurred in week 10 at 75 ppm [one male] and in week 11 at 375 ppm [two females]. 

Body-weight gains were decreased at the high-dose level in both sexes throughout the study [weeks 0-13: males 

84%/females 80% of control; overall: males 86%/females 75% of control], and a corresponding depression in 

average food consumption was observed at the high-dose level for both sexes for the first 26 weeks and for 

females throughout week 78 of the study. 

Based on ophthalmologic examination, the incidence of total cataract increased with increasing dose and time 

11
on study. At 13 weeks, 1 male at 75 ppm [2%], 11 males at 375 ppm [22%] and 2 females at 375 ppm [4%] 

displayed total cataracts. At 26 weeks, the incidence of total cataracts was 4% [75 ppm males], 78% [375 ppm 

males], and 76% [375 ppm females] and at 52 weeks, the incidence was 4% [75 ppm males], 94% [375 ppm 

males], and 90% [375 ppm females]. At 78 weeks, the incidence of total cataracts reached 100% in males at the 

high-dose level and 98% in females at the high-dose level. At study termination, one rat/sex at 15 ppm [males 

4.5%/females 5.0%], 3 rats/sex at 75 ppm [males 14.3%/females 15.0%], and all [100%] of the high-dose rats 

[both sexes] displayed total cataracts. No evidence of total cataract was observed in either sex at 5 ppm [lowest 

dose] or in control females at any time point, but one control male displayed total cataract at week 78 only [none 

were observed at study termination in this group]. Additionally, rats with severe cataracts showed secondary, 

extralenticular, eye lesions, which included vitreous adhesions, retinal detachment, iritis, and intraocular 

hemorrhage and were considered secondary to the extrusion of degenerate lens material. Microscopic findings 

showed a greater severity in the 15 ppm groups than in the controls and 5 ppm dose groups. Severity grades 

[cataractous change] of marked and severe were not found in the control or 5 ppm groups but were observed in 

both sexes at the 15 ppm, 75 ppm, and 375 ppm dose levels. 

Males at the two highest dose levels displayed an increased incidence of nephropathy in the kidneys, and the 

high-dose males displayed increased incidences of arteritis/periarteritis in blood vessels and paracortical cell 

hyperplasia in the lymph nodes. There was no treatment-related increase in any tumor type in either sex. 

There was no treatment-related increase in tumor incidence in either sex. The NOAEL was 15 ppm [males 

0.58 mg/kg/day/females 0.72 mg/kg/day], based on eye lesions [total cataracts] at the LOAEL of 75 ppm 

[males 2.91 mg/kg/day/females 3.64 mg/kg/day]. 

This chronic toxicity/carcinogenicity study is classified ACCEPTABLE/Guideline, and it satisfies the guideline 

requirement [OPPTS 870.4100; §83-1(a)] for a chronic toxicity study in rats. 

870.4100b Chronic Oral Toxicity (diet) - Dog 

In a chronic toxicity study [MRID 41730301], beagle dogs [4/sex/dose] were fed diets containing Diquat 

dibromide [26.7% cation] at target concentrations of 0, 0.5, 2.5, and 12.5 mg/kg/day, expressed as the diquat 

ion [cation], for 52 weeks [achieved intakes: males 0, 0.46, 2.42, and 11.48/females 0, 0.53, 2.53, and 13.21 

mg/kg/day]. 

No treatment-related effects were observed on survival, clinical signs, hematology, clinical chemistry, urinalysis, 

and gross pathology [except eye] at any dose level. Decreased body-weight gains were observed only during the 

first two weeks of dosing in both sexes at the high-dose level [males 46%/females 32% of control], although 

there was no decrease in food consumption at any time point. 

At necropsy, bilateral lens opacity was observed in all high-dose males and 3/4 high-dose females. Unilateral 

lens opacity was observed in 2 mid-dose females at necropsy. The first occurrence of lens opacity was at week 

8 in one mid-dose female [one other mid-dose female displayed lens opacity at week 40]. The first occurrence 

of lens opacity at the high-dose level was at week 16 in males and week 24 in females. Decreased epididymal 

weights were observed in males at the two highest dose levels, and increased kidney weights were observed in 

both sexes at the highest dose level. These alterations were not corroborated with histopathological changes in 

the adrenal, epididymis, or kidneys. Treatment-related, histopathological changes were observed at the high-dose 

level [both sexes] and included cataracts and chronic inflammatory changes in the large intestine. Slight-tomarked bilateral cataractous change [cataract] was observed in 3 high-dose dogs/sex, and minimal or slight 

unilateral cataractous change was observed in 1 high-dose dog/sex. One female at the mid dose also displayed 

histopathological changes in the eye [unilateral lens opacity]. Chronic inflammatory changes were detected in 

12
the colon and rectum of all high-dose dogs [4/sex] and in the cecum of all high-dose males and 2 of the 4 highdose females. Treatment-related effects were not found in the 0.5 mg/kg/day dogs. 

The NOAEL is 0.5 mg/kg/day, based on unilateral cataracts in females and decreased epididymides 

weights in males at the LOAEL of 2.5 mg/kg/day. At the high-dose level [12.5 mg/kg/day], bilateral 

cataracts, inflammatory lesions in the large intestine, and increased absolute and relative kidney weights 

were observed in all dogs, and decreased relative adrenal and epididymides weights were observed in 

males. 

This chronic oral toxicity study is classified ACCEPTABLE/Guideline, and it satisfies the guideline requirement 

[OPPTS 870.4100; §83-1(b)] for a chronic oral toxicity study in non-rodents. 

4.4 Carcinogenicity 

Adequacy of Database for Carcinogenicity: The data base for carcinogenicity is considered complete. 

No additional studies are required at this time. The carcinogenic potential of Diquat dibromide was classified 

as Category E [evidence of non-carcinogenicity to human]. 

870.4200a Carcinogenicity Study - rat 

In a combined chronic toxicity/carcinogenicity study [MRID 00145855, 00155474, 41085601], male and female 

Sprague-Dawley rats [50/sex/dose] were fed diets containing 0, 5, 15, 75, and 375 ppm of Diquat dibromide 

[equivalent to 0, 0.19, 0.58, 2.91, and 14.88 mg/kg/day (males)/0, 0.24, 0.72, 3.64, and 19.44 mg/kg/day 

(females) of diquat cation] for 104 weeks. In addition, 10 rats/sex/dose were treated similarly and sacrificed at 

12 months. See EXECUTIVE SUMMARY under Chronic Toxicity [OPPTS 870.4100], above. 

There was no treatment-related increase in tumor incidence in either sex. The NOAEL was 15 ppm [males 

0.58 mg/kg/day/females 0.72 mg/kg/day], based on eye lesions [total cataracts] at the LOAEL of 75 ppm 

[males 2.91 mg/kg/day/females 3.64 mg/kg/day]. 

This combined chronic toxicity/carcinogenicity study is classified ACCEPTABLE/Guideline, and it satisfies the 

guideline requirements [OPPTS 870.4200 and 870.4300] for a chronic toxicity/carcinogenicity study in rats. 

13
870.4200b Carcinogenicity (feeding) - Mouse 

In a carcinogenicity study [MRID 42219801, 42880701, 42905901, 42919501], Diquat dibromide [21.09% 

cation concentration] was administered in the diet for 104 weeks to male CD-1 mice [60/sex/dose] at 0, 30, 100, 

and 300 ppm [expressed as 0, 3.56, 11.96, and 37.83 mg/kg/day (males) and 0, 4.78, 16.03, and 48.27 mg/kg/day 

(females). At 12 months, 10 mice/sex/dose were sacrificed [interim]. 

There was no treatment-related adverse effect on survival of either sex, although a greater number of treated 

females [37%, 47%, 40% with increasing dose] were killed in extremis compared to the control females [25%]. 

Treatment-related clinical signs were observed in both sexes and included an increased incidence of eye 

discharge [mid-dose males and the high-dose mice of both sexes] and an increased incidence of thin appearance 

[males] and subdued behavior [mid-dose females and high-dose (both sexes)]. Decreased body weight was 

observed throughout the study in both sexes [males 3.5%-8.7%/females 2.9%-9.4% below control] at the highdose level and in males at the mid-dose level [3.8%-4.7% below control] from week 95 until termination 

compared to the control. Body-weight gains were decreased in these same groups during the same time intervals 

[mid-dose males 11%; high-dose males 4%-12%; high-dose females 10%-28% below control]. Food 

consumption was decreased for both sexes at the high-dose level. 

No treatment-related effects were observed on hematology parameters or gross pathology at any dose level. 

Increased kidney weight was observed at the mid- and high-dose levels in males, and decreased brain weight 

was observed in the high-dose females. There was a treatment-related, slight increase in microscopic lesions in 

the kidney [tubular dilatation (both sexes) and tubular hyaline droplet formation (females)], liver [extramedullary 

hemopoiesis (both sexes)], and lymph node, mesenteric [lymphoid proliferation (females)] at the high-dose level, 

mainly at the terminal sacrifice. 

The systemic NOAEL is 30 ppm [males 3.56 mg/kg/day/females 4.78 mg/kg/day]. The systemic LOAEL 

is 100 ppm [males 11.96 mg/kg/day/females 16.03 mg/kg/day], based on clinical signs [eye discharge 

(males), subdued behavior (females)], and decreased body weight/body-weight gain [males]. Diquat 

dibromide was not carcinogenic in male or female CD-1 mice. 

This carcinogenicity study is classified ACCEPTABLE/Guideline, and it satisfies the guideline requirement 

[OPPTS 870.4200; §83-2] for a carcinogenicity study in mice. 

4.5 Developmental Toxicity 

Adequacy of data base for Developmental Toxicity: The data base for developmental toxicity is 

considered complete. In the rat, developmental toxicity was observed at the highest dose tested, 40 

mg/kg/day, based on delayed skeletal ossification. Maternal toxicity was observed as decreased bodyweight gain and food consumption. In the rabbit, maternal toxicity was observed as decreased bodyweight gain and food consumption. Developmental toxicity was indicated by increased incidence of fetuses 

with friable and/or mottled livers and a higher incidence of skeletal alterations. Clinical signs [mortality 

(both species), piloerection (rat), subdued activity (both species), diarrhea (rabbit)] were observed only 

at the highest dose in both species. In the mouse, maternal toxicity was observed as increased incidence 

of deaths, clinical signs [piloerection, dyspnea, respiratory noise, abnormal posture (hunched or raised 

tail)], and decreased body-weight gain. Developmental toxicity was observed as decreased fetal body 

weight and increased incidence of overall fetal skeletal alterations. 

14
870.3700a Prenatal Developmental Toxicity Study - Rat 

In a developmental toxicity study [MRID 41198902], pregnant Wistar-derived Alderley Park strain SPF rats 

[23-24 rats/group] were administered technical grade Diquat [water-soluble concentrate; 26.2 g diquat ion/L] 

via gavage at dose levels of 0 [deionized water], 4, 12, and 40 mg/kg/day [expressed as the diquat cation] from 

gestation days 7 through 16. The rats were sacrificed on gestation day 22, and uteri were examined for live 

fetuses and intra-uterine deaths. Fetuses were weighed, sexed, and examined for external, visceral, and skeletal 

alterations. 

One high-dose dam died on day 15, and this dam appeared hunched with piloerection and urinary incontinence 

one day before being found dead. There was an increased incidence of piloerection at the high-dose level, and 

several of the high-dose dams appeared subdued during the last half of the study. During the first four days of 

dosing, decreased body-weight gains were observed at all dose levels [78% (low)/61% (mid) of control], with 

the high-dose group displaying a negative gain [-5.4 grams]. Decreased body-weight gains persisted during the 

remainder of the dosing period at the mid- [89% of control] and high-dose [16% of control] levels. Only the 

high-dose dams displayed an overall decrease on body-weight gain [78% of control]. The decrease in bodyweight gain at the lowest dose appeared to be transient, slight, and equivocal. Food consumption was 

significantly decreased at all dose levels during the first 4 days of dosing and in the mid- and high-dose groups 

throughout the dosing period. 

Three of the high-dose dams were not pregnant. All other rats in all dose groups were pregnant. There were no 

treatment-related effects on the numbers of corpora lutea/dam or implantations/dam, and the mean litter size and 

the % males were comparable among the groups. Gravid uterine weight was slightly lower at the high-dose level 

[91% of control], but statistical significance was not attained. There was a statistically-significant decrease in 

both mean litter weight [88% of control] and mean fetal body weight [91% of control] at the high-dose level. 

At the high-dose level, there was an increased incidence of hemorrhagic kidney [none in the control (297 fetuses 

in 24 litters) vs 5/239 fetuses in 4/20 litters] and poorer ossification, as evidenced by higher incidences of minor 

skeletal alterations [unossified ventral tubercle, centra of the cervical vertebrae, 4th cervical vertebra, and 

partially ossified 2nd and 5th sternebrae]. 

The maternal toxicity NOAEL was 4 mg/kg/day, based on decreased maternal body-weight gain and food 

consumption during dosing at the LOAEL of 12 mg/kg/day. At the highest dose tested [40 mg/kg/day], one 

dam died, the dams lost weight during the first three days of dosing, there was an increased incidence of 

subdued appearance and piloerection, and a slightly lower gravid uterine weight. 

The developmental toxicity NOAEL was 12 mg/kg/day, based on decreased fetal body weight [91% of 

control], decreased litter weight, an increased incidence of hemorrhagic kidney, and poorer ossification 

compared to the control at the developmental toxicity LOAEL of 40 mg/kg/day. 

This developmental toxicity study is classified ACCEPTABLE/Guideline, and it satisfies the guideline 

requirement [OPPTS 870.3700; §83-3] for a developmental toxicity study in rodents. 

870.3700b Prenatal Developmental Toxicity Study - Rabbit 

15
In a developmental toxicity study [MRID 41198901], pregnant New Zealand White rabbits [20 rabbits/group] 

were administered technical grade Diquat [water-soluble concentrate; 26.2 g diquat ion/L] via gavage at dose 

levels of 0 [deionized water], 1, 3, and 10 mg/kg/day [expressed as the diquat cation] from gestation days 7 

through 19. The rabbits were sacrificed on gestation day 30, and uteri were examined for live fetuses and intrauterine deaths. Fetuses were weighed, sexed, and examined for external, visceral, and skeletal alterations. 

There were three abortions [one low dose (day 27); two high dose (days 20, 29)] and three deaths [high dose on 

days 17, 21, 22]. At the high-dose level, there was an increased incidence of diarrhea, subdued appearance, and 

thin appearance. During the dosing period, two high-dose does lost weight but rapidly gained weight after 

dosing. At the mid-dose level, does also lost weight but only during the first three days of dosing. Overall, there 

was no dose-related effect on body-weight gain. Food consumption was significantly decreased at the mid- and 

high-dose levels during the first 4 days of dosing and in the high-dose group during the remainder of the dosing 

period. Both the mid- and high-dose does showed a significant increase in food consumption after day 19. 

There was no adverse effect on the number of pregnant rabbits in each group, although due to the deaths and 

abortions at the high-dose level, there were fewer litters at the high-dose level [13] compared to the control [18] 

and lower dose groups [15 and 20]. There were no treatment-related effects on the numbers of corpora lutea/doe, 

implantations/doe, % pre- and post-implantation losses, gravid uterine weight, mean litter size, mean litter 

weight, mean fetal body weight, or the % males. 

At the high-dose level, there was an increased incidence of friable and mottled livers [on a fetal basis]. There 

was an increase in the percent of fetuses with extra 13th ribs [normal length], with the incidence being statistically 

significant at the mid- [69%] and high-dose [74%] levels. Additionally, there was a corresponding, dose-related, 

increase in the percent of litters [83%, 87%, 90%, and 92% for the control, low-, mid-, and high-dose groups, 

respectively] with fetuses with an extra 13th rib, but statistical significance was not attained. The incidence 

[percent] of partially ossified ventral tubercle of the cervical vertebrae was significantly increased at all dose 

levels [fetal basis: 0.6%, 4%, 5%, and 10% for the control, low-, mid-, and high-dose groups, respectively], and 

the incidence of partially-ossified 6th sternebrae [on a fetal basis] was significantly increased at the mid- [15%] 

and high-dose [17%] levels. Also on a fetal basis, the incidence of 27 pre-sacral vertebrae was significantly 

increased at the high-dose level [51%] compared to the control [31%]. The incidence of sternebrae [6th] not 

ossified was increased significantly at the high-dose level on both a fetal [6%] and litter [38%] basis [none in 

the control]. 

The maternal toxicity NOAEL was 1 mg/kg/day, based on maternal body-weight loss during GD 7-10 and 

decreased food consumption during dosing [GD 7-10] at the LOAEL of 3 mg/kg/day. At the high dose [10 

mg/kg/day], three does died, there was an increase in clinical signs [diarrhea, subdued and thin appearance], 

body-weight loss during the first three days of dosing and lower body-weight gain throughout the dosing period 

[20% of control], and decreased food consumption. 

The developmental toxicity NOAEL was 3 mg/kg/day, based on an increased incidence of friable and/or 

mottled livers and poorer ossification, as evidenced by minor skeletal alterations at the LOAEL of 10 

mg/kg/day. 

16
This developmental toxicity study is classified ACCEPTABLE/Guideline, and it satisfies the guideline 

requirement [OPPTS 870.3700; §83-3(b)] for a developmental toxicity study in rabbits. 

870.3700a Prenatal Developmental Toxicity Study - Mouse 

In a developmental toxicity study [MRID 00061637], pregnant Alderley Park albino SPF mice [32-34 

mice/group] were administered Diquat dibromide [analytical standard] via gavage at dose levels of 0 [distilled 

water], 1, 2, and 4 mg/kg/day [expressed as the diquat cation] from gestation days 6 through 15. The dams were 

sacrificed on gestation day 17, and fetuses were examined for external, visceral, and skeletal alterations. 

There was a dose-related increase in the number of deaths. One low-dose [day 15 after 10 doses], three mid-dose 

[days 9, 10, 14], and five high-dose [days 9, 15, 16] dams died. There was an increase in the incidence of clinical 

signs of toxicity [piloerection (all three dose groups), dyspnea, respiratory noise (all dose groups), abnormal 

posture (hunched or tail raised), lethargy (1 mid-, 2 high-dose mice), tremors (3 high-dose mice), unsteadiness 

on feet, emaciation, ptosis], which were predominantly found in the mid- and high-dose animals. High-dose 

dams displayed a slightly lower body weight on gestation days 15 [89% of control] and 17 [91% of control] 

compared to the control, and there was a dose-related decrease in body-weight gain during the dosing period 

[overall: 87%, 82%, and 63% of control, with increasing dose]. 

There was an increased incidence of gastrointestinal disorders and ruptured lungs at necropsy in those dying on 

test, and congested lungs and severe pulmonary changes were noted at the mid- and high-dose levels in those 

sacrificed at study termination. 

Pregnancy rate, number of implantations and live fetuses/dam, fetal sex ratio, pre- and post-implantation losses, 

and litter size were comparable among the groups. Fetal body weight [87% of control] and litter weight [90% 

of control] were decreased at the high-dose level. 

There was no increase in the incidence of minor visceral abnormalities. There was a dose-related [slight] increase 

in the incidence of major malformations [0.6%, 0.6%, 2.1%, and 2.5% (% fetuses examined); 7.4%, 7.4%, 20%, 

and 21.7% (% litters) with increasing dose]. The incidence of minor skeletal abnormalities [incomplete 

ossification, extra ribs, variant sternebrae] was increased at all dose levels compared to the control [10.3%, 

18.5%, 24.3%, and 23.4% with increasing dose], and the corresponding values for the mean percentage of minor 

skeletal abnormalities per litter were 10.5%, 20.1%, 28.1%, and 27.0%* with increasing dose. The percent of 

fetuses with extra ribs was comparable among the groups, but the incidence of fetuses with variant sternebrae 

was increased at all dose levels compared to the control [38.7%, 60.7%**, 57.3%, and 62.1%** with increasing 

dose]. 

The maternal toxicity NOAEL was 1 mg/kg/day, based on clinical signs, deaths, and macroscopic lesions 

in the gastrointestinal tract and lungs at the maternal toxicity LOAEL of 2 mg/kg/day. 

The developmental toxicity NOAEL was 2 mg/kg/day, based on decreased fetal body weight [88% of 

control] and an increased incidence of overall skeletal alterations at 4 mg/kg/day. 

17
This developmental toxicity study is classified ACCEPTABLE/Guideline, and it satisfies the guideline 

requirement [OPPTS 870. 3700; §83-3] for a developmental toxicity study in rodents. NOTE: The HIARC 

reevaluated the mouse developmental toxicity study and determined that it is an acceptable study, but it is not 

useful for risk assessment due to, among other things, the poor dosing technique, which resulted in an 

inappropriate introduction of test material into the lungs. 

4.6 Reproductive Toxicity 

Adequacy of data base for Reproductive Toxicity: The data base for reproductive toxicity is considered 

complete. Reproductive toxicity was observed in both generations, as evidenced by decreased numbers of 

live F1 pups/litter and decreased pup body-weight gain [F1 and F2]. 

870.3800 Two-Generation Reproduction Study - Rat 

In a two-generation reproduction study [MRID 41531301], groups of 30 Alpk:APfSD [Wistar-derived] 

rats/sex/dose were fed diets containing Diquat dibromide [21.09% diquat ion] at concentrations of 0, 16, 80, and 

400/240 ppm of diquat cation [0, 0.8, 4, and 20/12 mg/kg/day, using standard conversion factor] for 12 weeks 

[11 weeks for F1 generation] before mating, through mating, gestation, and lactation periods. NOTE: Due to 

adverse effects in the F1 rats, the dose was reduced from 400 ppm to 240 ppm approximately 4 weeks after 

selection. 

There were no treatment-related deaths. Parental toxicity was observed mostly at the high-dose level, in both 

generations, as increased incidences of clinical signs [lack of grooming, piloerection, opaque eyes, and ulcers 

on the palate and tongue (F1)], ophthalmoscopic signs [eye opacity, partial or total lenticular cataracts, and 

iritis], decreased body-weight gains during the premating [F0 males 15%-40%/F0 females 10%-37%; F1 males 

6%-37%/F1 females 79% week 1 only], and decreased food consumption during the premating period. Maternal 

body- weight gains of the high-dose F0 dams were significantly lower than the control throughout gestation, with 

the magnitude of the deficit increasing with time [20%-23% lower than control]. During lactation, the high-dose 

dams displayed lower body-weight gains [54%-80% lower than control] during the latter part of lactation [days 

16-22], with the magnitude of the deficit increasing with time. During gestation, F1 dams displayed comparable 

body-weight gains among the groups, but the high-dose F1 dams displayed a progressive deficit in body-weight 

gain during lactation [27%-42% lower than control] compared to the control. High-dose F0 dams displayed 

decreased food consumption during gestation and lactation, and food consumption was comparable among the 

F1 dams throughout gestation and lactation. 

Ophthalmoscopic examination revealed partial/total cataracts at the high-dose level in both sexes and both 

generations following the premating dosing periods, as well as at week 4 after selection of the F1 pups [prior 

to dosing]. At the high-dose level in both generations and both sexes, the incidence of partial and/or total cataract 

increased with time. In the F1 generation parental mid-dose females, there was an increase in the incidence of 

partial cataract and the incidence increased with time; i.e., 1 at week 4, 3 at week 11, and 4 at week 21. A similar 

finding was not observed in the mid-dose males, and there were no total cataracts at the mid-dose level in either 

sex. 

There were no adverse effects on female fertility at any dose level [both generations], and gestation indices and 

18
gestation length were comparable among the groups [both generations]. The live birth index, viability index, and 

lactation index were comparable among the groups in both generations. In both generations, the fetal sex 

distribution was comparable among the groups. There was a slight decrease [84%-85% of control] in the mean 

number of live F1 pups/litter at the high-dose level, and mean F1 pup body weight on day 22 of lactation was 

decreased significantly [both sexes] at the high-dose level [F1 males 79%/F1 females 82% of control; F2 87% 

of control, both sexes] compared to the control. Body-weight gains were decreased at the high-dose level [F1 

males 76%/F1 females 79% of control; F2 males 85%/F2 females 84% of control] compared to the controls. 

Histopathological examination confirmed the clinical signs/gross observations found in the parental rats. In the 

F0 adults at the high-dose level, ocular opacity was due to cataractous changes in the eye [both sexes], ulceration 

of the tongue [7/30 males; 25/30 females] was confirmed microscopically, along with granulomatous 

inflammation [2/30 males; 1/30 females], loss of normal arrangements in the epithelial papillae and rete pegs 

[5/30 males], abscess formation [4/30 males], mixed inflammatory cell infiltration [2/30 males], and acanthosis 

[3/30 males]. F1 adults displayed ocular opacity, ulceration of the hard palate, loss of palatine ridges, and 

ulceration of the tongue grossly, and one 80 ppm female displayed ulceration of the tongue. Microscopic 

examination of the F1 adults showed cataractous changes at the high-dose level that were similar in incidence 

and severity to the F0 adults. Other ocular changes at the high-dose level included retinal detachment, vitreous 

adhesions, and lens enucleation. Ulceration of the hard palate and tongue was observed at the high-dose level 

in both sexes. In the F1 pups at the high-dose level [both sexes], ulceration of the hard palate and increased 

incidences of pyelitis, ureteritis, and cortical tubular dilatation were observed. Cataracts were not observed in 

the F1 pups. Gross findings in the high-dose F2 pups included distended caecum and ocular opacity [one 

female]. F2 high-dose pups displayed increased incidences of hypertrophy and hyperplasia of the collecting duct 

epithelium in the kidney, cystitis, pyelitis, and slight cortical tubular dilatation in males and females. 

The parental systemic toxicity NOAEL is 16 ppm [0.8 mg/kg/day], based on the increased incidence of 

clinical signs, including ophthalmoscopic signs and gross and microscopic findings [partial cataract and 

ulceration of the tongue] in females at the LOAEL of 80 ppm [4 mg/kg/day]. At the high-dose level, in 

addition to the above findings in both sexes, clinical signs [piloerection, opaque eyes, and ulcers on the 

palate], ophthalmoscopic signs [eye opacity, total cataracts, and iritis], decreased body-weight gain and 

food consumption were observed in both sexes. 

The reproductive/developmental NOAEL was 80 ppm [4 mg/kg/day], based on decreased number of live 

pups per litter on days 1-22, decreased pup body-weight gain during lactation, and increased incidence 

of kidney lesions in the F2 pups at the LOAEL of 400/240 ppm [12 mg/kg/day]. 

This two-generation reproduction study is classified ACCEPTABLE/Guideline, and it satisfies the guideline 

requirement [OPPTS 870.3800] for a reproduction study in rodents. 

4.7 Neurotoxicity 

Adequacy of data base for Neurotoxicity: The data base for neurotoxicity is considered complete. No 

additional studies are required at this time. Following acute exposure, there was an increased incidence of 

diarrhea, staining of the nose, piloerection, urinary incontinence, mouth staining, upward curvature of 

19
the spine, tip-toe gait, hunched posture, subdued behavior, and sides pinched in. However, the Agency has 

concluded that these symptoms may not be due to direct neurotoxicity. No evidence of neurotoxicity was 

observed in the functional observational battery, motor activity measurement, or neurohistopathology 

examination following subchronic exposure. Neuropathology was not observed in any study. Several of 

the clinical signs suggestive of neurotoxicity [piloerection, hunched posture, unsteadiness, muscular 

weakness, and inability to stand, hypothermia, hypoactivity, dyspnea, cyanosis, pale extremities] were 

observed in pregnant mice after oral administration on days 6-15 of gestation and in rats following dermal 

exposure, but these can be attributed to the general poor health of the animals in these studies. 

870.6100 Delayed Neurotoxicity Study - Hen 

This is not a data requirement for Diquat dibromide. 

870.6200 Acute Neurotoxicity Screening Battery 

In an acute neurotoxicity study [MRID 42666801, Diquat dibromide [20.1% a.i.] was administered to 10 

Alpk:APfSD rats/sex/group via gavage at single dose levels of 0, 25, 75, and 150 mg/kg. Five rats/sex/dose were 

used for neuropathological examination at study termination. The functional observational battery [FOB] and 

motor activity assessment were performed approximately 1 week pre-test, at 6 hours post dose, and on days 8 

and 15 post dose. The rats were sacrificed on day 16 post dose. 

There was one treatment-related death at the high-dose level [female sacrificed in extremis on day 6]. Treatmentrelated clinical signs were observed mainly at the high-dose level during days 2-6 post dose and included 

piloerection [high dose: males 1/10, females 7/10], diarrhea [high dose: 1/10 males, 5/10 females; 2/10 mid-dose 

females], staining around nose [1/10 males in each treatment group, 3/10 mid-dose and 3/10 control females], 

urinary incontinence [3/10 high-dose females], upward curvature of the spine [3/10 high-dose females], tip toe 

gait [3/10 high-dose females], hunched posture [2/10 high-dose females], subdued behavior [2/10 high-dose 

females], and pinched sides [1/10 high-dose female]. Slightly decreased body weights [4%-5%] were observed 

by day 8 in both sexes at the high-dose level, and decreased body-weight gains [males 17%/females 23%] were 

observed during the first week only at this dose level in both sexes. Food consumption was decreased at the mid­

[males -10%] and high-dose [males -22%/females -35%] levels during the first week following dosing. 

The only FOB parameter showing an apparent effect was landing foot splay, which was significantly increased 

[14%] in the high-dose males on day 1. High-dose females who displayed clinical signs suggestive of a 

neurological effect did not display any changes in FOB. Motor activity was not affected by treatment in either 

sex. No treatment-related effects were reported in the gross/histopathological examinations at study termination. 

HED has determined that the signs observed in this study may not be due to direct neurotoxicity. 

The systemic NOAEL is 75 mg/kg, based on clinical signs and decreased body-weight gain at the systemic 

LOAEL of 150 mg/kg. 

This acute neurotoxicity study is classified ACCEPTABLE/Guideline, and it satisfies the guideline requirement 

[OPPTS 870. 6200; §81-8] for an acute neurotoxicity study in rats. NOTE: Neurobehavioral tests [performed 

6 hours post dose] may not have been performed at peak effect time. The clinical signs observed occurred 

20
between days 2 and 6 post dose. 

870.6200 Subchronic Neurotoxicity Screening Battery 

In a subchronic neurotoxicity study [MRID 42616101], Diquat dibromide [20.8% a.i.] was administered to 12 

Alpk:APfSD rats/sex/group at dietary levels of 0, 20, 100, and 400 ppm [males 0, 1.6, 8.0, and 32.4 mg/kg/day; 

females 0, 1.9, 9.5, and 38.5 mg/kg/day (expressed as the cation)] for 13 weeks. Five rats/sex/dose were used 

for neuropathological examination at study termination. 

There were no treatment-related deaths. Treatment-related clinical signs were observed at the high-dose level 

in both sexes at the end of the study [opaque eyes: 7/12 males and 8/12 females (weeks 13 and 14); eye pallor: 

3/12 males and 1/12 females (weeks 12 and 13); decreased visual placement response: 3/12 males and 1/12 

females]. Decreased body weights [.9%] were observed throughout the study in both sexes at the high-dose 

level, and decreased body-weight gains [males 20%/females 18%] and food utilization were also observed at 

this dose level in both sexes. 

There was an increased incidence of cataracts and/or posterior lens opacities at the high-dose level in both sexes 

at study termination. Total cataracts were observed in 5/12 high-dose males and 7/12 high-dose females. 

Posterior opacity of the lens was observed in 8/12 high-dose males and 6/12 high-dose females. 

There was no evidence of neurotoxicity. No treatment-related effects were reported in the functional 

observational battery [weeks 5, 9, and 14 post dose], motor activity assessment [weeks 5, 9, and 14 post dose], 

and gross/histopathological examination at study termination. 

The NOAEL for neurotoxicity is 400 ppm [males 32.4/females 38.5 mg/kg/day], the highest dose tested. 

The systemic NOAEL is 100 ppm [males 8.0/females 9.5 mg/kg/day], based on cataracts and decreased 

body-weight gain and food utilization at the systemic LOAEL of 400 ppm [males 32.4/females 38.5 

mg/kg/day]. 

This subchronic neurotoxicity study is classified ACCEPTABLE/Guideline, and it satisfies the guideline 

requirement [OPPTS 870. 6200; §82-7] for a subchronic neurotoxicity study in rats. 

870.6300 Developmental Neurotoxicity Study 

There is no developmental neurotoxicity study [DNT] on Diquat dibromide. 

4.8 Mutagenicity 

Adequacy of data base for Mutagenicity: The data base for mutagenicity is considered adequate based 

on pre-1991 mutagenicity guidelines. No additional studies are required at this time. Diquat dibromide was 

negative for mutagenicity in a bacterial gene mutation [Ames] assay. Diquat dibromide was, however, 

positive for gene mutations in a mammalian cell line [mouse lymphoma] but at cytotoxic doses. Similarly, 

Diquat dibromide was clastogenic in cultured human lymphocytes, but the response was generally weak 

21
and was observed at cytotoxic levels. In contrast, there was no evidence of clastogenicity in somatic cells 

[mouse bone marrow] or germinal cells [mouse spermatogonia] or unscheduled DNA synthesis [UDS] in 

rat hepatocytes in a series of in vivo studies. Overall, the data suggest that there is no concern for 

mutagenicity. 

Gene Mutation 

Guideline 870.5265. Ames, reverse 

mutation; MRID 40323103 

classification: Acceptable 

0.01-100 Fg/plate. No evidence of bacterial mutation in S. Typhimurium strains 

TA1535, TA1537, TA1538, TA98, TA100, and one strain of Escherichia coli 

[Wp2uvrA pKM 101], w/ and w/out S9 

Guideline 870.5300. mouse lymphoma 

[L5178Y]; 

MRID 40323101 

classification: Acceptable 

6.25-100 Fg/mL and 3.12-50 Fg/mL, w/ and w/out S9 mix, respectively; 

concentration-dependent cytotoxicity observed at all dose levels w/ and w/out S9. 

Mutagenic; colony sizing was not performed and increased mutant frequency 

occurred at cytotoxic doses. 

Cytogenetics 

Guideline 870.5385. in vivo 

chromosome aberration [C57B1/6J/ 

Alpk mouse bone marrow]; 

MRID 40323104 

classification: Acceptable 

62.5 or 100 mg/kg as diquat cation [50% and 80% of Median Lethal Dose]. 

Cytotoxicity at both dose levels. Not clastogenic. 

Guideline 870.5375. in vitro 

chromosome aberration [human 

lymphocytes]; MRID 40323106 

classification: Acceptable 

1-129 Fg/mL. MTD 129 Fg/mL not clastogenic at dose levels of 12.9 Fg/mL [±S9] 

and 25.8 Fg/mL [+S9], where cytotoxicity was not apparent; other concentrations 

induced weak but statistically significant increases in chromosomal damage [5.5%-

30% > control] and cytotoxicity was apparent at these dose levels. 

Guideline 870.5450. dominant lethal 

assay; MRID 00061636 

classification: Acceptable 

0, 0.1, 1.0, or 10 mg/kg/day for 5 consecutive days. No evidence of dominant lethal 

activity in Charles River CD-1 mice at dose levels up to 50% of the LD50. 

Other Genotoxicity 

Guideline 870.5450. Unscheduled DNA 

synthesis in vivo rat hepatocyte assay; 

MRID 40323107; classification: 

Acceptable 

225, 450, or 900 mg/kg primary rat hepatocytes; varying degrees of cytotoxicity in 

hepatocytes at all dose levels, as evidenced by pyknotic and deeply staining nuclei 

coupled with reduced numbers of cells of normal morphology. No evidence of 

induction of unscheduled DNA synthesis. 

4.9 Metabolism 

Adequacy of data base for metabolism: The data base for metabolism is considered to be complete. 

Following oral exposure, the majority of the administered dose is eliminated in the feces (.89% of the 

administered dose), indicating that diquat is poorly absorbed from the gastrointestinal tract. That portion 

absorbed is rapidly eliminated in the urine (.6% of the administered dose). Unchanged Diquat dibromide is the 

major excretion product in both the urine and feces. The major metabolites are diquat monopyridone and diquat 

dipyridone, and these are considered to have the same toxicity as the parent. No substantial retention was 

22
observed in any tissue. 

870.7485 Metabolism - Rat 

In a metabolism study [MRID 00065592], male and female rats and mice [numbers and strains not specified in 

review] were dosed either orally or intravenously with single doses of Diquat dibromide. 

Diquat dibromide was slowly absorbed from the gastrointestinal tract of male and female rats. Irrespective of 

the type of dosing [oral or intravenous], Diquat did not accumulate in tissues of rats or mice. Following a single 

oral dose of [14C]-Diquat dibromide [60 mg/kg, expressed as the diquat cation], only 5.5% of the administered 

radioactivity was excreted in the urine of rats within 7 days. Following an oral [feeding] dose of unlabeled 

Diquat dibromide [250 ppm, expressed as the diquat cation] to male and female rats for 2, 4, or 8 weeks, there 

was no retention [as determined by colorimetrically] of Diquat in the brain, liver, lung, stomach, small and large 

intestine, muscle, and blood, and little retention in the kidneys [0.18, 0.25, and 1.17 ppm during weeks 2, 4, and 

8, respectively. Ten minutes after an iv injection of [14C]-Diquat dibromide [60 mg/kg, expressed as the diquat 

cation], there were indications [whole body autoradiography] that Diquat concentrated in the cartilaginous 

tissues, the liver, and the urinary bladder. Most other tissues also showed the presence of radioactivity, including 

small amounts in the brain and spinal cord. After one hour, the amounts of radioactivity declined in most tissues. 

After 24 hours, radioactivity was detected only in the urinary bladder and in the small and large intestines. There 

was still some radioactivity in the intestines, but none in the bladder at 72 hours post dose. 

In another metabolism study [MRID 00065593], rats [number, sex, strain, dose levels not specified] were dosed 

with [

14C]-Diquat dibromide either by stomach tube or by subcutaneous injection, and their urine and feces were 

monitored at 24-hour intervals for 4 days. Following oral administration, the rats excreted 6.3% and 89.3% of 

the administered radioactivity in the urine and feces, respectively, within 4 days. Most of this radioactivity was 

excreted during the first 48 hours. In the urine, most of the excreted radioactivity [5.3%] was unchanged, 

whereas the remaining 1% was associated with the following metabolites: Diquat monopyridone [0.2%], Diquat 

dipyridone [0.1%], and unidentified metabolites [0.3%]. In the feces, 65.5% of the excreted radioactivity was 

detected in the sulfuric acid-extractable fraction and 15.7% in the ammonium sulfate-unextractable fraction. In 

the sulfuric acid fraction, the radioactivity was distributed as follows: unchanged Diquat [57.1%], Diquat 

monopyridone [4.3%], and unidentified material [4.1%]. The ammonium sulfate fraction was not analyzed for 

metabolites. Following subcutaneous administration of [14C]-Diquat dibromide, 87.1% of the dose was recovered 

in the urine during 4 days, but only 4.8% was recovered in the first 24 hours. Most of the radioactivity [78.8%] 

was unchanged Diquat. The amount of radioactivity recovered in the feces and the percent distribution of 

monopyridone and dipyridone in urine and feces, after the subcutaneous dose, were not reported in the available 

review. 

In a third study [MRID 00055107], rats [number, sex, strain not specified in review] were dosed orally with 

[

14C]-Diquat dibromide and their urine and feces were quantitated for radioactivity at selected time intervals 

following dosing. About 90% of the radioactivity was eliminated in the feces, indicating that Diquat was poorly 

absorbed from the gastrointestinal tract. Following subcutaneous injection of [14C]-Diquat dibromide, to 

circumvent the intestine, nearly all of the radiolabeled material was recovered in the urine within 2 days. 

The three studies together are classified as Acceptable/Guideline, and together they satisfy the guideline 

23
requirement [OPPTS 870.7485] for a general metabolism study. 

5.0 TOXICITY ENDPOINT SELECTION

5.1 See Section 9.2 for Endpoint Selection Table

5.2 Dermal Absorption

870.7600 Dermal Absorption - Rat

Adequacy of the dermal absorption data: There is an adequate dermal absorption study available. Diquat 

dibromide is readily soluble in water, and it ionizes in aqueous solutions. Such compounds can be expected to 

be absorbed very slowly and in small amounts through the skin.. The dermal absorption of Diquat dibromide 

through intact rat skin is considered very low. 

Executive Summary: In an in vivo percutaneous absorption study [MRID 41238701], aqueous solutions of [14C] 

Diquat dibromide were applied dermally [10 cm2

] to the shaved backs of 4 Sprague-Dawley rats/group. 

Following 24 hours of exposure, dose levels of 0.05, 0.5, and 5 mg diquat cation/rat resulted in 2.3%, 2.1%, and 

3.3% absorption. The unabsorbed Diquat dibromide was recovered from the application site. Based on these 

findings, the dermal absorption of Diquat dibromide through intact rat skin is considered very low. 

Application to a 10 cm2 area of the rat’s back resulted in the following percent absorption 

exposure 

time [hr] 

0.05 mg/rat 0.5 mg/rat 5 mg/rat 

on./in skin skin wash absorbed on/in skin skin wash absorbed on/in skin skin wash absorbed 

2 2.9 92.6 1.2 1.7 96.0 1.1 1.0 96.3 1.8 

10 3.6 89.1 1.9 1.8 94.4 3.7 1.1 92.0 3.1 

24 5.1 81.9 2.3 2.6 95.1 2.1 1.1 95.1 3.3 

This study is classified Acceptable/guideline; it satisfies the guideline requirement for a dermal penetration

study (OPPTS 870.7600) in the rat.

Dermal Absorption Factor: 4.1%, based on exposure pattern and duration of exposure [low-dose at 2 hours;

residential exposure].

5.3 Classification of Carcinogenic Potential

5.3.1 The data available for Diquat dibromide provide no evidence of a carcinogenic effect. 

5.3.2 Classification of Carcinogenic Potential 

The carcinogenic potential of Diquat dibromide was classified as Category E [Evidence of NonCarcinogenicity for Humans], according to EPA Guidelines for carcinogen Risk Assessment 

24
[CFR September 24, 1986]. 

5.3.3 Quantification of Carcinogenic Potential 

Not applicable. 

6.0 FQPA CONSIDERATIONS 

6.1 Special Sensitivity to Infants and Children 

The data provided no indication of increased sensitivity of rats, mice, or rabbits to in utero and/or 

postnatal exposure to Diquat dibromide. In the regulatory-quality prenatal developmental toxicity studies 

in rats and rabbits and the two-generation reproduction study in rats, effects in the offspring were 

observed only at or above treatment levels that resulted in evidence of parental toxicity. 

6.2 Recommendation for a Developmental Neurotoxicity Study 

The HIARC Committee determined that a developmental neurotoxicity study in rats is not required 

[HIARC Report TXR No. 014670] at this time. 

25
7.0 REFERENCES in MRID order 

00055107 Daniel, J. W. and Gage, J. C. (1966) Absorption and Excretion of Diquat and Paraquat in Rats. 

(Published Study from Imperial Chemical Industires Limited, Industrial Research Laboratories, 

Alderley Park, Cheshire, Great Britain). Brit. J. Industr. Med., 1966, 23, 133-136. 

00061636 McGregor, D.B. (1974) Dominant Lethal Study in Mice of Diquat: 401567: Report No. 148. 

(Unpublished study received Jan 27, 1981 under 239-1663; prepared by Inveresk Research 

International, submitted by Chevron Chemical Co., Richmond, Calif.; CDL: 244244-D) 

00061637 Palmer, A.K.; Edwards, J.A.; Woodhouse, R.N. (1978) Effect of Diquat on Pregnancy of the Mouse: 

ICI/167/77642. (Unpublished study received Jan 27, 1981 under 239-1663; prepared by Huntingdon 

Research Centre, England, submitted by Chevron Chemical Co., Richmond, Calif.; CDL:244244-E) 

00065592 Litchfield, M. H., Daniel, J. W., and Longshaw, S. (1973) The Tissue Distribution of the 

Bipyridylium Herbicides Diquat and Paraquat in Rats and Mice. (Published study from Industrial 

Hygiene Research Laboratories and Pharmaceuticals Division of Imperial Chemical Industries 

Limited, Alderley Park, Cheshire, Great Britain). Toxicology, 1973, 1, 155-165. 

00065593 (1972). Diquat: Disposition and Metabolism in the Rat. Study No. CTL/P/21H. (Unpublished study 

prepared by ICI England, submitted by Chevron Chemical Co., Richmond, Calif.). 

00081506 (1979) The Acute Oral Toxicity of Diquat Water Weed Killer. Study No. S 1431 (Unpublished study 

submitted by Chevron Chemical Co., Richmond, Calif.) 

00081507 (1976) The Eye Irritation Potential of CC 7019. Study No. S-960 (Unpublished study submitted by 

Chevron Chemical Co., Richmond, Calif.) 

00100614 (1979) The Acute Dermal Toxicity of Diquat Water Weed Killer in Adult Male and Female Rabbits. 

Study No. S-1623 (Unpublished study submitted by Chevron Chemical Co., Richmond, Calif.) 

00107903 (1979) The Skin Irritation Potential of Diquat Water Weed Killer. Study No. S-1624 (Unpublished 

study submitted by Chevron Chemical Co., Richmond, Calif.) 

00145855 Colley, J.; Warren, S.; Heywood, R. (1985) Diquat Dibromide Evaluation of Potential 

Carcinogenicity and Chronic Toxicity by Prolonged Dietary Administration to Rats: Final Report: 

HRC Report No. ICI 406-837/63. Unpublished study prepared by Huntingdon Research Centre. 

2660 p. [Accession Nos. 256983-256988]. 

00160673 Huntingdon Research Centre (1985) Diquat Dibromide: Evaluation of Potential Carcinogenicity and 

Chronic Toxicity by Prolonged Dietary Administration to Rats. Unpublished compilation. 42 p. 

40185602 Zimmerman, R. (1981) Supplemental Information in Support of Diquat Rat Chronic 

26
Toxicity/Oncogenicity Study: Laboratory Project ID: ICI 383/80935. Unpublished study prepared 

by Huntingdon Research Centre. 6 p. 

40301701 Bruce, E.; Griffis, L. (1987) Three-Week Aerosol Inhalation Toxicity Study of Diquat Concentrate 

in Rats: Laboratory Project ID: S-2908; CEHC 2663. Unpublished study prepared by Chevron Envi 

ronmental Health Center, Inc. 420 p. 

40308101 Auletta, C. (1987) A Twenty-one Day Dermal Toxicity Study in Rats with Diquat Technical: Lab 

Project ID: 87-3137. Unpublished study prepared by Bio/dynamics, Inc. 477 p. 

40323101 Cross, M. (1986) Diquat Bromide (Technical): Assessment of Mutagenic Potential Using L5178Y 

Mouse Lymphona Cells: Lab Project ID: CTL/P/1602. Unpublished study prepared by Imperial 

Chemical Industries, PLC. 31 p. 

40323102 Cross, M. (1986) Diquat Dibromide: Assessment of Mutagenic Potential Using L5178Y Mouse 

Lymphoma Cells: Lab Project ID: CTL/P/1554. Unpublished study prepared by Imperial Chemical 

Industries PLC. 31 p. 

40323103 Callander, R. (1986) Diquat Dibromide (Technical): An Evaluation of Mutagenic Potential Using 

S. typhimurium and E. coli: Lab Project ID: CTL/P/1463. Unpublished study prepared by Imperial 

Chemical Industries PLC. 42 p. 

40323104 Sheldon, T.; Richardson, C.; Shaw, J. (1986) Diquat Dibromide (Technical): An Evaluation in the 

Mouse Micronucleus Test: Lab Project ID: CTL/P/1532. Unpublished study prepared by Imperial 

Chemical Industries PLC. 29 p. 

40323105 Wildgoose, J.; Braithwaite, I.; Howard, C.; et al. (1986) Diquat Dibromide: A Cytogenic sic Study 

in Human Lymphocytes in vitro: Lab Project ID: CTL/P/1469. Unpublished study prepared by 

Imperial Chemical Industries PLC. 30 p. 

40323106 Richardson, C.; Howard, C.; Wildgoose, J. (1986) Diquat Dibromide (Technical): A Cytogenetics 

Study in Human Lymphocytes in vitro: Lab Project ID: CTL/P/1561. Unpublished study prepared 

by Imperial Chemical Industries PLC. 30 p. 

40323107 Trueman, R. (1987) Assessment for the Induction of Unscheduled DNA Synthesis in Rat 

Hepatocytes in vivo: Lab Project ID: 8703557. Unpublished study prepared by Imperial Chemical 

Industries PLC. 45 p. 

40640801 Chevron Chemical Co. (1988) Submission of Data To Support the Regi stration of Ortho Diquat 

Concentrate: Toxicity Data. Transmital of 1 study. 

41198901 Hodge, M. (1989) Diquat: Teratogenicity Study in the Rabbit: Report No. CTL/P/2379: Study No. 

RB0404. Unpublished study prepared by ICI Central Toxicology Laboratory. 305 p. 

27
41198902 Wickramaratne, G. (1989) Diquat: Teratogenicity Study in the Rat: Report No. CTL/P/2331: Study 

No. RR0399. Unpublished study prepared by ICI Central Toxicology Laboratory. 394 p. 

41238701 Brorby, G., Griffis, L. (1989) The Percutaneous Absorption of Diquat (SX-1750) in Male Rats: 

Study No. CEHC 2762. Unpublished study prepared by Chevron Environmental Health Center, Inc. 

46 p. 

41531301 Hodge, M. (1990) Diquat: Multigeneration Study in the Rat: Lab Project Number: CTL/P/2462: 

RRO393. Unpublished study prepared by ICI Central Toxicology Laboratory. 2174 p. 

41730301 Hopkins, M. (1990) Diquat: One Year Feeding Study in Dogs: Lab Project Number: CTL/P/2596. 

Unpublished study prepared by ICI Central Toxicology Laboratory. 476 p. 

42219801 Hodge, M. (1991) Diquat: Two Year Feeding Study in Mice: Lab Project Number: PM0749. 

Unpublished study prepared by ICI Central Toxicology Laboratory. 2674 p. 

42616101 Horner, J. (1992) Diquat: Subchronic Neurotoxicity Study in Rats: Lab Project Number: 

CTL/P/3751: PR0886. Unpublished study prepared by ICI Central Toxicology Laboratory. 400 p. 

42666801 Horner, J. (1992) Diquat: Acute Neurotoxicity Study in Rats: Lab Project Number: CTL/P/3789: 

AR5421. Unpublished study prepared by ICI Central Toxicology Laboratory. 330 p. 

42880701 Ishmael, J. (1993) Supplement to MRID 42219801: Diquat: Two-Year Feeding Study in Mice: Lab 

Project Number: CTL/P/3409. Unpublished study prepared by Zeneca Central Toxicology Lab. 50 

p. 

42905901 Ishmael, J. (1993) Supplemental Information to MRID 42291801: Diquat: Two-year Feeding Study 

in Mice: Lab Project Number: CTL/P/3409. Unpublished study prepared by Zeneca Agrochemicals, 

Central Toxicology Lab. 6 p. 

42919501 Ishmael, J. (1993) Supplemental Information to MRID 42291801: Diquat: Two-Year Feeding Study 

in Mice: Lab Project Number: CTL/P/3409. Unpublished study prepared by Central Toxicology 

Lab., Zeneca Agrochemicals. 5 p. 

43383203 Hodge, M. (1994) Diquat: 28 Day Feeding Study in Mice: Lab Project Number: CTL/L/2495: 

PM0734. Unpublished study prepared by Zeneca Central Toxicology Lab. 10 p. 

28
8.0 APPENDICES

Tables for Use in Risk Assessment

29
8.1 Toxicity Profile Summary Tables

8.1.1 Acute Toxicity Table - See Section 4.1

8.1.2 Subchronic, Chronic, and Other Toxicity Tables

Toxicity Profile 

Subchronic Toxicity of Diquat dibromide 

Guideline Study Type/MRID/doses Results 

870.3200 

[§82-2] 

21-day dermal toxicity - rats 

MRID: 40308101 [1987] 

Classification: Acceptable/Guideline 

Diquat dibromide (20.64% diquat cation) 

Dermal Toxicity NOAEL < 5 mg/kg/day 

Dermal Toxicity LOAEL = 5 mg/kg/day, based on dermal irritation 

at application site [erythema, edema, atonia, and desquamation] and 

tissue destruction [necrosis and eschar formation].. 

Systemic Toxicity NOAEL = 5 mg/kg/day 

Systemic Toxicity LOAEL = 20 mg/kg/day, based on a dose-related 

mortality and clinical signs [hypothermia, hypoactivity, dyspnea, 

cyanosis, pale extremities, general poor condition, and emaciated 

appearance]. Based on the severity of the effects observed [death and 

clinical signs (hypothermia, hypoactivity, dyspnea, cyanosis, pale 

extremities, general poor condition, and emaciated appearance)] and 

the extent of skin toxicity [dermal irritation (erythema, edema, and 

desquamation) and tissue destruction (necrosis and eschar 

formation); sores, severe erythema, fissures, acute necrotizing 

purulent dermatitis, and degeneration of the hair follicles and 

sebaceous glands] observed at the site of application in one or both 

sexes, it was concluded that the study was not appropriate for use in 

risk assessment since the NOAEL is artificially low due to the fact 

that the skin is compromised. 

870.3465 

[§82-4] 

Subchronic Inhalation - Rats (3 weeks) 

MRID: 40301701, 40640801 [1987, 1988] 

Classification: Acceptable/Guideline, when 

both studies considered together. NOTE: 

Duration of study is 21 days, not 90 days. 

Diquat dibromide (21.6%/23.5% diquat cation) 

NOAEL: 0.1 Fg/L/day [males 0.027 mg/kg/day; females 0.0.029 

mg/kg/day], based on increased lung weights and microscopic 

lesions [mottling and reddening of the lungs in females, multifocal, 

chronic, interstitial pneumonia and alveolar macrophages in both 

sexes] in the lungs at the LOAEL of 0.49 Fg/L [males 0.134 

mg/kg/day; females 0.144 mg/kg/day]. 

LOAEL = Lowest Observable Adverse Effect Level; NOAEL = No Observable Adverse Effect Level 

30
Chronic Toxicity/Carcinogenicity of Diquat dibromide 

Guideline Study Type/MRID/doses Results 

870.4100 

[§83-1b] 

Chronic feeding study in beagle dogs [0, 0.5, 2.5, 

and 12.5 mg/kg/day for 52 weeks] 

MRID 41730301 [1990] 

Classification: Acceptable/guideline 

Diquat dibromide (26.7% w/v cation) 

NOAEL: 0.5 mg/kg/day 

LOAEL: 2.5 mg/kg/day, based on unilateral cataracts in females, and 

decreased weights of epididymides and adrenals in males. At the HDT, 

bilateral lenticular opacity [cataracts], macroscopically and 

microscopically [in all dogs, both sexes]; inflammatory lesions in the large 

intestine [in all dogs, both sexes]; increased kidney weight [both sexes]. 

870.4200 

[§83-2] 

Carcinogenicity study -CD-1 mice [0, 30, 100, 300 

ppm [males 0, 3.56, 11.96, and 37.83/females 0, 

4.78, 16.03, and 48.27 mg/kg/day] for 104 weeks 

MRID 42219801, 42880701, 42905901, 42919501 

[1991] 

Classification: Acceptable/guideline 

Diquat dibromide (21.09% w/v cation) 

NOAEL = 30 ppm [3.56/4.78 mg/kg/day] 

LOAEL: 100 [11.96/16.03 mg/kg/day], based on clinical signs [eye 

discharge (males), increased incidence of thin appearance and subdued 

behavior (females)], increased kidney weights (males). At HDT, increased 

incidences of microscopic lesions in the kidney, liver, and lymph node 

(mesenteric) . 

There was no treatment-related increase in tumor incidence in either sex. 

870.4300 

[§83-5] 

Chronic feeding/carcinogenicity study - SpragueDawley rats [0, 5, 15, 75, and 375 ppm (0, 0.19, 

0.58, 2.91, and 14.88 mg/kg/day for males and 0, 

0.24, 0.72, 3.64, and 19.44 mg/kg/day for females)] 

for 104 weeks. 

MRID 00145855, 00155474, 41085601 [1985] 

Classification: Acceptable/guideline 

Diquat dibromide (0.24-18.38% diquat cation) 

NOAEL: 15 ppm [0.58/0.72 mg/kg/day] 

LOAEL: 75 ppm [2.91/3.64 mg/kg/day], based on eye lesions [total 

cataracts]. NOTE: The incidence of eye lesions increased with time on 

study, and effect observed at lower dose level with time. 

There was no treatment-related increase in tumor incidence in either sex. 

31
Developmental Toxicity of Diquat dibromide 

Guideline Study Type/MRID/doses Results 

870.3700 

[§83-3a] 

Developmental Toxicity - Wistar-derived 

Rats 

[0, 4, 12, and 40 mg/kg/day] 

MRID 41198902 [1989] 

Classification: Acceptable/Guideline 

Diquat dibromide (26.2% cation) 

Maternal NOAEL: 4 mg/kg/day 

Maternal LOAEL: 12 mg/kg/day, based on decreased body-weight 

gains. At HDT, there was one death [GD 15], and clinical signs 

[piloerection and subdued activity] were observed [GD 13-22]. 

Developmental NOAEL: 12 mg/kg/day 

Developmental LOAEL: 40 mg/kg/day, based on decreased fetal, 

litter, and gravid uterine weights, an increased incidence of fetuses 

with hemorrhagic kidney, and delayed skeletal ossification 

[increased incidence of minor skeletal variations, including 

unossified ventral tubercle, unossified cervical vertebral centra, and 

delayed ossification of the 2nd and 5th sternebrae]. 

870.3700 

[§83-3b] 

Developmental Study - NZW Rabbits 

[0,1, 3, 10 mg/kg/day] 

MRID 41198901 [1989] 

Classification: Acceptable/Guideline 

Diquat dibromide (26.2% cation) 

Maternal NOAEL: 1 mg/kg/day 

Maternal LOAEL: 3 mg/kg/day, based on decreased body-weight 

gain and food consumption. At HDT, there were deaths and clinical 

signs [diarrhea, subdued activity, thin appearance, mucus, blood, 

little or no feces in tray] 

Developmental NOAEL: 3 mg/kg/day 

Developmental LOAEL: 10 mg/kg/day, based on decreased fetal 

body weight, an increased incidence of friable/mottled livers, and an 

increased incidence of minor skeletal alterations [partially ossified 

ventral tubercle of cervical vertebrae, partially ossified 6th 

sternebrae, and unossified 6th sternebrae and presacral vertebrae] . 

870.3700 

[§83-3a] 

Developmental Toxicity Study - Mice 

[ Alderley Park ] 

[0, 1, 2, and 4 mg/kg/day] 

MRID 00061637 [1978] 

Classification: Acceptable/Guideline 

Diquat dibromide (analytical standard) 

Maternal NOAEL: 1 mg/kg/day [as diquat cation] 

Maternal LOAEL: 2 mg/kg/day, based on mortality, clinical signs 

[piloerection, respiratory sounds], and decreased body-weight gain 

[during dosing period]. At HDT, additional clinical signs [abnormal 

posture (hunched or tail raised), lethargy, tremors, unsteadiness on 

feet, emaciation, ptosis] and a slight decrease in body weight [91% 

of control] at termination were observed also. NOTE: Maternal 

effects were attributed to the inappropriate introduction of test 

material into the lungs [poor dosing technique]. 

Developmental NOAEL: 2 mg/kg/day 

Developmental LOAEL: 4 mg/kg/day, based on decreased fetal 

body weight and an increased incidence of overall skeletal 

alterations. 

32
Reproductive Toxicity of Diquat dibromide 

Guideline Study Type/MRID/doses Results 

870.3800 

[§83-4] 

2-Generation Reproduction Toxicity in 

Alpk:APfSD [Wistar derived] Rats 

0, 16, 80, 400/240 ppm [0, 0.8, 4, 20/12 

mg/kg/day] 

MRID 41531301 [1990] 

Classification: Acceptable guideline 

Diquat dibromide (20.09% diquat cation) 

Parental NOAEL: 16 ppm [0.8 mg/kg/day] 

Parental LOAEL: 80 ppm [4 mg/kg/day], based on clinical 

signs, ulceration of the tongue, and partial/total cataract. At 

HDT, increased incidence of clinical signs including 

ophthalmoscopic signs and lack of grooming, and gross and 

microscopic findings [ulceration of the tongue and partial/total 

cataract]. 

Reproductive/Developmental NOAEL: 80 ppm [4 mg/kg/day] 

Reproductive/Developmental LOAEL: 400/240 ppm [12 

mg/kg/day], based on decreased number of live pups per litter 

on days 1-22, decreased pup body-weight gain during 

lactation, and increased incidence of kidney lesions. 

Neurotoxicity of Diquat dibromide 

Guideline Study Type/MRID/doses Results 

870.6200 

[§81-8] 

Acute oral neurotoxicity - Rats 

[0, 25, 75, and 150 mg/kg] 

MRID: 42666801 [1992] 

Classification: Acceptable/Guideline 

Diquat dibromide (20.1% w/v diquat cation) 

NOAEL: 75 mg/kg 

LOAEL: 150 mg/kg/day, based on clinical signs [diarrhea, 

staining of the nose, piloerection, urinary incontinence, mouth 

staining, upward curvature of spine, tip-toe gait, hunched 

posture, subdued behavior, and sides pinched in]. 

NOTE: Agency concluded that signs were not due to direct 

neurotoxicity. 

870.6200 

[§82-7] 

Subchronic neurotoxicity - Alpk:APfSD rats 

0, 20, 100, and 400 ppm [males 0, 1.6, 8.0, 

32.4 mg/kg/day/females 0, 1.9, 9.5, and 38.5 

mg/kg/day] 

MRID: 42616101 [1992] 

Classification: Acceptable/Guideline 

Diquat dibromide (20.8% diquat cation) 

Systemic Toxicity NOAEL = 100 ppm [8.0/9.5 mg/kg/day 

Systemic Toxicity LOAEL = 400 ppm [32.4/38.5 mg/kg/day, 

based on evidence of cataracts and decreased body-weight 

gain and food utilization in both sexes. 

There was no evidence of neurotoxicity at any dose level. 

33
Metabolism Studies on Diquat dibromide 

Guideline Study Type/MRID/doses Results 

870.7485 [§85-1] Disposition and metabolism 

MRID 00065592 

Classification: Acceptable/guidelineW

Diquat dibromide did not accumulate in tissues and was slowly absorbed 

following or iv exposure to single doses of 14C] Diquat dibromide to 

rats or mice of both sexes. Following a single dose of 60 mg/kg, only 5.5% of the 

radiolabel was excreted in urine within 7 days. Following an oral [feeding] dose 

of unlabeled Diquat dibromide [250 ppm] to rats of both sexes for 2, 4, or 8 

weeks, no retention of Diquat was observed int he brain, liver, lung, stomach, 

small and large intestine, muscle, and blood, and little retention in the kidneys 

[0.18, 0.25, and 1.17 ppm during weeks 2, 4, and 8, respectively]. Ten minutes 

after iv injection, there were indications that Diquat concentrated in cartilaginous 

tissues, liver, and urinary bladder, as well as the brain and spinal cord. After 24 

hours, radiolabel was detected only in the urinary bladder and intestines. 

870.7485 [§85-1] Metabolism - excretion 

MRID: 00065593 

Classification: Acceptable/guidelineW

Rats excreted 6.3% and 89.3% of [14C] in the urine and feces, respectively, within 

4 days following oral exposure, with most being excreted within the first 48 hours 

In urine, most [5.3%] of the [

14C] was unchanged Diquat, whereas the remaining 

1% was associated with: diquat monopyridone [0.2%], diquat dipyridone [0.1%], 

and unidentified metabolites [0.3%]. In feces, 65.5% of excreted [14C] was 

detected in ulfuric acid-extractable fraction and 15.7% in the ammonium sulfateunextractable fraction. In the sulfuric acid fraction, [14C] was distributed as 

follows: unchanged diquat [57.1%], diquat monopyridone [4.3%], and 

unidentified material [4.1%]. 

870.7485 [§85-1] Metabolism 

MRID 00055107 

Classification: Acceptable/guidelineW

Following oral dosing, .90% of 14C] was eliminated in the feces, indicating that 

Diquat was poorly absorbed for the gastrointestinal tract. Following a 

subcutaneous injection of 14C]-Diquat to circumvent the intestine, nearly all 

[

14C] was recovered in the urine within 2 days. 

[1973] 

either oral [

[1972] 

s

[1966] 

[

[

Wwhen considered with the two other studies, the guideline [OPPTS 870.7485] for a metabolism study is satisfied 

34
8.2 Summary of Toxicological Dose and Endpoints for DIQUAT DIBROMIDE for Use in Human Risk Assessment 

EXPOSURE 

SCENARIO 

DOSE ENDPOINT STUDY 

Acute Dietary 

females 13-50 years of age 

none 

Acute RfD = none 

Acute Dietary 

general population including 

infants and children 

NOAEL= 75 mg/kg/day 

UF = 100 

NOAEL = 75 mg/kg, based on clinical signs and 

decreased body-weight gain at the LOAEL of 150 

mg/kg/day. 

Acute neurotoxicity 

rat 

Acute RfD = 0.75 mg/kg 

Chronic Dietary 

NOAEL = 0.5 mg/kg/day 

UF = 100 

NOAEL = 0.5 mg/kg/day, based on cataracts in 

females and decreased adrenal and epididymides 

weights in males at the LOAEL of 2.5 mg/kg/day. 

chronic toxicity dog 

Chronic RfD = 0.005 mg/kg/day 

Incidental Oral, Short- Term NOAEL = 1 mg/kg/day 

MOE = 100 

NOAEL = 1 mg/kg/day, based on decreased 

body-weight gain and food consumption at the 

LOAEL of 3 mg/kg/ day. 

Developmental 

toxicity 

rabbit 

Incidental Oral, IntermediateTerm 

NOAEL = 0.5 

mg/kg/day 

MOE = 100 

NOAEL = 0.5 mg/kg/day, based on cataracts in 

females and decreased adrenal and epididymis 

weights at the LOAEL of 2.5 mg/kg/ day. 

Chronic oral 

toxicity 

dog 

Short-Term a b 

(Dermal) 

NOAEL = 1 mg/kg/day 

MOE = 100 

NOAEL = 1 mg/kg/day, based on decreased bodyweight gain and food consumption at the LOAEL of 

3 mg/kg/ day. 

Developmental 

toxicity 

rabbit 

Intermediate-Term 

(Dermal) 

NOAEL = 0.5 mg/kg/day 

MOE = 100 

NOAEL = 0.5 mg/kg/day, based on cataracts in 

females and decreased adrenal and epididymis 

weights at the LOAEL of 2.5 mg/kg/ day. 

Chronic oral toxicity 

dog 

Long-Term (Dermal) NOAEL = 0.5 

mg/kg/day 

MOE = 100 

NOAEL = 0.5 mg/kg/day, based on cataracts in 

females and decreased adrenal and epididymis 

weights at the LOAEL of 2.5 mg/kg/ day. 

Chronic oral 

toxicity 

dog 

Short Term 

(Inhalation) 

NOAEL = 0.1 Fg/L 

MOE = 100 

NOAEL = 0.1 Fg/L [ 0.024 mg/kg/day], based on 

increased mean lung weight in males, mottling and 

reddening of lungs in females, and lung lesions 

[multifocal chronic interstitial pneumonia and 

alveolar macrophages] at the LOAEL of 0.49 Fg/L 

[0.117 mg/kg/day]. 

21-day inhalation 

toxicity 

rat 

Intermediate Term 

(Inhalation) 

NOAEL = 0.1 Fg/L 

MOE = 100 

NOAEL = 0.1 Fg/L [0.024 mg/kg/day], based on 

increased mean lung weight in males, mottling and 

reddening of lungs in females, and lung lesions 

[multifocal chronic interstitial pneumonia and 

alveolar macrophages] at the LOAEL of 0.49 Fg/L 

[0.117 mg/kg/day]. 

21-day inhalation 

toxicity 

rat 

Long Term 

(Inhalation) 

NOAEL = 0.1 Fg/L 

MOE = 100 

NOAEL = 0.1 Fg/L [0.024 mg/kg/day], based on 

increased mean lung weight in males, mottling and 

reddening of lungs in females, and lung lesions 

[multifocal chronic interstitial pneumonia and 

alveolar macrophages] at the LOAEL of 0.49 Fg/L 

[0.117 mg/kg/day]. 

21-day inhalation 

toxicity 

rat 

a A 4.1% dermal absorption factor should be used for this risk assessment. b Since an oral value was selected, route-to-route extrapolation should be followed. 

35