UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WAS H I N GTON, 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 Subm ission: S603025 FROM: L inda 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 dibrom ide. The toxicology chapter for Diquat dibrom ide is attached.

1

### DIQUAT DIBROMIDE PC Code: 032201 Toxicology Disciplinary Chapter for the Tolerance Reassessment Eligibility Decision (TRED) Document

Date comp leted:
Decem ber 14, 2001

Health Effects Division Office of Pesticide Program s U.S. Environm ental Protection Agency Arlington, VA 22202
Prepared by: Linda L. Taylor, Ph.D. Reregistration Branch I

2TABLE OF CONTENTS

1

. 0 H A Z A R D C H A R A C T E R I Z A T I O N

........................................... 3
2

. 0 R E Q U I R E M E N T S

......................................................... 6 3

. 0 D A T A G A P ( S )

............................................................ 7
4

. 0 H A Z A R D A S S E S S M E N T

.................................................. 7 4

. 1 A c u t e T o x i c i t y ...................................................... 7 4

. 2 S u b c h r o n i c T o x i c i t y .................................................. 7 4

. 3 C h r o n i c T o x i c i t y ................................................... 1 0 4.4 Carcinogenicity

.................................................... 1 2 4

. 5 D e v e l o p m e n t a l T o x i c i t y ............................................. 1 3 4.6 Reproductive Toxicity

............................................... 1 7 4

. 7 N e u r o t o x i c i t y ...................................................... 1 9 4

. 8 M u t a g e n i c i t y ...................................................... 2 1 4

. 9 M e t ab o l i s m ....................................................... 2 2 5.0 TOXICITY ENDPOINT SELECTION

........................................ 2 3 5.1 See Section 9.2 for Endpoint Selection Table

............................. 2 3 5

. 2 D e r m a l A b s o rp t i o n.................................................. 2 3 5.3 Classification of Carcinogenic Potential

................................. 2 4
6

. 0 F Q P A C O N S I D E R A T I O N S

................................................ 2 4 6.1 Special Sensitivity to Inf a nts and Children

............................... 2 4 6

. 2 R e c o mm e n d a t i o n f o r a D e v e l o p m e n t a l N e u r o t o x i c i t y S tu d y ................. 2 4

7

. 0 R E F E R E N C E S

.......................................................... 2 5 8

. 0 A P P E N D I C E S

........................................................... 2 8 8

. 1 T o x i c i t y P r o f i l e S u mm ar y T ab l e s ...................................... 2 9 9.1.1 Acute Toxicity Table 9.1.2 Subchronic Toxicity Table 9.1.3 Chronic Toxicity Table 9.1.4 Prenatal Developm ental Toxicity Tables 9.1.5 Reproductive Toxicity Table 9.1.6 Other Tables 8.2 Summ ary of Toxicological Dose and Endpoints

........................... 3 41.0 HAZ ARD CHARACTERIZ ATION The toxicity data base forDiquat dibromide is ade quate for the selection of endpoints for use in risk assessm ent. The Health Effects Division [HED] Hazard Identification Asse ssm ent Review Com mittee [HIARC] evaluated the acceptable st udi es 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 , interm ediate-t e r m, a nd long-term derm al and inhalation exposure scenarios. The HIARC also evaluated available studies to determ in e if there is a special sensitivity f o r inf a nts and children. Diquat dibrom ide is not acutely toxic via the oral [Toxicity Category III] and inhal a t i on [Toxicity Category III] routes of exposure. Diquat dibrom ide is m oderately to severely toxic via the derm al route of exposure, as evidenced by the acute derm al toxicity study [Toxicity Ca t e gor y I I ] , as well as by the 21-day repeated dose derm al toxicity study in rats . Deaths and clinical signs of toxicity [hypothermia, hypoactivity, dyspnea, cyanosis, pale extremities, general poor condition, and em a c i a t e d a ppearance] were observed at the lowest observed adverse effect leve l [LOAEL] of 20 m g /kg/day fol l o wing repeatderm al exposure. However, Diquat dibromide was not found to be a de rm al irritant [Toxicity Category IV] or a derm al sensitizer. Diquat dibromide is toxic to the eye, as evidencedby the eye irritation study, which showed slight to severe eye irritation f o llowing acute exposure [Toxicity Category II]. Additionally, cataracts were observed in rats and dogs following repeat e d oral exposure [ f o r 12 week and longer] to Diquat dibromide.
In ar e peat-dose [subchronic] inhalation study, Diquat dibrom ide was shown to be toxic via the inhalation route of exposure, as evidenced by increased lung weight, m o ttling and r e ddeni ng of the lungs, and lung lesions [multifocal chronic inters titial pneum onia and alveolar m acrophages] following a 3-week exposure period. Following repeat derm al exposure [6 hours/day, 7 days/week for 3 consecutive weeks] to rats, severe systemic toxicity was observed, as evidenced by high m o rtality and clinical si gns [hypothermia, hypoactivity, dyspnea, cyanosis, pale extremities, general poor condition, and em aciated appearance]. These effects were attributed to the fact that the derm al barrier had been comp r o mi sed. Derm al irritation [erythem a, edem a, and desquam a tion] and tissue destruction [necrosis an deschar form ation] were observed at the application site a tall dose levels. Sores, severe erythem a , fissures, acute necrotizing purulent derm atitis, and degeneration of the hair f o llicles and sebaceous glands were observed at the application site in both sexes, a nd congestion of the lungs, li ve r , a nd ki dneys were observed in both sexes. In a non-guideline repeat de rm al toxicity study in rabbits [24-hour exposures for 20 consecutive days], m oderate systemic toxicity was observed, as evidenc e d by loss of weight, unsteadiness, mu scular weakness and inability to st and, and mi croscopic lesions i n t h e kidneys [cell necrosis in the distal convoluted renal tubules]. Derm al irritation was observed at the site of application [ e rythem a and scabbing] .The data indicate that the rat is m o re sensitive f o llowing repeat derm al exposure than the rabbit. The chronic data provide evidence that the eyes [cat aracts, extralenticular lesions (vitreous adhesions,
4retinal detachm e nt and synechia)] are a target organ in both the rat and dog, the adrenal and epididymides are also target organs in m a le dogs, and the kidney is a target organ in mi ce, dogs, and rabbits. Developm ental toxicity was observed in both the rat and rabbit, as evidenced by delayed skeletal ossif i cation in the rat and an incr eased incidence of f

e tuses with f r iable and/or m o ttled livers and a higher incidence of skeletal alterations in the rabb it. Maternal toxicity was observed as decreased bodyweight gain and food consumption in both the rat a nd rabbit. At the highest dose tested, clinical signs [m ortality (both species), piloerection (rat), subdued acti v i t y (both species), diarrhea (rabbit)] were observed. In the m ouse, m a ternal toxicity was observe d as increased incidence of deaths, clinical signs [piloerection, dyspnea, respiratory noi s e , abnorm a l posture (hunched or raised tail)], and decreased body-weight gain. The ma t e rnal effects in the m ouse were attributed to poor dosing technique. Developm ental toxicity was observed in the m ouse, 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 num bers of live F1 pups/litter and decreased pup body-weight gain[F1 and F2]. Parental toxicity was observed as increased incidences of clinical signs [piloer ection, opaque eyes, and ulcers on the palate and tongue (F1)], ophthalm oscopic signs [eye opacity, partial or total lenticular cataracts, and iritis], and decreased body-weight gains and food consumption during the prem ating period. Al t hough increased incidences of diarrhea, staining of the nose, piloerection, urinary incontinence, m outh st a i ning, upward curvature of the spine, tip-toe gait, hunched posture, subdued behavior, and sides pinched in wer e observed in fem a les followi ng acute oral exposure in the acute neurotoxicity study, the Agency has concluded that these symp tom s m a y not be due to direct neurotoxicity. Several of these [piloerection, hunched posture, and hypoac tivity] and other clinical s i gns indicative of neurotoxicity [unsteadiness, m u s c u l ar w e akness, and inability to stand, hypothermia, dyspnea, cyanosis, pale extrem ities] were observed in pregnant rats a nd mi ce af ter oral adm i nistration during gestation and i n rats following subchronic derm al exposure. However, no evidence of neurotoxicity was obs e r ve d in the functional observational battery, mot o r activity m easurem ent, or neurohistopathology examination in the subchronic neurotoxicity study in rats. Neuropathology was notobs erved in any study. The data provided no indication of increased sens itivity of rats, mi ce, or rabbits to in utero and/or early postnatal exposure to Diquat dibromide. The HED HIARC determined that a developm ental ne ur ot oxicity study was not required for Diquat dibrom ide based on the fact that (1) the r e i s no indication of abnorm a lities in the developm ent of the fetal nervous system in prenatal developm ental toxicity studies in rats, m i ce, and rabbits at oral dos e levels that were m a ternally 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 subchr onic neurotoxicity study, and (4) no effects were observed i n t h e brai n weights or histopathology of the nervous system in the chronic toxicity studies with Diquat dibrom ide 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 tum o r incidence inthe carcinogenicity studies in rats and mi ce. The
5carcinogenic potential of Diquat dibromide was classified as Ca t e gor y E [evidence of nonca r c inogenicity to hum ans] by the Health Eff ects Division Reference Dose (RfD)/Peer Review Committee. The mu tagenic data indicated that there was no concern for mu tagenicity. Diquat dibromide was poorly absorbed from the gastrointestinal tract following oral exposure [single and repeat], and it was elim inated m a inly in the feces. Approxim a tely 6% of the admi nistered dose was found in the urine within 4 days after dosing. Only a sm all portion of the absorbed Diquat dibromide, which was rapidly eliminated in the urine, was m e tabolized to m onopyridone and dipyridone analogs. Diquat dibromide did not accumu late in any tissue m onitored. There are no data gaps at the present tim e.

62.0 REQUIREMENTS (updated Decem b er 14, 2001) The requirem e nts (CFR 158.135) for Food/Feed Use for Diquat dibromide are in Table 1. Use of the new guideline num bers does not imply that the new (1998) guideline protocols were used. Table 1. Test Technical Required Satisfied 870.1100 Acut e Oral Toxi ci ty 870.1200 Acut e Derm al Toxi ci ty 870.1300 Acut e Inhal a t i on Toxi ci ty

870.2400 Pri m ary Ey e Irri t a t i o n 870.2500 Pri m ary Derm al Irri t a t i o n

870.2600 Derm al Sensitization yes yes yes yes yes yes yes yes yes yes yes yes 870.3100 Oral Subchroni c (rodent ) 870.3150 Oral Subchroni c (nonrodent ) 870.3200 21-Day Derm al 870.3250 90-Day Derm al 870.3465 90-Day Inhal a t i o n yes yes yes no no yes * yes * yes no yes / 870.3700a Devel opm ent a l Toxi ci ty (rodent ) 870.3700b Devel opm ent a l Toxi ci ty (nonrodent ) 870.3800 R e product i o n yes yes yes yes yes yes 870.4100a C h roni c Toxi ci ty (rodent ) 870.4100b C h roni c Toxi ci ty (nonrodent ) 870.4200a C arci nogeni ci ty (rat ) 870.4200b C arci nogeni ci ty (m ouse) 870.4300 C h roni cToxi ci ty / C arci nogeni ci ty (rodent ) yes yes yes yes yes yes yes yes yes yes 870.5100 M u t a geni ci ty —Gene M u t a t i on - bact eri a l 870.5300 M u t a geni ci ty —Gene M u t a t i on - m a mm a l i a n 870.5xxx M u t a geni ci ty —Structu ral C h rom o som a l Aberrat i ons 870.5xxx M u t a geni ci ty —Oth er Genot oxi c Effect s yes yes yes yes yes yes yes yes 870.6100a Acut e Del a y e d Neurot ox. (hen)

870.6100b 90-Day Neurot oxi ci ty (hen) 870.6200a Acut e Neurot ox. Screeni ng B a tt e ry (rat ) 870.6200b 90 Day Neuro. Screeni ng B a tt e ry (rat ) 870.6300 Devel op. Neuro no no yes yes no -

- yes yes no 870.7485 General Metabolism 870.7600 Dermal Penetration ye s ye s ye s ye s S p ecial S tudies for Ocular Effects Acute Oral (rat) Subchronic Oral (rat) Six-month Oral (dog) no

* chronic toxicity study is availa ble and satisfies this requirem e nt; / 2 studies of 21 -day s duration available; although these studies do not satisfy the guideline requirement [OPPTS 870.3465; §82-4] for a subchronic [90-day ] inhalation toxicity s tudy , they provide useful informa tion regarding repeated [21 day s ] inhalation expos ure. At the present tim e, long-term inhalation exposure is not anticipated. However, if long-term inhala tion exposure scenarios are identified in the future, this issue will n eed to be revisited.

73.0 DATA GAP(S) There are no data gaps at this tim e. A developm ental neurotoxicity study in rats [OPPTS 870.6300] m a y be required in the future. 4.0 HAZ ARD ASSESSMENT (updated AUGUST, 2001) 4.1 

### Acute Toxicity Adequacy of data base for acute toxicity : The database for acute toxic ity is considered com p lete. No additional studies are required at this tim e. The acute toxicity data indicate that Diquat dibrom ide is not acutely toxic via the oral [Toxicity Category III] and inhalat i on [Toxicity Category III] routes of exposure, but it is m oderately-to-severely toxic via the derm al [Toxicity Category II] route of exposure. Additionally, Diquat dibromide is not a skin irritant [Toxicity Category IV], bu t it is co ns id e r e d a m oderate-to-severe eye irritant [Toxicity Category II]. Diquat dibromide is not a skin sensitizer. The acute toxicity data on Diquat dibromide are summ arized below in Table 2.

Tab l e 2. Acu t e Toxicity Data on DIQUAT DIBROMIDE Guideline No. S tudy Type MRID #(S) Results T oxicity Category
870.1100 acute oral - rat Diquat W a ter W eed Killer 00081506 rat LD 50 = 810 mg/kg % rat LD 50 = 600 mg/kg & III

870.1200 acute dermal - rat Diquat W a ter W eed Killer 00100614 rabbits LD 50 = 262 mg/kg % rabbits LD 50 = 315 mg/kg & rabbits LD 50 = 288.5 mg/kg % + & II

870.1300 acute inhalation - rat Diquat W a ter W eed Killer 26385 * rat LC 50 = 0.80 mg/L % rat LC 50 = 1.09 mg/L & rat LC 50 = 0.97 mg/L % + & III

870.2400 primary ey e irritation - Diquat W a ter W eed Killer 00081507 rabbit slight to severe ey e irritant II

870.2500 primary skin irritation - Diquat W a ter W eed Killer 00107903 slight irritation IV

870.2600 Derm al Sensitization 00107903 not a derm al sensitizer N/A * Accession No.; With the exception of the dermal sensitization study , wh ich was conducted with the t echnical diquat [ D iquat Her bicide Concentrate] , the above studies were conduc ted with the end-use products [Diquat Wate r Weed Killer and Diquat 2 Spray (ey e irri tation study only )] and not in term s 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 sa tisfy the generic data requirem e nts for acu te studies. The above LD and LC values are expres s e d in terms of the test material and not, as is commonl y done with diquat, in terms of the diquat cation. 4.2 

### Subchronic Toxicity Adequacy of data base for subchronic toxicity : The database for subchroni c t oxi c ity is considered comp lete. No additional studies are required at this tim e. The subchronic database provides evidenc e t h at Diquat dibromide is toxic mainly to the port of entry. Exposure via the dermal route resulted in mortality, clinical signs [loss of w e ight, unsteadiness, mu scular w e akness, 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]
8and tissue destruction [necrosis and eschar formation at all dose levels] at the application site, and sores, severe erythema, fissures, acute necrotiz i ng purulent derm atitis and degeneration of the hair follicles and sebaceous glands at the site of application. Exposure via the inhalation route re sulted in increased lung w e ights, mottling and reddening of th e lungs, and lung lesions [multifoc al 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 dibr omi d e ; however, the chronic oral toxicity study in rats satisfies this data requirem e nt [see be low under Chronic Toxicity]. The guideline subchronic oral toxicity study requirem e nt is satisfied by the chr onic toxicity guideline requirem e nt [OPPTS 870. 4100]. 870.3200 Repeated Dose Dermal – Rat In a repeated [21-day] derm al exposure study [MRI D 40308101], 9-week old m a le and fem a le Sprague-Dawley rats [6/sex/dose] were e xposed derm ally [intact skin; exposure site 2.5 cm x 1.5 cm , m i d-dorsal surface] to Di qua t dibrom ide [20.64% w/w cation] at dose levels of 0 [deionized, distilled water], 5, 20, 40, and 80 m g /kg/day for 3 weeks [6 hours/day, 7 days/week]. Collars were worn throughout the treatm e nt period to prevent ingestion of the test m a terial. Additionally, following the daily [6-hour] exposure, the residual test m a terial was rinsed from the skin with water, and the skin was wiped dry. Mortality occurred at the thr e e hi ghe st dose levels. At 20 m g /kg/day, one fem a le was sacrificed m o ribund on day 19. At 40 m g /kg/day, one m a le [day 19] and four fe m a les [days 9, 14, 18, and 22] died or were sacrificed m o ribund. At 80 m g /kg/day, five of th e six m a les [days 7, 8, 10, 11, and 13] and all of the fem a les [days 7, 7, 8, 8, 12, 20] died or were sacrificed m o ribund. Clinical signs of toxicity [hypotherm ia, hypoactivity, dyspnea, cyanosis, pale extremities, anogenital staining, little or no stool, general poor condition, em aciated appearance] were observed in the rats that died. At the high-dose level, decreased body weights [by day 7, m a les 87%/fem ale data not m eani ngful] and body-weight gains throughoutstudy [negative gain by day 3 (both sexes)] were observed in both sexes, and these findi ngs were consistent with the general poor condition of the rats in this group. Males at the other dose levels displayed sligh tly lower body weights than the control m a les throughout the study [91%

- 98% of control], and body-weight gains al so were decreased in all groups comp ared to the control, but there was no dose response. Fem a les 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 m g /kg/day [63% of

control] and 40 m g /kg/day [ 51% of control] . T h er e also w a s a decrease in f ood consumption that w a s associated with the decreased body-weight gains.
Derm al irritation [erythem a, edem a, and desquam a tion] and tissue destruction [necrosis and eschar form ation] were observed at all dose levels at the site of application. Additionally, sores, severe erythem a , fissures, acute necrotizing purulent derm atitis, and degeneration of the ha ir follicles and sebaceous glands were observed at the site of application in one or both sexes at $ 20 m g /kg/day. The incidence and severity of the derm al effects were generally dose-related, but considerable anim al-to-anim al variability was noted. Most of the derm al ef f

e cts were first observed on day 8 or 11 and were still evident at study termination. An acute necrotizing purulent derm atitis was the m o st prominent tissue alteration in the treated skin in the three highest dose groups [m ales 2/6, fem a les 4/5; m a les 5/6, fem a les 6/6; and m a les 6/6, fem a les 6/ 6 with increasing dose. The lesion was characterized by necrosis of the epidermi s a nd pa pi llary layer of the dermis with m a ssive infiltrates of neutrophils. The viable epidermi s was described as thick and hyperkeratotic.

9Alterations in clinical chemistry and organ we ights c a n be attributed to the poor condition [m alnutrition/starvation] of the highe st 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 fem a les. The systemic toxicity NOAEL w a s 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]. Derm al irritation [characteriz e d by erythema, edema, and desquamation] and tissue destruction [characteriz e d by necrosi s and eschar f o rm ation] w ere observed at all dose levels in both sexes at the site of application. How e ver, by day 21, necrosis and eschar formation w ere no l o nger observed att h e l o w- dose l e vel [ 5 m g /k g/ day] . Addi t i onally, sores, severe erythema, fissures, acute necrotiz i ng purulent dermatitis, and degeneration of the hai r f o l l i cles and sebaceous glands w ere 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 requirem e nt [OPPTS 870. 3200; §82-2] for a subchronic derm al toxicity study in rats. 870.3265 Subchronic Inhalation Toxicity – Rat In a repeated [21-day] inhalation exposure study [MRID 40301701], m a le and fem a le Fischer 344 rats [10/ s e x/ dos e ] we r e exposed via inhalation [ w hole body] to respirable aer osols of Diquat Concentrate [23.5% w/w cation] at dose levels of 0 [distilled water], 0.49, 1.1, and 3.8 F g/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 assessm ent of reversibility of toxic e ffects. A subsequent study [MRID 40640801] in which m a le and fem a le Fischer 344 rats [10/sex/dose] were exposed via inhalation [whole body] to respir ab l e a e rosols of Diquat Concentrate [23.5% w/w ca t i on] a tdose levels of 0 [distilled water] and 0.1 F g/L for 3 weeks [6 hours/day, 5 days/week] was perform e d to determine a NOAEL. There were no deaths. Clinical signs of toxicity [abnorm a l respiratory sounds (both sexes) and anogenital discharge (fem ales)] were observed at the high-dose leve l, and the incidence increas ed over tim e. Only a few rats had abnorm a l respiratory sounds during the first w eek of exposure, but over th e dosing period, 80% of the high-dose m a les and 65% of the high-dose fem a les displayed this condition. The m e an onset of a nogenital discharge was 4 days and 80% of the high-dose fem a les had this condition. At the high-dose level, a slight, but statistically-significant, decrease in body weight was observed in both sexes thr oughout the study [m ales 94%- 95%/fem ales 94%-97%], and body-weight gains were decr eased during the first week [m ales 41%/fem ales 38% of control] and overall [m ales 79%/fem ales 86% of control]. Decreased food c o nsumption was observed throughout the study at the high-dose level [both sexes] a nd at the mi d-dose level [m ales] during the first week of exposure. No adverse effects were observed on any of the hem a to logy, clinical chemistry, or ophthalm ological param e ters m onitored at termination only. There was a dose-related incr ease in lung weight in both sexes, with statisticallysignificant increases at all dose levels in m a les and at the mi d- and high-dose leve ls in fem a les. At necropsy, m o ttling and/or reddening of the lungs was observed at all dose levels in fem a les and in the mi d- and high-dose m a les. Microscopic lesion s w e re o b s erv e dinth e anteriornasal tissues [epithelial dysplasia (mid- and high-dose), er osi on (high dose), and rhinitis (high dose)] in both sexes and in the lungs [multifocal chronic interstitial pneum onia (all dose levels), alveolar edem a (mid-dose f e m a les, high-dose both sexes), and alveolar m acrophages (all dose levels)] of both sexes. No effects were observed in the single-dose [0.1 F g/L] study. Following the 3-week recovery period, the clinical signs of toxicity [abnorm a l respiratory sounds and anogenital 10discharge] and mi croscopic lung and nasal lesions were no longer evident, and lung weights were comp arable to the controls. The high-dose fem a le body weight was co mp arable to the control fem a le body weight following the recovery period, but the high-dose m a les continued to display a slight decrease in body weight [statistically significant] comp ared to the control. However, body-we ight gains during the recovery period were com p arable between the groups for both sexes. One rat/sex at the high-dose level displayed m o ttled lung and one m a le and two fem a le high-dose rats displayed red lung foll owi ng t h e r e c o very phase comp ared to none in the control groups. The NOAEL is 0.1 F g/L [males 0.024 mg/kg/day; femal e s 0.026 mg/kg/day], based on increased lung w e ights and microscopic lesions in the lungs at the LOAEL of 0.49 F g/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 requirem e nt [OPPTS 870.3465; §82-4] for a subchronic [ 90-day] inhalation toxicity study, th ey provide useful inform ation regarding repeated [ 21 days] inhalation exposure. At the present tim e, long-term inhalation exposure is not anticipated. However, if long-term inhalation exposure scen arios 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 f o r chronic toxicity is considered comp lete. No additional studies are required at this tim e. The chronic data provide evidence that the eyes [cat aracts, extralenticular lesions (vitreous adhesions, retinal detachm e nt and synechia)] are a target organ in rats and dogs, the adrenal and epididymides are also target organs in m a le dogs, and the kidney is a target organ in mi ce and rats. There w a s no treatment-related increase in the inciden ce of any tumor type in either the rat or mouse carcinogenicity study . The dose levels were considered adequate in the rat and m ouse studies, based on m oderate reductions in body-weight gain in both species and on histopathological ch anges [lens opacity, severe cataracts, and extralenticular lesions] in the eyes of the rats. 870.4100 Chronic Feeding – Rat
In a com b ined chronic toxicity/carcinogenicity study [MRID 00145855], m a le and fem a le Sprague-Dawley rats [50/sex/dos e ] we r e fed diets c ontaining 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 m g /kg/day (m ales)/0, 0.24, 0.72, 3.64, and 19.44 m g /kg/day (f em ales) of diquat cation; 26.5%] for 104 weeks. In addition, 10 rats/s ex/dose were treated sim ilarly and sacrificed at 12 m onths.
Treatm e nt had no adverse effect on survival. W ith the ex ception of effects on the eye, there were no treatm e ntrelated 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 m o re transparent than usual. This was f o llowed temporally by opacity, which first occurred in week 10 at 75 ppm [ one m a le] and in week 11 at 375 ppm [t wo fe ma l e s ]

. Body-weight gains were decreased at the high-dose le vel in both sexes throughout the study [weeks 0-13: m a les 84%/fem ales 80% of control; overall: m a les 86%/fem ales 75% of control], and a corresponding depression in average food consumption was observed at the hi gh- dos e level for both sexes for the first 26 weeks and for fem a les throughout week 78 of the study. Based on ophthalm ologic examination, the incidence of to tal cataract increased with increasing dose and tim e

11on study. At 13 weeks, 1 m a le at 75 ppm [2%], 11 m a les at 375 ppm [22%] and 2 fem a les at 375 ppm [4% ] displayed total cataracts. At 26 weeks, the incidence of total cataracts was 4% [75 ppm m a les], 78% [375 ppm m a les], and 76% [375 ppm fem a les] and at 52 weeks, the incidence was 4% [7 5 ppm m a les], 94% [375 ppm m a les], and 90% [375 ppm fem a les]. At 78 weeks, the incidence of total cataracts reached 100% in m a les at the high-dose level and 98% in fem a les at the high-dose leve l. At study termination, one rat/sex at 15 ppm [m ales 4.5%/fem ales 5.0%], 3 rats/sex at 75 ppm [m ales 14.3%/fem ales 15.0%], a nd all [100%] of the high-dose rats [both sexes] displayed total cataracts. No evidence of to tal cataract was observed in either sex at 5 ppm [lowest dose] or in control fem a les at any tim e point, but one control m a le displayed total cataract at week 78 only [none were observed at study term ination in this group] . Add itionally, rats with severe cataracts showed secondary, extralenticular, eye lesions, which included vitreous adhesions, retinal detachm e nt, iritis, and intraocular hem o rrhage and were considered secondary to the extrus ion of degenerate lens m a terial. Microscopic findings showed a greater severity in the 15 ppm groups t h a n i n t h e controls and 5 ppm dose groups. Severity grades [cataractous change] of m arked and se vere 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 di s p l a yed an increased incidence of nephropathy in the kidneys, and the high-dose m a les displayed increased inc i dences of arteritis/periarteritis in blood vessels and paracortical cell hyperplasia in the lymph nodes. There was no treatm e nt-related increase in any tum o r type in either sex. There w a s no treatment-related increa se in tumor incidence in eith er sex. The NOAEL w a s 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 classifi ed ACCEPTABLE/Guideline, and it satisfies the guideline requirem e nt [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 di e t s c ont aining Diquat dibromide [26.7% cation] at target concentrations of 0, 0.5, 2.5, and 12.5 m g /kg/day, expressed as the diquat i on [c a tion], for 52 weeks [achieved intakes: m a les 0, 0.46, 2.42, and 11.48/fem a les 0, 0.53, 2.53, and 13.21 m g /kg/day].
No treatm e nt-related ef f ects w e re observed on survival, c linical signs, hem a tology, clinical chemistry, urinalysis, and gross pathology [except eye] at any dose level. D ecreased body-weight gains were observed only during the first two weeks of dosing in both sexe s a tt h e high-dos e level [m ales 46%/fem ales 32% of control], although there was no decrease in food consum ption at any tim e point. At necropsy, bilateral lens opacity was observed in all high-dose m a les and 3/4 high-dose fem a les. Unilateral lens opacity was observed in 2 m i d-dose fem a les at necr opsy. The first occurrence of lens opacity was at week 8 in one mi d-dose fem a le [one other mi d-dose fem a le di splayed lens opacity at week 40]. The first occurrence of lens opacity at the high-dose leve l was at week 16 in m a les and week 24 in fem a les. Decreased epididym al weights were observed in m a les at the two highest dos e levels, and increased kidney weights were observed in both sexes at the highest dose level. These alterations were not corroborated with histopathological changes in th e adrenal, epididymis, or kidneys. Treatm e nt-related, histopathological change s we r e obs e r ve d a t th e hi gh- dos e level [bot h sexes] and included cataracts and chronic infl amm a tory changes in the large intestine. Slight-tom arked bilateral cataractous change [cata r a c t ] wa s ob served in 3 high-dose dogs/sex, and mi nim a l or slight unilateral cataractous change was observed in 1 high-dos e dog/sex. One fem a le at the mi d dose also displayed histopathological changes in the eye [unilateral lens op acity]. Chronic inflamm a tory changes were detected in
12the colon and rectum of all high-dose dogs [4/sex] and in the cecum of all high-dose m a les and 2 of the 4 highdose fem a les. Treatm e nt-related effects were not found in the 0.5 m g /kg/day dogs. The NOAEL is 0.5 mg/kg/day, based on unilateral cataracts in females and decreased epididymides we i g ht s in males at the LOAEL of 2.5 mg/kg/day. Atthe high-dose level [12.5 mg/kg/day], bilat e r a l cataracts, inflammatory lesion s in the large intestine, and increased absolute and relative kidney w e ights w ere observed in all dogs, and d ecreased rel at i v e adrenal and epidid ymides w e ights w ere observed in males

. This chronic oral toxicity study is classified ACCEPT ABLE/Guideline, and it satisf i es the guideline requirem e nt [OPPTS 870.4100; §83-1(b)] for a chronic or al toxicity study in non-rodents.
4.4 

### Carcinogenicity Adequacy of Database for Carcinogenicity : The data base for carcinogenicity is considered comp lete. No additional studies are required at this tim e. The carcinogenic potential of Diquat dibrom ide was cla ssified as Category E [evidence of non-carcinogenicity to hum an]. 870.4200a Carcinogenicity Study - rat
In a com b ined chronic toxicity/carcinogeni city study [MRID 00145855, 00155474, 41085601], m a le and fem a le Sprague-Dawley rats [50/sex/dose] were fed diet s c ontaining 0, 5, 15, 75, and 375 ppm of Diquat dibrom ide [equivalent to 0, 0.19, 0.58, 2.91, and 14.88 m g /kg/day (m ales)/0, 0.24, 0.72, 3.64, and 19.44 m g /kg/day (fem ales) of diquat cation] for 104 week s. In addition, 10 rats/sex/dose were treated similarly and sacrificed at 12 m onths. See EXECUTIVE SUMMARY under Chronic Toxicity [OPPTS 870.4100], above. There w a s no treatment-related increa se in tumor incidence in eith er sex. The NOAEL w a s 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 com b ined chronic toxicity/carci nogenicity study is classif i ed ACCEPT ABLE/Guideline, and it satisfies the guideline requirem e nts [OPPTS 870.4200 and 870.4300] for a ch ronic toxicity/carcinogenicity study in rats.

13870.4200b Carcinogenicity (feeding) - Mouse
In a carcinogenicity study [ M RID 42219801, 42880701, 42905901, 42919501] , Diquat dibromide [ 2 1.09% cation concentration] was adm i nistered in the diet fo r 104 weeks to m a le CD-1 mi ce [60/sex/dose] at 0, 30, 100, and 300 ppm [expressed as 0, 3.56, 11.96, and 37.83 m g / kg/day (m ales) and 0, 4.78, 16.03, and 48.27 m g /kg/day (fem ales). At 12 m onths, 10 mi ce/sex/dose were sacrificed [interim ]. There was no treatm e nt-related adverse effect on survival of either sex, although a great e rnumbe rof treated f

e m a les [ 37%, 47%, 40% with increasing dose] were killed in extremis comp ared to the control fem a les [25%]. Tr e a t me nt-related clinical signs were observed in both sexes and included an increased incidence of eye discharge [mid-dose m a les and the high-dose mi ce of both se xes] and an increased incidence of thin appearance [m ales] and subdued behavior [m id- dos e fem a les and high-dose (both sexes)]. Decreased body weight was observed throughout the study in both sexes [m ales 3.5%- 8.7%/fem ales 2.9%-9.4% below control] at the highdose level and in m a les at the mi d-dose level [ 3.8%- 4.7% below control] f r om w e ek 95 until term ination comp ared to the control. Body-weight gains were decreas ed in these sam e groups during the sam e tim e intervals [mi d

- dos e m a les 11%; high-dose m a les 4%-12%; high-dose fem a les 10%-28% below control]. Food consumption was decreased for both sexes at the high-dose level.
No treatm e nt-related effects were obs e r ve d on hem a tology param e ters or gross pathology at any dose level. I n c r e a s e d ki dney weight was observed at the m i d- and high-dose levels in m a les, and decreased brain weight was observed in the high-dose fem a les. There was a treat m e nt-related, slight increase in m i croscopic lesions in the kidney [ tubular dilatation (both sexe s) and tubular hyaline droplet form a tion (f em ales)] , liver [ e xtram e dullary hem opoiesis (both sexes)], and lym ph node, m e senteric [ l ym phoid prolif er ation (f em ales)] at the high-dose level, m a inly at the terminal sacrif ice. 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/ k g/day/females 16.03 mg/kg/d ay], based on clinical signs [eye discharge (males), subdued behavior (fem a l e s )], and decreased body w e ight/body-w e ight gain [males]. Diquat dibromide w a s not carcinogenic in male or female CD-1 mice. This carcinogenicity study is classified ACCEPTABLE/Guideline , and it satisfies the guideline requirem e nt [OPPTS 870.4200; §83-2] for a carcinogenicity study in m i ce. 4.5 

### Developmental Toxicity Adequacy of data base for Developm ental Toxicity : The data base f o r developm ental toxicity is considered comp lete. In the rat, developmental t oxi ci t y was observed at the highest dose tested, 40 mg/kg/day, based on delayed skeletal ossification. Ma ternal toxicity w a s observed as de c reased bodyw e ight gain and food consumpti o n. In t h e rabbit, maternal toxicity w a s observed as decreased bodyw e ight gain and food consumption. Developmen ta l to x i city w a s indicated by increased incidence of fetuses w i th friable and/or mottled livers and a higher inciden ce of skeletal alterations. Clinical signs [mortality (both species), piloerection (rat), subdued activity (b oth species), diarrhea (rabbit)] w ere observed only at the highest dose in both species. In the mous e, maternal toxicity w a s ob served as increased incidence of deaths, clinical signs [piloerection, dyspnea, respira tory noise, abnormal posture (hunched or raised tail)], and decreased body-w eight gain. Developmental toxicity w a s observed as decreased fetal body w e ight and increased incidence of overall fetal skeletal alterations.

14870.3700a Prenatal Developmental Toxicity Study - Rat In a developm ental toxicity study [MRID 41198902], pregnant Wistar-derived Alderley Park strain SPF rats [23- 24 r a t s / g r oup] were admi nistered technical grad e Diquat [water-soluble concentrate; 26.2 g diquat ion/L] via gavage at dose levels of 0 [dei onized water], 4, 12, and 40 m g /kg/day [expressed as the diquat cation] from gestation days 7 through 16. The rats were sacrif iced on gestation day 22, and uteri were exam ined f o r 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 appearedhunched with piloerection and urinary incontinence one day before being found dead. There was an increased incidence of pilo erection at the high-dose level, and several of the high-dose dam s appeared subdued during the last half of the study. During the first four days of dosing, decreased body-weight gains were observed at a ll dose levels [78% (low)/61% (mid) of control], with the high-dose group displaying a negative gain [-5.4 gram s]. Decreased body-weight gains persisted during the rem a inder of the dosing pe r i od a tthe mi d- [89% of cont rol] and high-dose [16% of control] levels. Only the high-dose dam s displayed an overall decrease on body-we ight gain [ 78% of control] . The decrease in bodyweight gain at the lowest dose appeared t o be tr ansient, slight, and equivocal. Food consumption was significantly decreased at all dose levels during the firs t 4 days of dosing and in the mi d- and high-dose groups throughout the dosing period. Three of the high-dose dam s were not pregnant. All othe r rats in all dose groups were pregnant. There were no treatm e nt-related ef f

ects on the num bers of corpora lut ea/dam or implantations/dam , and the m ean litter size and the % m a les were comp arable am ong the groups. Gravid uter ine weight was slightly lower at the high-dose level [91% of control], but statistical significance was not a ttained. There was a statistically-significant decrease in both m ean litter weight [88% of control] and m ean feta l body weight [91% of control] at the high-dose level. At the high-dose level, there was an increased incidence of hem o rrhagic kidney [none in the control (297 fetuses in 24 litters) vs 5/239 fetuses in 4/20 litters] and poorer ossifica tion, as evidenced by higher incidences of mi nor skeletal alterations [unossified ventral tubercle, centra of the cervical vertebrae, 4 thcervical vertebra, and partially ossif i ed 2 ndand 5 thsternebrae]. The maternal toxicity NOAEL w a s 4 mg/kg/day, base d on decreased maternal body-w eight gain and food consumption during dosing at the LO AEL of 12 mg/kg/day. At the highest dose tested [40 mg/kg/day], one dam died, the dams lost w e ight during the first th ree days of dosing, there w a s an increased incidence of subdued appearance and piloerection, and a slightly low er gravid uterine w e ight. The developmental toxicity NOAEL w a s 12 mg/kg/day, based on de c r e a sed fetal body w e ight [91% of control], decreased litter w e ight, an increased inci dence of hemorrhagic kidney, and poorer ossification compared to the control at the developmental toxicity LOAEL of 40 mg/kg/day. This developm ental toxicity study is clas sified ACCEPTABLE/Guideline, and it satisfies the guideline requirem e nt [OPPTS 870.3700; §83-3] for a deve lopm ental toxicity study in rodents. 870.3700b Prenatal Developmental Toxicity Study - Rabbit
15In a developm ental toxicity study [MRID 41198901], pre gnant New Zealand W h ite rabbits [20 rabbits/group] were admi nistered technical grade Diquat [w ater-soluble concentrate; 26.2 g diquat ion/L] via gavage at dose levels of 0 [deionized water], 1, 3, and 10 m g /kg/day [e xpressed as the diquat cation] from ge s t a t i on 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 exam in ed for external, visceral, and skeletal alterations. There were three abortions [one low dose (day 27); tw o high dose (days 20, 29)] and three deaths [high dose on days 17, 21, 22]. At the high-dose level, there was an in creased incidence of diarrhea, subdued appearance, and thin appearance. During the dosing period, two high-dose does lost weight but rapidly ga i n e d weight after dosing. At the mi d-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 cons umption was significantly decreased at the mi d- and high-dose levels during the first 4 da ys of dosing and in the high-dose gr oup during the rem a inder of the dosing period. Both the m i d- and high-dose does showed a significant increase in food consumption after day 19. There was no adverse e ffe c ton the num ber of pregnant rabbits in each group, although due to the deaths and abortions at the high-dose level, there were f e wer litters at the high-dose level [ 13] comp ared to the control [ 18] and lower dose groups [15 and 20]. There were no treatm e nt -related effects on the num bers of corpora lutea/doe, implantations/doe, % pre- and post-implantation losses, gravid uterine weight, m ean litter size, m e an litter weight, m ean fetal body weight, or the % m a les. At the high-dose level, there was an increased inciden ce of f r iable and m o ttled livers [ on a f e tal basis] . There was an increase in the percent of fetuses with extra 13 thribs [ norm a l length] , with the incidence being statistically significant at the mi d- [69%] and hi gh-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-, mi d-, and high-dose groups, respectively] with f e tuses with an extra 13 th r i b, but statistical significance was not attained. The incidence [ p ercent] of partially ossif i ed ventral tubercle of th e cervical ver t ebr ae was significantly increased at all dose levels [fetal basis: 0.6%, 4%, 5%, a nd 10% for the control, low-, mi d-, and high-dose groups, respectively], and the incidence of partially-ossif i ed 6 thsternebrae [on a fetal basis] was signi ficantly increased at the mi d- [15%] and high-dose [17%] le vels. Also on a fetal basis, the incidence of 27 pre-sacral vertebrae was significantly increased at the high-dose level [51%] com p ared to the control [31%]. The incidence of sternebrae [6 th ] not ossified was increased significantly at the high-dose le vel on both a fetal [6%] and litter [38%] basis [none in the control]. The maternal toxicity NOAEL w a s 1 mg/kg/day, based on maternal bo dy-w eight 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 m g /kg/day], three does di e d, t h e r e was an increase in clinical signs [diarrhea, subdued and thin appearance], body-weight loss during the first thr ee days of dosing and lower body-wei ght gain throughout the dosing period [20% of control], and decreased food consumption.

The developmental toxicity NOAEL w a s 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 t h e LO AEL of 10 mg/kg/day.
16This developm ental toxicity study is class i fied ACCEPTABLE/Guideline, and it satisfies the guideline requirem e nt [OPPTS 870.3700; §83-3(b)] for a de velopm ental toxicity study in rabbits. 870.3700a Prenatal Developmental Toxicity Study - Mouse In a developm ental toxicity study [MRID 00061637], pr e gnant Alderley Park albino SPF mi ce [32-34 mi ce/group] were admi nistered Diqua t dibromide [analytical standard] via gavage at dose levels of 0 [ d istilled water], 1, 2, and 4 m g /kg/day [expresse d as the diquat cation] from gestation days 6 through 15. The dam s were sacrificed on gestation day 17, and fetuses were examin ed for external, visceral, and skeletal alterations. There was a dose-related increase in the num ber of deaths. One low-dose [day 15 after 10 doses], three mi d-dose [days 9, 10, 14], and five high-dose [days 9, 15, 16] dam s died. There was an increase in the incidence of clinical signs of toxicity [piloerection ( a l l t h r e e dose groups), dyspnea, respiratory noise (all dose groups), abnorm a l posture (hunched or tail raised), lethargy (1 mi d-, 2 high-dose mi ce), trem ors (3 high-dose m i ce), unsteadiness on feet, em aciation, ptosis], which were pr e domi n a n tly found in the mi d- and high-dose anim als. High-dose dam s displayed a slightly lower body weight on gestati on days 15 [89% of control] and 17 [91% of control] comp ared to the control, and there was a dose-related decrease in body-weight ga in 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 pulm onary c h anges were noted at the m i d- and high-dose levels in those sacrificed at study term ination. Pregnancy rate, num ber of implantations and live fetuses/ dam , fetal sex ratio, pre- and post-implantation losses, and litter size were comp arable am ong the groups. Fetal body weight [87% of contro l] and litter weight [90% of control] were decreased at the high-dose level. There was no increase in the incidence of mi nor visceral abnorm a lities. There was a d o s e-related[ s light] increase in the incidence of m a jor m a lform a tions [0.6%, 0.6%, 2.1%, and 2.5% (% fetuses examined); 7.4%, 7.4%, 20%, and 21.7% (% litters) wi t h i n creasing dose]. The incide nce of mi nor skeletal abnorm a lities [incomplete ossification, extra ribs, variant sternebrae] was increasedat all dose levels comp ared to the control [10.3%, 18.5%, 24.3%, and 23.4% with increasing dose], and the corresponding values for the m e an percentage of mi nor skeletal abnorm a lities per litter were 10.5%, 20.1%, 28.1%, and 27.0%* with increasing dose. The percent of fetuses with extra ribs was comp arable am ong the groups, but the incidence of fetuses with variant sternebrae was increased at all dose levels comp ared to th e control [38.7%, 60.7%**, 57.3%, and 62.1%** with increasing dose]. The maternal toxicity NOAEL w a s 1 mg/kg/day, based on clinical signs, deaths, and macroscopic lesions in the gastrointestinal tract and lungs at th e maternal toxicity LOAEL of 2 mg/kg/day. The developme n t a l t oxicity NOAEL w a s 2 mg/kg/d ay, based on decreased fetal body w e ight [88% of control] and an increased incidence of ov erall skeletal alterations at 4 mg/kg/day.

17This deve lopm ental toxicity study is classified ACCEPTABLE/Guideline, and it satisfies the guideline requirem e nt [OPPTS 870. 3700; §83-3] for a developm enta l toxicity study in rode nts. NOTE: The HIARC reevaluated the m ouse developm ental toxicity study and determ ined that it is an acceptable study, but it is not useful for risk assessm ent due to, am ong other thi ngs, t h e poor dosing technique, which resulted in an inappropriate introduction of test m a terial into the lungs.
4.6 

### Reproductive Toxicity Adequacy of data base for Reproductive Toxicity : The data base for reproductive toxicity is considered comp lete. Reproductive toxicity w a s observed in both ge nerations, as evidenced by decreased numbers of live F1 pups/litter and decreased pup body-w eight gain [F1 and F2]. 870.3800 Tw o-Generation Reproduction Study - Rat In a two-generation reproduction study [M RI D 41 531301], groups of 30 Alpk:APfSD [W istar-derived] rats/sex/dose were fed diets containing Diquat dibromid e [21.09% diquat ion] at conc entrations of 0, 16, 80, and 400/240 ppm of diquat cation [0, 0.8, 4, and 20/12 m g /kg/da y, using standard convers ion factor] for 12 weeks [11 weeks for F1 generation] before m a ting, through m a ting, gestation, and l a c t a t i on periods. NOTE: Due to adve r s e e ffe c t s in the F1 rats, the dose was reduced from 400 ppm to 240 ppm approxim a tely 4 weeks after selection. There were no treatm e nt-related deaths. Parental toxicity was observed mos t l y a tt h e 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)] , ophthalm oscopic signs [ e ye opacity, partial or total lenticular cataracts, and iritis], decreased body-weight gains during the prem a ting [F0 m a les 15%-40%/F0 fem a les 10%-37%; F1 m a les 6%-37%/F1 fem a les 79% week 1 only], and decreased food consumption during the prem ating period. Maternal body- weight gains of the high-dose F 0 dam s were signi ficantly lower than the control throughout gestation, with the m a gnitude of the deficit increasi ng with tim e [20%-23% lower than c ontrol]. During lactation, the high-dose dam s displayed lower body-weight gains [54%-80% lower th an control] during the latte r part of lactation [days 16-22], with the m a gnitude of the defi cit increasing with tim e. During gestation, F1 dam s displayed comp arable body-weight gains am ong the groups, but the high-dose F1 dam s displayed a progressive deficit in body-weight gain during lactation [27%-42% lower than control] co mp ared to the control. High-dose F0 dam s displayed decreased food consumption during gestation and lact ation, and food consumption was comp arable am ong the F1 dam s throughout gestation and lactation. Ophthalm oscopic exam ination reveal ed partial/total cataracts at the high-dose level in both sexes and both generations following the prem ating dosing periods, as well as at week 4 after selec tion of t h e F1 pups [prior to dosing]. At the high-dose level in both generations and both sexes, the incide nce of partial and/or total cataract increased with tim e. In the F1 generation parental m i d- dose fem a les, there was an increase in the incidence of partial cataract and the incidence increas ed with tim e; i.e., 1 at week 4, 3 at week 11, and 4 at week 21. A similar finding was not observed in the m i d-dose m a les, and there were no total cataracts at the m i d-dose level in either sex. There were no adverse ef f

ects on f e m a le f e rtility at any dose level [ both generations] , and gestation indices and
18gestation length were comp arable am ong the groups [both generations]. The live birth index, viability index, and lactation index w e re comp arable am ong the groups in both generations. Inboth generations, the f e tal sex distribution was comp arable am ong the groups. There was a slight decrease [84%-85% of control] in the m ean num ber of live F1 pups/litter at the high-dose level, and m ean F1 pup body weight on day 22 of lactation was decreased significantly [both sexes] at the high-dose level [F1 m a les 79%/F1 fem a les 82% of control; F2 87% of control, both sexes] comp ared t o the control. Body-weight gains were decreased at the high-dose level [F1 m a les 76%/F1 fem a les 79% of control; F2 m a les 85%/F2 fem a les 84% of control] comp ared to the controls. Histopathological examination confirm e d 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 m a les; 25/30 f e m a les] was c onf irm e d mi croscopically, along with granulom atous inflamm a tion [2/30 m a les; 1/30 fem a les], loss of norm a l arrangem e nts in the epithelial papillae and rete pegs [ 5 /30 m a les] , abscess f o rm ation [ 4 /30 m a les] , mi xed inf l amm a tory cell inf iltration [ 2 /30 m a les] , and acanthosis [3/30 m a les]. F1 a dul t s di s p layed ocular opacity, ulcer ation of the hard palate, loss of palatine ridges, and ulceration of the tongue grossly, and one 80 ppm f

e m a le displayed ulceration of the tongue. Microscopic examination of the F1 adults showed cataractous changes at the high-dose level that were sim ilar in incidence and severity to the F0 adults. Other ocular changes at the high-dose level included retinal detachm e nt, vitreous adhesions, and lens enucleation. Ulceration of the hardpalate and tongue was observed at the high-dose level in both sexes. In the F1 pups at t h e 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 hi gh-dose F2 pups included distended caecum and ocular opacity [one fem a le]. F2 high-dose pups displayed increased inciden ces of hypertrophy and hyperplasia of the collecting duct epithelium in the kidney, cystitis, pyelitis, and slight cortical tubular dilatation in m a les and fem a les. The parental systemic toxicity NOAEL is 16 ppm [ 0.8 mg/kg/day], based on the incr e a s e d 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]. Atthe high-dose l e vel , i n addition to the above findings i n bo t h sexes, clinical signs [piloerectio n, opaque eyes, and ulcers on the palate], ophthalmoscopic signs [eye opacity, total ca taracts, and iritis], decreased body-w eight gain and food consumption w ere observed in both sexes. The reproductive/developmental NOAEL w a s 80 ppm [4 mg/kg/day], based on decreased number of live pups per litter on days 1-22, decreased pup body-w eigh t 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 satisfi e s t h e guideline requirem e nt [OPPTS 870.3800] for a reproduction study in rodents.



### 4.7 

### Neurotoxicity Adequacy of data base for Neur ot oxicity : The data base for neurotoxicity is considered com p lete. No additional studies are required at this tim e. Follow i ng acute exposure, t h er e was an increased incidence of diarrhea, staining of the nose, piloerection, urinar y incontinence, mouth staining, upw ard curvature of
19the spine, tip-toe gait, hunched posture, subdued behavi or, and sides pinched in. How e ver, the Agency has concluded that these symptoms may not be due to di rect neurotoxicity. No evid ence of neurotoxicity w a s observed in the functional observational battery, motor activity measurement, or neurohistopathology examination follow i ng subchronic exposure. Neuropathology w a s not observed in any study. Several of the clinical signs s u gge s t i v e of neurotoxicity [p iloerection, hunched posture, unsteadiness, muscular w e akness, and inabil i t y to stand, hypothermia, hyp oactivity, dyspnea, cyanosis, pale extremities] w ere observed in pregnant mice after oral administration on days 6-15 of gestation and in rats follow i ng dermal exposure, but these can be attributed to the gen eral poor health of the animals in these studies. 870.6100 Delayed Neurotoxicity Study - Hen This is not a data requirem e nt for Diquat dibromide. 870.6200 Acute Neurotoxicity Screening Battery In an acute neurotoxicity study [MRID 42666801, Diquat dibromide [20.1% a.i.] was adm i nistered to 10 Alpk:APfSD rats/sex/group via gavage at single dose levels of 0, 25, 75, and 150 m g /kg. Five rats/sex/dose were used for neuropathological examination at study termin ation. The functional observational battery [FOB] and m o tor activity assessm ent were perform e d approxim a tely 1 week pre-test, at 6 hour s post dose, and on days 8 and 15 post dose. The rats were sacrificed on day 16 post dose. There was one treatm e nt-related death at the high-dose level [ f e m a le sacrif iced in extremis on day 6]. Treatm e ntre lated clinical signs were observed m a inly at the high-dose level during days 2-6 post dose and included piloerection [high dose: m a les 1/10, fe m a les 7/10], diarrhea [high dose: 1/10 m a les, 5/10 fem a les; 2/10 mi d-dose fem a les], staining around nose [1/10 m a les in each treatm e nt group, 3/10 m i d-dose and 3/10 control fem a les], urinary incontinence [3/10 high-dose fem a les], upward curv ature of the spine [3/10 high-dose fem a les], tip toe gait [3/10 high-dose fem a les], hunched posture [2/10 high-dose fem a les], subdued behavior [2/10 hi gh-dose fem a les], and pinched sides [1/10 high-dose fem a le]. Slightly decreased body weights [4%-5%] were observed by day 8 in both sexes at the high-dose level, and d ecreased body-weight gains [m ales 17%/fem ales 23%] were observed during the first week only at this dose level inboth sexes. Food consumption was decreased at the mi d­ [m ales -10%] and high-dose [m ales -22%/fem ales - 35%] levels during the first week following dosing. The only FOB param e ter showing an apparent effect was landing foot splay, which was significantly increased [14%] in the hi gh- dos e ma l e s on day 1. High-dose fem a le s who displayed clinical signs suggestive of a neurological effect did not display any changes in FOB. Motor activity was not af f

e cted by treatm ent in either sex. No treatm e nt-related effects were reported in the gr oss/histopathological exam inations at study term ination. HED has determined that the signs observed in th is study m a y not be due to direct neurotoxicity. The systemic NOAEL is 75 mg/kg, based on clinical signs and decreased body-w eight gain at the systemic LOAEL of 150 mg/kg. This acute neurotoxicity study is classified ACCEPTAB LE/Guideline, and it satisfies the guideline requirem e nt [OPPTS 870. 6200; §81-8] for an acute neurot oxi c i t y study in rats. NOTE: Neurobehavioral tests [perform ed 6 hours post dose] m a y not have been perform e d at peak effect tim e. The clinic al signs observed occurred
20between 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 admi nistered to 12 Alpk:APfSD rats/sex/group at dietary levels of 0, 20, 100, and 400 ppm [m ales 0, 1.6, 8.0, and 32.4 m g /kg/day; fem a les 0, 1.9, 9.5, a nd 38.5 m g /kg/day (expressed as the cation)] for 13 weeks. Five rats/sex/dose were used for neuropathological exam ination at study termination. There were no treatm e nt-related deaths. Treatm e nt-relate d clinical signs were observed at the high-dose level in both sexes at the end of the study [opaque eyes: 7/12 m a les and 8/12 fem a les (weeks 13 and 14); eye pallor: 3/12 m a les and 1/12 fem a les (weeks 12 a nd 13); decreas ed visual placem ent response: 3/12 m a les and 1/12 f

e m a les] . D ecreased body weights [ . 9%] were observed throughout the study in both sexes at the high-dose level, and decreased body-weight gains [m ales 20%/fem ales 18%] and food utilization were also obser ved at this dose level in both sexes. There was an increased incidence of cataracts and/or poste rior lens opacities at the high-dose level in both sexes at study term ination. Total cataracts were observed in 5/12 high-dose m a les and 7/12 high-dose fe ma l e s. Posterior opacity of the lens was observed in 8/12 high-dose m a les and 6/12 high-dose fem a les. There was no evidence of neurotoxicity. No treatm e nt-related effects we r e reported in the functional observational battery [weeks 5, 9, and 14 post dose], m o tor activity assessm ent [weeks 5, 9, and 14 post dose], and gross/histopathological examination at study term ination. The NO AEL 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 cataract s and decreased body- w e i ght gain and food utiliz ation at the systemic LOAEL of 400 ppm [males 32.4/females 38.5 mg/kg/day]. Thi s s ubchronic neurotoxicity study is classified ACCEPTABLE/Guideline, and it satisfies the guidel i n e requirem e nt [OPPTS 870. 6200; §82-7] for a s ubchronic neurotoxicity study in rats. 870.6300 Developmental Neurotoxicity Study There is no developm ental neurotoxicity study [DNT] on Diquat dibrom ide.



### 4.8 

### Mutagenicity Adequacy of data base for Mutagenicity : The data base for mu tagenicity is considered adequate based on pre-1991 mu tagenicity guide l i n e s . No additional studies are required at this tim e. Diquat dibromide w a s negative for mutagenicity in a bac t e r i al gene muta tion [Ames] assay. Diquat dibromide w a s, how e ver, positive for gene mutations in a mammalian cell line [mouse lymphoma] but at cytotoxic doses. Similarly, Diquat dibromide w a s clastogenic in cultured human lymphocytes, but the response w a s generally w e ak
21and w a s observed at cytotoxic levels. In contrast, th ere w a s no evidence of clastogenicity in somatic cells [mouse bone marrow ] or germinal cells [mouse sp ermatogonia] or unscheduled DNA synthesis [UDS] in rat hepatocytes in a series of in vivo st udies. Overall, the data suggest that there is no concern for mutagenicity. Gene Mutation Guideline 870.5265. Am es, reverse mu tation; MRID 40323103 classification: Acceptable 0.01-100 F g/plate. No evidence of bacterial mutation in S. Typhimurium strains TA1535, TA1537, TA1538, TA98, TA100, and one strain of Escherichia coli [W p2uvrA pKM 101], w/ and w/out S9

Guideline 870.5300. m ouse ly m phom a [L5178Y]; MRID 40323101 classification: Acceptable 6.25-100 F g/mL and 3.12-50 F g/mL , w/ and w/out S9 mi x, respectively ; concentration-dependent cy totoxicity observed at all dose levels w/ and w/out S9. Mutagenic; colony siz i ng w a s not performed and increased mutant frequency occurred at cytotox i c doses. Cytogenetics Guideline 870.5385. in vivo chrom o som e aberration [C57B1/6J/ Alpk m ouse bone m arrow]; MRID 40323104 classification: Acceptable 62.5 or 100 m g /kg as diquat cation [50% and 80% of Median Lethal Dose]. Cy totoxicity at both dose levels. Not clastogenic.

Guideline 870.5375. in vitro chrom o som e aberration [hum an ly m phocy t es]; MRID 40323106 classification: Acceptable 1-129 F g/mL . MTD 129 F g/mL not clastogenic at dose levels of 12.9 F g/mL [±S9] and 25.8 F g/mL [+S9], where cy totoxicity was not apparent; other concentrations induced weak but statistically significant increases in chromosomal damage [5.5%- 30% > control] and cy totoxicity was apparent at these dose levels.

Guideline 870.5450. dominant lethal assay ; MRID 00061636 classification: Acceptable 0, 0.1, 1.0, or 10 m g /kg/day for 5 consecutive day s . No evidence of dominant lethal activity in Charles River CD-1 mi ce at dose levels up to 50% of the LD 50 . Other Genotoxicity Guideline 870.5450. Unscheduled DNA sy nthesis in vivo rat hepatocy te assay ; MRID 40323107; classification: Acceptable 225, 450, or 900 m g /kg prim ary rat hepatocy tes; vary ing degrees of cy totoxicity in hepatocy tes at all dose levels, as evidenced by py knotic and deeply staining nuclei coupled with reduced num bers of cells of norm a l m o rphology

. No evidence of induction of unscheduled DNA synthesis.
4.9 

### Metabolism Adequacy of data base for m e tabolism : The data base f o r m e tabolism is considered to be comp lete. Following oral exposure, the m a jority of the admi nistered dose is eliminated in t h e feces ( . 89% of the admi nistered dose), indicating that diquat is poorly abso rbed from the gastrointestina l tr a c t. That portion absorbed is rapidly elim inated in the urine ( . 6% of the admi nistered dose). Un changed Diquat dibromide is the m a jor excretion product in both the urine and feces. The m a jor m e tabolites are diquat m onopyridone and diquat dipyridone, and these are considered to have the sam e toxicity as the parent. No substantial retention was 22observed in any tissue. 870.7485 Metabolism - Rat
In a m e tabolism study [MRID 00065592], m a le and fem a le ra ts and mi ce [num bers and strains not specified in review] were dosed either orally or intravenously with single doses of Diquat dibrom ide. Diquat dibromide was slowly absorbed from the gastroin testinal tract of m a le and fem a le rats. Irrespective of the type of dosing [oral or intravenous ], Diquat did not accumu late in tissues of rats or m i ce. Following a single oral dose of [ 14 C]-Diquat dibromide [60 m g /kg, expressed as th e diquat cation], only 5.5% of the admi nistered radioactivity was excreted in the urine of rats with in 7 days. Following an oral [feeding] dose of unlabeled Diquat dibromide [250 ppm , expressed as the diquat cation] to m a le and fem a le rats for 2, 4, or 8 weeks, there was no retention [as determined by colorim e trically] of Diquat in the brain, liver, lung, stom ach, sm all and large intestine, mu scle, and blood, and little retention in the kidneys [0.18, 0.25, and 1.17 ppm during weeks 2, 4, and 8, respectively. Ten mi nutes after an iv injection of [ 14 C]-Diquat dibromide [60 m g /kg, expressed as the diquat cation], there were indications [whole body autoradiogr aphy] that Diquat concentrated in the c a rtilaginous tissues, the liver, and the urinary bladder. Most other ti ssues also showed the presen ce of radioactivity, including sm all am ounts in the brain and spinal cord. After one hour, the am ounts of radi oactivity declined in m o st tissues. After 24 hours, radioactivity was detectedonly in the urinary bladder and in the sm all and large intestines. There was still som e radioactivity in the intestines, but none in the bladder at 72 hours post dose. In another m e tabolism study [MRID 00065593], rats [num ber, sex, strain, dose levels not specified] were dosed with [ 14 C]-Diquat dibromide either by stom ach tube or by s ubcutaneous injection, and their urine and feces were m onitored at 24-hour intervals for 4 days. Following or al adm i nistration, the rats excreted 6.3% and 89.3% of the admi nistered radioactivity in the urine and feces, respectively, within 4 da ys. Most of this radioactivity was excreted during the first 48 hours. In the urine, m o st of the excreted radioactivity [5.3%] was unchanged, whereas the rem a ining 1% was associated with the following m e tabolites: Diquat m onopyridone [0.2%], Diquat dipyridone [0.1%], and unidentified m e tabolites [0.3%]. Inthe feces, 65.5% of the ex creted radioactivity was detected in the sulfuric acid-extractable fraction and 15.7% in the am m onium sulfate-unextractable fraction. In the sulfuric acid fraction, the radioactivity was distributed as foll ows: unchanged Diquat [57.1%], Diquat m onopyridone [4.3%], and unidentified m a terial [4.1%]. The amm onium sulfate fraction was not analyzed for m e tabolites. Following subcutan eous administration of [ 14 C]- D i qua tdibromide, 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 am ount of radioactivity recovered in the feces and the percent distribution of m onopyridone and dipyridone in urine and feces, after the s ubcutaneous dose, were not reported in the available review. In a third study [MRID 00055107], r a t s [number, sex, strain not specified in review] were dosed orally with [ 14 C]-Diquat dibromide and their urine and feces were qua ntitated for radi oact i v i t y at selected tim e 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 [ 14 C]-Diquat dibr omi d e , to circum vent the intestine, nearly all of the radiolabeled m a terial was recovered in the urine within 2 days. The three studies together are classified as A c ceptable/Guid e lin e , and together they satisfy the guideline
23requirem e nt [OPPTS 870.7485] for a general m e tabolism 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 derm al absorption data : There is an adequat e de r m a l ab s o rption 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 sm all am ounts through the skin.. The derm al absorpt i on of Diquat dibromide through intactrat skin is considered very low . Executive Summ ary : In an in vivo percutaneous absorption study [MRID 41238701], aqueous solutions of [ 14 C] Diqua tdi bromide were applied derm ally [10 cm2 ] to the shaved backs of 4 Sprague-Dawley rats/group. Following 24 hours of exposure, dose levels of 0.05, 0.5, a nd 5 m g diquat cation/rat resulted in 2.3%, 2.1%, and 3.3% absorption. The unabsorbed Diquat dibromide was r ecovered from the a ppl i c a tion site. Based on these findings, the derm al absorption of Diquat dibrom ide through intact rat skin is considered very low.

Application to a 10 cm 2 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 wa sh ab sorbe d on/in skin skin wa sh ab sorbe d on/in skin skin wa sh ab sorbe d 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 satisf i es the guideline requirem e nt f o r a derm al penetration study (OPPTS 870.7600) in the rat.
Derm al Abs o rp t i o n F a c t or : 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 dibrom ide 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 Hum a ns], a ccording to EPA Guidelines for carcinogen Risk Assessm ent 24[CFR Septem ber 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 i ndication of increased sensitivity of rats, m i ce, or rabbits to in utero and/ or postnatal exposure to Diquat dibromid e. In the regulatory-quality prenat al developm ental toxicity studies in rats a nd r abbi t s and the two-generation reproduc tion study in rats, effects in the offspring were observed only at or above treatm e nt levels that resulted in evidence of parental toxicity. 6.2 Recommendation for a Developmental Neurotoxicity Study The HIARC Committee determined that a developm ental neurotoxicity study in rats is not re qui r e d [HIARC Report TXR No. 014670] at this tim e.

257.0 REFERENCES in MRID order 00055107 Daniel, J. W

. and Gage, J. C. (1966) Abs o rp t i on and Excretion of Diquat and Paraquat in Rats. (Published Study from Imperial Chemical Industires Lim ited, Industrial Researc h Laboratories, Alderley Park, Cheshire, Great Brita in). Brit. J. Industr. Med., 1966, 23, 133-136. 00061636 McGregor, D.B. (1974) Domi nant Letha l St udy in Mice of Diquat: 401567: Report No. 148. (Unpubl i s he d s t udy received Jan 27, 1981 under 239-1663; prepared by Inveresk Research International, submitted by Chevron Chemical Co., Richm ond, Calif.; CDL: 244244-D) 00061637 Palm er, A.K.; Edwards, J.A.; W oodhouse, R.N. ( 1978) Effect of Diquat on Pregnancy of the Mouse: IC I/167/77642. (Unpublished study received Jan 27, 1981 under 239-1663; prepared by H untingdon ResearchC e n tre, E n g l and, subm itted by Chevr on Chemical Co., Richm ond, Calif.; CDL:244244-E) 00065592 Litchfield, M. H., Daniel, J. W ., and Longs haw, S. (1973) The Ti s s u e Distribution of the Bipyridylium Herbicides Diquat and Paraquat in Rats and Mice. (Published study from Industrial H ygiene R e search Laboratories and Pharm aceutical s D i vision of Imperial C h emical 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., Richm ond, Calif.). 00081506 (1979) The Acute Oral Toxicity of Diquat W ater W eed Killer. Study No. S 1431 (Unpublished study submitted by Chevron Chem ical Co., Richm ond, Calif.) 00081507 (1976) The Eye Irritation Potential of CC 7019. Study No. S-960 (Unpublished study subm itted by Chevron Chemical Co., Richm ond, Calif.) 00100614 (1979) The Acute Derm al Toxicity of Diquat W a te r W eed Killer in Adult Male and Fem a le Rabbits. Study No. S-1623 (Unpublished study subm itted by Chevron Chem ical Co., Richm ond, Calif.) 00107903 (1979) The Skin Irritation Potential of Diqua t W a ter W eed Killer. Study No. S-1624 (Unpublished study submitted by Chevron Chemical Co., Richm ond, Calif.) 00145855 Colley, J.; W arren, S.; Heywood, R. ( 1985) Diquat Dibrom ide Evaluation of Potential Carcinogenicity and Chronic Toxicity by Prolonge d Dietary Adm i nistration to Rats: Final Report: HRC Report No. ICI 406-837/63. Unpublished study pr e p a r e d by Huntingdon Research Centre. 2660 p. [Accession Nos. 256983-256988]. 00160673 Huntingdon Research Centre (1985) Diquat Dibromide: Evaluati on of Potential Carcinogenicity and Chronic Toxicity by Prolonged Dietary Adm i nistration to Rats. Unpublished comp ilation. 42 p.

40185602 Zi mme r m a n, R. (1981) Supplem ental Inform ation in Support of Diquat Rat Chroni c
26Toxicity/Oncogenicity Study: Laboratory Pr oject ID: ICI 383/80935. Unpublished study prepared by Huntingdon Research Centre. 6 p. 40301701 Bruce, E.; Griffis, L. (1987) Three-W eek Aero sol Inhalation Toxicity Study of Diquat Concentrate in Rats: Laboratory Project ID: S-2908; CEHC 2663. Unpublished study prepared by Chevron Envi ronm ental Health Center, Inc. 420 p. 40308101 Auletta, C. (1987) A Twenty-one Day Derm al T oxicity Study in Rats with Diquat Technical: Lab Project ID: 87-3137. Unpublished study prepared by Bio/dynam i cs, Inc. 477 p. 40323101 Cross, M. (1986) Diquat Bromide (Technical): Assessm ent of Mutagenic Potential Using L5178Y Mouse Lymphona Cells: Lab Project ID: CTL/P/1602. Unpubl i s he d study prepared by Imperial Chemical Industries, PLC. 31 p. 40323102 Cross, M. (1986) Diquat Dibrom i d e : Assessm ent of Mutagenic Potential Using L5178Y Mouse Lymphom a Cells: Lab Project ID: CTL/P/1554. U npublished study prepared by Im perial Chemical Industries PLC. 31 p. 40323103 Callander, R. (1986) Diquat Dibromide (Technical): An Evaluation of Mutagenic Potential Using S. typhimu rium 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) Diqua t Dibrom ide (Technical): An Evaluation in the Mouse Micronucleus Test: Lab Project ID: C TL/P/1532. Unpublished study prepared by Imperial Chemical Industries PLC. 29 p. 40323105 W ildgoose, J.; Braithwaite, I.; Howard, C.; et al. (1986) Diquat Dibromid e: A Cytogenic sic Study in Hum a n Lymphocytes in vitro: Lab Pr oj e c t ID: CTL/P/1469. Unpublished study prepared by Imperial Chemical Industries PLC. 30 p. 40323106 Richardson, C.; Howard, C.; W ildgoose, J. (1986) Diquat Dibromide (Technical): A Cytogenetics Study in Hum a n Lymphocytes in vitro: Lab Pr oject ID: CTL/P/1561. Unpublished study prepared by Imperial Chemical Industries PLC. 30 p. 40323107 Truem a n, R. (1987) Assessm ent for t h e Induc tion of Unscheduled DNA Synthesis in Rat Hepatocytes in vivo: Lab Project ID: 8703557. U npublished study prepared by Im perial Chemical Industries PLC. 45 p. 40640801 Chevron Chemic a l Co. (1988) Submission of DataTo 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.
2741198902 W i ckram aratne, G. (1989) Diquat: Teratogenic ity 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 Environm ental Health Center, Inc. 46 p. 41531301 Hodge, M. (1990) Diqua t : Multigeneration Study in the Rat: Lab Project Num b er: 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 Num b er: CTL/P/2596. Unpublished study prepared by ICI Central Toxicology Laboratory. 476 p. 42219801 Hodge, M. (1991) Diquat: Two Year Feedi ng Study in Mice: Lab Pr oj e c tNum b er: PM0749. Unpublished study prepared by ICI Central Toxicology Laboratory. 2674 p. 42616101 Horner, J. (1992) Diqua t : S ubchronic Neurotoxicity Study in Rats: Lab Project Num b er: 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 Num b er: CTL/P/3789: AR5421. Unpublished study prepared by ICI Central Toxicology Laboratory. 330 p. 42880701 Ishm ael, J. (1993) Supplem ent to MRID 42219801: Diquat: Two-Year Feeding Study in Mice: Lab Project Num b er: CTL/P/3409. Unpublished study pr epared by Zeneca Central Toxicology Lab. 50 p. 42905901 Ishm ael, J. (1993) Supplem ental Inform ation to MRID 42291801: Diquat: Two-year Feeding Study inMice: L ab P r o j ect Num b er: CTL/P/3409. Unpublished study prepared by Zeneca Agrochemicals, Central Toxicology Lab. 6 p. 42919501 Ishm ael, J. (1993) Supplem ental Inform ation to MRID 42291801: Diquat: Two-Year Feeding Study in Mice: Lab Project Num b er: CTL/P/3409. U npublished study pr e p a r e dby Central Toxicology Lab., Zeneca Agrochem icals. 5 p. 43383203 Hodge, M. (1994) Diquat: 28 Day Feeding Study in Mice: Lab Project Num b er: CTL/L/2495: PM0734. Unpublished study prepared by Zeneca Central Toxicology Lab. 10 p.

288.0 APPENDICES Tables for Use in Risk Assessm ent

298.1 Toxicity Profile Summ ary Tables 8.1.1 Acute Toxicity Table - See Section 4.1 8.1.2 Subchronic, Chronic, and Other Toxicity Tables Toxicity Profile
Subc hr onic Toxic i ty of Diquat dibr omide Guideline S tudy Ty pe/MRID/doses Results
870.3200 [§82-2] 21-day d ermal toxicity - rats

MRID: 40308101 [1987]

Clas s i fication: Acceptable/Guideline Diquat dibr omide (20. 64% diquat c a tion) Dermal Toxicity NOAEL < 5 mg/kg/day Dermal Toxicity LOAEL = 5 mg/kg/ day , based on dermal irritation at application s ite [ery them a, edem a, atonia, and des quam a tion] and tis s u e des truction [necros is and es char form ation]

.. Sy stemic Toxicity NOAEL = 5 mg/kg/day Sy stemic Toxicity LOAEL = 20 mg /kg/day , based on a dose-related m o rtality and clinical signs [hy potherm ia, hy poactivity , dy spnea, cy anosis, pale extrem ities, general poor condition, and e m a c iated appearance]

. Bas e d on the s e verity of the effects obs erved [death and clinical signs (hy pothermia, hy po activity , dy spnea, c y a nosis, pale extrem ities, general poor condition, and em aciated appearance)] and the extent of skin toxicity [derm a l irritation (ery them a, edem a, and desquamation) and tissue destruction (necros is and es char forma tion); sore s, se ve re e ry the ma , fissu r e s, a c u te ne c r otiz ing purulent derm atitis, and dege ne ra t i on of the hair follicles and sebaceous glands] observed at the s ite of application in one or both sexes, it was concluded that the st udy was not appropriate for use in risk assessm ent since the NOAEL is artificially low due to the fact that the skin is comp rom i sed.
870.3465 [§82-4] Subchronic Inhalation - Rats (3 weeks) MRID: 40301701, 40640801 [1987, 1988]

Clas si fication: Acceptable/Guideline, when both studies considered together. NOTE: Duration of study is 21 day s , not 90 day s. Diquat dibromide (21.6%/23.5% diquat cation) NOAEL: 0.1 F g/L/day [males 0.027 mg/ kg/day ; females 0

. 0.029 mg/kg/day ] , based on increased lung weights and micr osco pic lesions [mottling and reddening of th e lungs in fem a les, mu ltifocal, chronic, inte rst itial pneumonia and alveolar macrophages in both sexes] in the lungs at the LOAEL of 0.49 F g/L [males 0. 134 mg/kg/day ; female s 0.144 mg/kg/day ]. LO A EL = Low e s tO bs e rvable A dvers e Effect Level; N O A EL = N o O bs e rvable A dvers e Effect Level

30Chr o nic Toxic i ty /Car c i noge nic i ty of Diquat dibr omide Guideline S tudy Ty pe/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]

Clas s i fication: Acceptable/guideline Diquat dibromide (26.7% w /v cation) NOAEL: 0.5 mg/kg/day L OAEL: 2.5 mg/kg/day , based on un ilateral cataracts in fem a les, a n d decreas ed weights of epididy m ides and adrenals in m a les

. At t h e HDT , bilateral lenticular opacity [cataracts] , m a c r osc opi c a lly and microscopically [in all dogs, both sexes] ; inflammatory lesions in the large intestine [in all dogs, both sexes] ; in creased 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]

Clas s i fication: Acceptable/guideline Diquat dibromide (21.09% w /v cation) NOAEL = 30 ppm [3.56/4.78 mg/kg/day ] LOAEL: 100 [11.96/16. 0 3 mg /kg/day ] , based on clinical signs [ey e discharge (males), increased incide nce of thin appearance and subdued behavior (fem a les ) ] , increas ed kidney weights (m ales ). At HDT, increas ed incid e n ces o f m i cr o s co p i c les i o n s in th e ki d n e y , liv er , an dly mp h node (m es enteric) . There was no treatm e nt-related increas e in tum o r incidence in either s e x. 870.4300 [§83-5] Chronic feeding/carcin ogenicity study - SpragueDawley r a t s [ 0 , 5, 15, 75, and 375 ppm (0, 0.19, 0.58, 2.91, and 14.88 mg/kg/day for ma l e s a n d 0, 0.24, 0.72, 3.64, and 19.44 mg/kg/day for females)] for 104 weeks. MRID 00145855, 00155474, 41085601 [1985] Clas s i fication: 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/da y ] , based on ey e lesions [to t al cataracts ] . NOTE: The incide nc e of ey e les i ons increas ed with tim e on study , and effect observed at lower dose level with time.

There was no treatm e nt-related increas e in tum o r incidence in either s e x.

31Developmental Toxicity of Diquat dibromide Guideline S tudy Ty pe/MRID/doses Results
870.3700 [§83-3a] Developmental Toxicity - Wistar-deri v ed Rats [0, 4, 12, and 40 mg/kg/day ]

MRID 41198902 [1989]

Clas s i fication: 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 wa s o n e 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 delay e d skeletal ossification [increas ed incidence of m i nor s k eletal variations , including unos s i fied ventral tubercle, unos s i fied cervical vertebral centra, and delay e d ossification of the 2nd and 5th sternebrae]

. 870.3700 [§83-3b] Devel opm ent a l Study - NZW R abbi t s [0,1, 3, 10 mg/kg/day ] MRID 41198901 [1989]

Clas s i fication: Acceptable/Guideline Diquat dibromide (26.2% cation) Maternal NOAEL: 1 mg/kg/day Maternal LOAEL: 3 mg/kg/da y , based on decreased body -we i ght gain and food consumption. At HDT , there were deaths and clinical signs [diarrhea, subdued activity , thin appeara n ce, mucus, blood, little or no feces in tray ] Developmental NOAEL: 3 mg/kg/day Developmental LOAEL: 10 mg/kg/ day , b a sed on decreased fetal body weight, an increased incidence of friable/m ottled livers, and an increas ed incidence of m i nor s k eletal alterations [partially os s i fied ventral tub e r c le of cervical vertebrae, partially ossified 6th s t ernebrae, and unos s i fied 6th s t ernebrae and pres acral vertebrae]

. 870.3700 [§83-3a] Developmental Toxicity Study - Mice [ Alderley Park ] [0, 1, 2, and 4 mg/kg/day ]

MRID 00061637 [1978]

Clas s i fication: Acceptable/Guideline Diquat dibr omide (analy tic a l standar d ) Maternal NOAEL: 1 mg/kg/day [as diquat cation] M a t e r n a l L O A E L : 2 m g /k g / d a y, b a s e d o n m o rtality, c l i n i c a l s i g n s [piloerection, respiratory sounds] , and decreased body -weight gain [during dosing period] . At HDT, a dditional clinical signs [abnormal posture (hunched or tail raised), lethargy , tremors, unsteadiness on feet, emaciation, ptosis] and a s light decrease in body weight [91% of control] at termination wer e o b s erved 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 sk eletal alterations.

32Re pr oduc tive Toxic i ty of Diquat dibr omide Guideline S tudy Ty pe/MRID/doses Results
870.3800 [§83-4] 2

- Ge n e r a t i o n Reproduction Toxi c i t y i n Alpk:APfSD [Wistar derived] Rats 0, 16, 80, 400/240 ppm [0, 0.8, 4, 20/12 mg/kg/day ]

MRID 41531301 [1990]

Clas s i fication: Acceptable guideline Diquat dibr omide (20. 09% diquat c a tion) Parental NOAEL: 16 ppm [0.8 mg/kg/day ] Parental LOAEL: 80 ppm [4 mg/kg/day ] , based on cl inical signs, ulceration of the tongue, and partial/total c a taract. At HDT, increas ed incidence of clinical s i gns i n cluding ophthalmosco p i c signs and lack of grooming, and gross and m i cro s co p i c f i n d i n g s [ u l cer ati o nof the tongue and partial/total cataract]

. Re produc t i ve /De velopm ental NOAEL: 80 ppm [4 m g /kg/ da y ] Reproductive/Developmental LOAEL: 400/240 p p m [12 m g /kg/day ] , based on decreased number of live pups per litter on day s 1-22, decreased pup body -weight gain during lactation, and increased incidence of kidney lesions.

Neurotoxicity of Diquat dibromide Guideline S tudy Ty pe/MRID/doses Results
870.6200 [§81-8] Acute oral neurotoxicity - Rats [0, 25, 75, and 150 mg/kg]

MRID: 42666801 [1992]

Clas s i fication: Acceptable/Guideline Diquat dibr omide (20. 1% w /v diquat c a tion) NOAEL: 75 mg/kg LOAEL: 150 mg/kg/d a y , b a sed on clinical signs [diarrhea, staining of the nose, piloerecti on, urinary incontinence, mouth staining, upward c u rvature of spine, tip-toe gait, hunched posture, subdued behavior, and sides pinched in]

. NOTE: Agency concluded that signs were not due to d i r e c t 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] Clas si fication: Acceptable/Guideline Diquat dibromide (20.8% diquat c a tion) 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 catara c ts and decreased body-weight gain and food utilization in both sexes.
There was no evidence of neurotoxicity at any dose level.

33M e t abolism Studie s on Diquat dibr omide Guideline S tudy Ty pe/MRID/doses Results 870.7485 [§85-1] Disposition and m e tabolism MRID 00065592

Clas s i fication: Acceptable/guideline W Diquat dibrom ide did not accumu late in t i s s u es and was s l owly abs o rbed following or iv exposure to single doses of 14 C] Diquat dibromide to rats or mice of both sexes. Following a si ngle dose of 60 mg/kg, only 5.5% of the radiolabel was excreted in urine within 7 day s . Following an oral [feeding] dose of unlabeled Diquat d i b r o m i d e [250 ppm] to rats of both sexes for 2, 4, or 8 we e k s, no retention of Diquat was observe d int he brain, liver, lung, stomach, sm all and large intestine, mu scle, and blood, and l ittle retention in the kidney s [0.18, 0.25, and 1.17 ppm during weeks 2, 4 , and 8, respectively ] . Ten minutes after iv injection, there were indicati ons that Diquat concentrated in cartilaginous tis s u es , liver, and urinary bladder, as well as the brain and s p inal cord. After 24 hours, radiolabel was detected only in the urinary bladder and intestines. 870.7485 [§85-1] Metabolism - excretion MRID: 00065593

Clas s i fication: Acceptable/guideline W Rats excreted 6.3% and 89.3% of [ 14 C] in the urine and feces , res p ectively , within 4 day s following oral exposure, with mostbeing excreted within the first 48 hours In urine, most [5.3%] of the [ 14 C] was unchanged Diquat, whereas the remaining 1% was associated with: diquat monopy ri done [0.2%] , diquat dipy ridone [0.1%] , and uni de ntified m e tabolites [0.3%]

. In feces, 65.5% of excreted [ 14 C] was detected in u lfuric acid-extractable fr action and 15.7% inth e amm onium sulfateunextractable fraction. In the sul f uri c acid fraction, [ 14 C] was distributed as follows: unchanged diquat [57.1%] , diq u a t monopy ridone [4.3%] , and unidentified material [4.1%]

. 870.7485 [§85-1] Metabolism MRID 00055107 Clas s i fication: Acceptable/guideline W Following oral dosing, . 90% of 14 C] was elim inated in the feces , indicating that Diquat was poorly absorbed for the gastr o i n t e st inal tract. Following a subcutaneous injection of 14 C] -Di qua t to circum vent the intestine, nearly all [ 14 C] was recovered in the urine within 2 day s . [1973] either oral [

[1972]

s

[1966] [ [

W when considered with the two othe r studies, the guideline [OPPTS 870.7485] for a metabolism study is satisfied

348.2 Summ ary of Toxicological Dose and Endpoints for DIQUAT DIBROMIDE for Use in Huma n Risk Asse ssme nt E X POSURE SCENARIO DOSE E NDPOINT STUDY
Acute Dietary females 13-50 y ears 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 fem a les and decreas ed adrenal and epididy m ides 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 m g / kg/ day M O E = 100 NOAEL = 1 m g / kg/ day , based on decreased body -wei ght gai n and food consum pt i on at th e LOAEL of 3 m g / kg/ day

. Devel opm ent a l to x i city rabbi t Incidental Oral, Interm ediateTerm NOAEL = 0.5 m g / kg/ day M O E = 100 NOAEL = 0.5 m g / kg/ day , based on cat aract s i n fem a les and decreased adrenal and epididymis wei ght s at th e LOAEL of 2.5 m g / kg/ day

. C h roni c oral to x i city

dog Short

- Term a b (Dermal) 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 Interm ediate-Term (Dermal) NOAEL = 0.5 mg/kg/day MOE = 100 NOAEL = 0.5 mg/kg/day , based on cataracts in fem a les and decreas ed adrenal and epididy m is weights at the LOAEL of 2.5 mg/kg/ day

. Chronic oral toxicity dog
Long-Term (Dermal) NOAEL = 0.5 m g / kg/ day M O E = 100 NOAEL = 0.5 m g / kg/ day , based on cat aract s i n fem a les and decreased adrenal and epididymis wei ght s at th e LOAEL of 2.5 m g / kg/ day

. C h roni c oral to x i city

dog Short Term (Inhal a t i on) NOAEL = 0.1 F g/L M O E = 100 NOAEL = 0.1 F g/L [ 0.024 mg/kg/day ] , based on increased m ean lung weight in m a les, m o ttling and reddening of lungs in fe males, and lung lesions [multifocal chronic interstitial pneum onia and alveolar macrophages] at the LOAEL of 0.49 F g/L [0.117 mg/kg/day ]

. 21-day inhalation toxicity

rat

Interm ediate Term (Inhalation) NOAEL = 0.1 F g/L MOE = 100 NOAEL = 0.1 F g/L [0.024 mg/kg/day ] , based on increased m ean lung weight in m a les, m o ttling and reddening of lungs in fe males, and lung lesions [multifocal chronic interstitial pneum onia and alveolar macrophages] at the LOAEL of 0.49 F g/L [0.117 mg/kg/day ]

. 21-day inhalation toxicity

rat

Long Term (Inhalation) NOAEL = 0.1 F g/L MOE = 100 NOAEL = 0.1 F g/L [0.024 mg/kg/day ] , based on increased m ean lung weight in m a les, m o ttling and reddening of lungs in fe males, and lung lesions [multifocal chronic interstitial pneum onia and alveolar macrophages] at the LOAEL of 0.49 F g/L [0.117 mg/kg/day ]

. 21-day i nhal a t i o n to x i city rat

a A 4.1% dermal absorption factor shoul d be used for this risk assessment. b Since an oral value was selected, rout e-to-route extrapolation should be followed.

35