### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D

. C. 20460



### MEMORA N DUM

Date: 26-MAR-2013 OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION



### SUBJECT : Imazapyr: Petition for the Establishmen t oflmport Tolerances on GeneticallyModified (GM) Soybean, Rapeseed subgroup 20A, Sunflower Subgroup 20B and

Lentils



### PC Code : 128821



### Decision No

. : 440569, 466036



### Petition No

. : OE7793, 2E8045



### Risk Assessment Type: Single

Chemical/ A g gregate


### TXR No.: None



### MRID No

. : None 

### DP Barcode: 384035, 403741 

### Registration No

. : 172267 

### Regulatory Action: Tolerance without 

### U.S. Registration



### Case No .: 3078



### CAS No

. : 81334-34-1



### 40 CFR: § 180.500

FROM: Mohsen. Sahafeyan, Chemist/Riskq\ssessor 

# fl4**~?17~** Nancy McCarroll, Toxicologist 

# L**~J-. ~**  

# f1.X

Bridgett Bobowiec, Biologist

## 1~**-f ~** **~** '

- 

### Risk Assessment Branch VI

Health Effects Division (7509P) 

# IJ-n

THROUGH: Felecia Fort, Branch Chief

# ~,); 

# '{\ J**C;f)~** ()'

# ~ Risk Assessment Branch VI

Health Effects Division (7509P)



### TO: Hope Johnson and Kable Davis Fungicide Branch Registration Division (7505P)

This document provides the Health Effects Division (HED) human health assessment for the proposed establishment of tolerances without U.S. registration for the herbicide imazapyr on imported GM soybean, rapeseed subgroup 20A, sunflower subgroup 20B and lentiL Th e field

trials were conducted on the GM crops with the following BASF names: soybean of Cultivance ®

Page 1 of 12

### Page 2 of 12

Production System, Clearfield ® 

### Canola, Clearfield ® 

### Sunflower

, and Clearfield ® 

### Lentils

. HED

notes that some of the formulations used in the field trials contain other active ingredients (imazapic and imazamox) which are addressed in separate documents

.

Introduction

Imazapyr [2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

- imidazol

- 2

- yl]

- 3

- pyridinecarboxylic acid] is a broad

- s pectrum, imidazolinone herbicide used for pre

- and post

emergence control of annual and perennial grass and broadleaf weeds, brush, vines, and

deciduous trees in occupational and residential settings . Imazapyr is currently registered to BASF Corporation f

or use on non

- cropland areas and on imidazolinone

- resistant field corn.

BASF has requested import tolerances without U. S. registration for residues of imazapyr on

imidazolinone

- tolerant soybean of Cultivance ® 

### Production System

, rapeseed subgroup 20A,

s unflower subgroup 20B and lentil

. The BASF tolerance request triggered a review of imazapyr toxicity database and endpoints for risk assessment. In September of 2012 , the HED imazapyr

review team called for a meeting of Hazard and Science Policy Council (HASPOC) to revisit the toxicity of imazapyr and determine whether a quantitative risk assessment is needed. After reviewing the available toxicology database for imazapyr

, HASPOC concluded, with reasonable certainty that there is no hazard identified for imazapyr in the available database and that dietary

, residential

, and occupational exposures to imazapyr do not pose a significant human health risk and, therefore, risk assessments are not needed.

BASF is proposing the following tolerances on the food commodities as shown below

.

Commodity Proposed Tolerance (ppm)

Soybean, seed 4.0 Soybean, meal 4.5 Rapeseed subgroup

20A 0.05

Sunflower subgroup

20B 0.05

Lentil 0.2

Proposed Use

Soybean: BASF has requested import tolerances for residues of imazapyr on imidazolinone

- tolerant soybean of Cultivance ® 

### Production System from Brazil using Soyvance ® 

### (soluble extract formulation with 48.0% m/v imazapyr) at 0.064 lb ai/A per application and Cultifix ® 

### ( water

disper sible granules formulation (WDG) with 52.5% m/m imazapyr and 17.5% m/m imazapic) at

maximum 0.047 lb ai/A per application on soybean

. The use pattern is one post

- emergence foliar application per season. The proposed PHI is 60 days. The submitted field trials wer e conducted

on GM soybean of Cultivance ® 

### Production System in Brazil

.

### Page 3 of 12

S unflower subgroup (crop subgroup 20B): BASF has requested an import tolerance for

residues of imazapyr on s unflower subgroup 20B crops imported from Argentina using Clear sol ®



### DF formulation ( W DG formulation containing 80 g imazapyr) applied at maximum 0.07 lb a i/A (0.08 kg ai/ha) and Clear sol ® 

### Plus formulation (soluble liquid formulation of co

- active ingredients imazapyr and imazamox with 15 and 33 g ai/L respectively ) applied at maximum 0.026 lb ai/A (0.03 kg ai/ha). The use pattern is one post

- emergence foliar application per season. The proposed PHI depends on the growth rate and is approximately 100 days. The

submitted field trials were conducted on GM sunflower ( Clearfield ® 

### sunflower )

.

R apeseed subgroup (crop subgroup 20A) : BASF has requested an import tolerance for

residues of imazapyr on r apeseed subgroup 20A crops imported from Argentina using ARES TM



### ( also a soluble liquid formulation of co

- active ingredients imazapyr and imazamox with 15 and 33 g ai/L respectively ) applied at maximum 0.008 lb ai/A (9 g ai /ha) . The use pattern is one

post

- emergence foliar application per season. The proposed PHI is 60 days. The submitted field

trials were conducted on GM c a nola ( Clearfield ® 

### canola)

.

Lentil: BASF has requested an import tolerance for residues of imazapyr o n imported lentil s using ARES TM 

### applied at maximum 0.008 lb ai/A (9 g ai /ha) . The use pattern is one post

emergence foliar application per season. The proposed PHI is 60 days. The submitted field

trials were conducted on GM lentil ( Clearfield ® 

### lentil)

.

Toxicity Data and Endpoint Selection

The latest assessment of the toxicity database for imazapyr was conducted in Sep tember 2012 ( Imazapyr: Summary of Hazard and Science Policy Council (HASPOC) Meeting of September
13, 2012: Recommendations on the type of risk assessment (quantitative vs. qualitative) to be

conducted. TXR# 0056464, 2/26/13) as part of the HASPOC determination on whether a risk assessment was necessary because there is no hazard identified for imazapyr in the available database ( i.e., no toxicity demonstrated in acceptable guideline studies generally up to the highest doses tested of 250

– 1000 mg/kg/day). Since July 2005, when the most recent Reregistration Eligibility Document (RED) for Imazapyr was prepared (Jarvis et al., 2005), no new data have been received that would warrant a change in the acute or chronic reference doses (RfD s), the occupational/residential toxicological endpoint select ions, the un certainty factors, or the FQPA Safety F actor.

Prior to HASPOC’s deliberations, the HED’s policy was to establish toxicological endpoints for all pesticides in anticipation of the RED. Consequently, the Hazard Identification Assessment Review Committee ( HIARC, 2003) chose 250 mg/kg/day and skeletal muscle effects, based on the imazapyr findings and analogy with imazapic, as the endpoint for the cRfD, the short

- term
and intermediate

- term incidental oral exposures as well as the short

- term and intermediate

- term dermal and the short, intermediate, and long

- term inhalation exposures. The data also show that

there is no evidence of neurotoxicity, immunotoxicity, genotoxicity, or carcino genicity. Further, no adverse developmental effects or adverse reproductive effects were detected in well

conducted guideline studies.

### Page 4 of 12

Viewed from a risk assessment perspective, the conservative tox icity endpoints assigned by HIARC amounted only to neg ligible exposures and risks from dietary, residential, s wimming

, and occupational routes.

Based on the above factors, t he HASPOC, with reasonable certainty, concluded that dietary, occupational

, and residential exposures to imazapyr do not pose a significant human health risk and, therefore, risk assessments are not needed. A lthough there is potential for exposure to imazapy, no hazard was identified from the toxicity studies. No adverse effect s were observed in the submitted toxicological studies regardless of the route of exposure or th e species tested. Therefore, risk assessment s are not required. Furthermore, according to the present HED policies, the toxicology database is considered to b e adequate and no additional studies are required.

Residue Data

Detailed review of residue chemistry data were not conducted and are not needed because of HASPOC determination of low/no risk associated with exposure to imazapyr. Adequate field

residue data in South America and in NAFTA regions were submitted fo r GM canola, GM

sunflower and GM lentil. Field trials for soybean were conducted in South America only. Except for lentil, most if not all of the residues from GM soybean, GM canola

, and GM

sunf lower were below the limit of quantitation (<LOQ) of the analytical method. However, if in

future

, BASF request s tolerances for residues of imazapyr on other GM crops or the same crops with different types of genetic modifications

, adequate rational and information should again be provided to show that the metabolic pathway s in non

- tolerant and tolerant plants are comparable.

Aggregate and Occupational Risk s

HASPOC in September 2012, concluded with reasonable certainty that dietary, occupational and residential exposures to imazapyr do not pose a significant human health risk and, therefore, risk

assessments are not needed.

Imazapyr risk assessments which were conducted previously showed that there are not significant risks from dietary (food + water), residential, swimming and occupational exposure

routes. The last chronic dietary exposure assessment for food and water ( Don ovan, W., D288806, 3/26/2003 ) resulted only in <1% of the chronic population adjusted dose (cPAD) for the U.S. population and all population subgroups. Even if higher doses in the dog study were assayed and adverse effects were seen, it would be virtually impossible to come up with risks of concern from dietary exposure. Since imazapyr is also registered as an aquatic herbicide, a

swimmer’s assessment was carried out resulting in incidental ingestion and dermal exposure

MOE estimates ranging from 68,000 t o 1,000,000. Similarly, a screen of the turf uses, analyzed as described in the new SOPs, shows MOEs in a range comparable to the swimmer’s scenario except for dermal which is being driven by a default conservative 100% dermal absorption

factor.

### Page 5 of 12

An acu te dietary exposure and risk assessment was not conducted because a toxicological endpoint attributable to a single dose has not been identified for imazapyr. Similarly, no cancer

assessment was conducted because i mazapyr has been classified as a “ C ategor y E Chemical” (adequate evidence of no carcinogenicity in two species) wh ich was confirmed ( TXR# 0051943

, May 22, 2003 )

.

HED concludes that the proposed uses of imazapyr on imported soybean , rapeseed crop subgroup 20A, sunflower crop subgroup 20 B and lentil will not result in significant aggregate
and occupational exposures and risk estimates

.

Adequacy of the Proposed Tolerances

The BASF proposed tolerances and existing MRLs are as shown in the Table below

.

Commodity Proposed Tolerance (ppm) Canadian MRL

Soybean, seed 4.0 Soybean, meal 4.5 Rapeseed subgroup

20A 0.05 0.05 seeds (borage, cuphea, echium, flax, gold of pleasure, hare's ear mustard, milkweed, mustard seed (oilseed type), oil radish, poppy, rapeseed (canola), sesame, sweet rocket Sunflower subgroup

20B 0.05

Lentil 0.2 0.2 dry lentil

T here are Canadian MRLs on rapeseed and lentil which are at the same levels as the proposed tolerances for those crops; the Canadian residue definition is also the same as that of U

. S. No

other international maximum residue limits ( MRLs ) or codex exist for any other imazapyr registered or proposed uses.

B ased on toxicity considerations, the HA S POC concluded that there are no risk concerns from exposure to imazapyr. Therefore, an exemption from the requirement of a tolerance would be appropriate for imazapyr if there were no tolerances on other crops

. In addition, lack of tolerance would provide trade irritation since there are existing MRLs on some crops. HED therefore, concluded that tolerances need to be established. HED agrees that the proposed tolerance levels are appropriate an d also harmonize with Canadian MRLs.

### Page 6 of 12

Conclusions

The toxicity database for imazapyr is considered adequate; no additional toxicolo gical studies are required

. The available toxicity studies (profile is attached) indicate that there are no risk

concerns from exposure to imazapyr from dietary (food and water), residentia l, swimming

, and occupational routes

. Adequate residue data are available to support the proposed import tolerances on GM soybean, rapeseed subgroup 20A, sunflower subgroup 20B, and lenti l. HED agrees that the proposed import tolerance levels are appropriate and also harmonize with

Canadian MRLs. Therefore, HED has no objections to granting the proposed import tolerances for residues of imazapyr in/on GM soybean, rapeseed subgroup 20A, sunflower subgroup 20B

, and lentil (as shown below).

The p etitioner should revise the proposed tolerance expressions for imazapyr , as follows:

Tolerances are established for residues of the herbicide, imazapyr , including its metabolites and degradate s, in or on the commodities in the table below. Compliance

with the tolerance levels specified below is to be determined by measuring only the

residues of imazapyr [2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

- imidazol

- 2

- yl]

- 3

- pyridinecarboxylic aci d]

.

Commodity Recommended Tolerance (ppm) Soybean, seed 4.0 Soybean, meal 4.5 Rapeseed subgroup

20A 0.05

Sunflower subgroup 20B 0.05

Lentil 0.2 0

### Page 7 of 12

Attachment 1: Supplemental Toxicology Table s

The toxicological data requirements (40 CFR 158.340) for food uses for imazapyr are listed in

Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table 1. Test Guideline Technical

Required Satisfied 1

870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ ................... 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Primary Eye Irritation

................................ .................... 870.2500 Primary Dermal Irritation

................................ ............... 870.2600 Dermal Sensitization

................................ ...................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rat and mouse)

................................ ... 870.3150 Oral Subchronic (dog)

................................ .................... 870.3200 21/28

- Day Dermal (rat)

................................ .................. 870.3250 90

- Day Dermal

................................ ............................... 870.3465 28

- Day Inhalation

................................ .......................... yes

yes

yes

no

no yes

yes

yes

---

---

870.3700a Developmental Toxicity (rat)

................................ ......... 870.3700b Developmental Toxicity (rabbit)

................................ .... 870.3800 Reproduction (rat)

................................ .......................... yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rat)

................................ .................... 870.4100b Chronic Toxicity (dog)

................................ ................... 870.4200a Carcinogenicity (rat)

................................ ...................... 870.4200b Carcinogenicity (mouse)

................................ ................ 870.4300 Chronic/Carcinogenicity (rat)

................................ ........ yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

................ 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

... 870.5395 Mutagenicity

— Mammalian Erythrocyte Micronucleus

. 870.5450 Mutagenicity

— Rodent dominant lethal assay 870.5500 Mutagenicity

— Bacterial DNA Damage or Repair Test 870.5550 Mutagenicity

— Unscheduled DNA Synthesis

................. yes

yes

yes

yes

no

no

no yes

yes

yes
see footnote 1

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity. (hen)

.............................. 870.6100b 90

- Day Neurotoxicity (hen)

................................ ........... 870.6200a Acute Neurotoxicity Screening Battery (rat)

.................. 870.6200b 90 Day Neurotoxicity Screening Battery (rat)

............... 870.6300 Developmental Neurotoxicity (rat)

................................ no

no

yes

yes

no ---

--- yes

yes
see footnote 1

870.7485 General Metabolism (rat)

................................ ............... 870.7600 Dermal Penetration

, in vivo (male rat)

........................... yes

no yes

yes

870.7800 Immunotoxicity (rat and mouse)........................... yes see footnote 1

### Page 8 of 12

Table 1. Test Guideline Technical

Required Satisfied 1

Non

- Guideline : Comparative dermal absorption, in vitro (rat

and human skin) no

--

1 According to the present HED policies, the toxicology database is considered to be adequate and no additional studies are required. This is because, HASPOC confirmed that the available data do not suggest that there is a concern for neurotoxicity, immunotoxicity, genotoxicity, or carcinogenicity ( Imazapyr: Summary of Hazard and Science Policy Council (HASPOC) Meeting of September 13, 2012: Recommendations on

the type of risk assessment (qua ntitative vs. qualitative) to be conducted. TXR# 0056464, 2/26/13).

Table.2: Acute Toxicity of Imazapyr Technical Grade Active Ingredient (TGAI)

Guideline No/Study Type MRIDs Results Toxicity Category

870.1100 Acute Oral 41551002 (1990) 93048016 (1990) LD 50 = > 5000 mg/kg IV

870.1200 Acute Dermal 41551003 (1990) 93048017 (1990) LD 50 = >2000 mg/kg III

870.1300 Acute Inhalation

TXR# 0006998 00132032 (1983) 93048018 (1990) LC 50 = >1.3 mg/L (gravimetric)

> 5.1 mg/L (nominal) III

870.2400 Primary Eye Irritation/NZW

rabbit 41551001 (1990) 93048019 (1990) 2/6 rabbits with corneal opacity

at 21 days; d ischarge in 1/6 rabbits at 21 days;

v ascularization of c ornea in 1/6 rabbits at 21 days;

Irreversible Eye Damage I

Tested with 99.3%

technical fine powder

870.2400 Primary Eye Irritation/NZW

rabbit Accession#

252004 Corneal opacity cleared within

72 hours; conjunctivitis reversible by day 7 III

Tested with 93%

technical

870.2500 Primary Skin Irritation 41551004 (1990) 93048020 (1990) non

- irritating to slight erythema

and edema IV

870.2600 Dermal Sensitization 00131607 (1983) 93048021 (1990) Negative

-

### Page 9 of 12

Table 3: Toxicity Profile of Imazapyr Technical.

Guideline No./ Study Type MRID No. (year)/

Classification/Doses Results

870.3100

90

- Day oral toxicity rodents (rat) 42774401 (1992) Acceptable/guideline 0, 15,000, or 20,000 ppm (equivalent to 0, 1248, or 1695 mg/kg bw /day in males and 0, 1423 or 1784 mg/kg bw/day in females). NOAEL =1,695 mg/kg/day for males and =1,784 mg/kg/day for females (HDT).

LOAEL = None.

870.3200

21/28

- Day dermal toxicity (rabbit) 00131609 (1983) 93048022 (1990) Acceptable/guideline
0, 100, 200 or 400 mg/kg/day, 6 hrs/day for 5 d/week during a 21

- day period. NOAEL =400 mg/kg/day (HDT).

LOAEL = None.

870.3700a Prenatal developmental toxicity in rodents (rat) 00131611 ( 1983 ) 93048023 (1990) Acceptable/guideline 0, 0, 100, 300 or 1,000 mg/kg/day from days 6 through 15 of gestation. Maternal NOAEL = 300 mg/kg bw/day. LOAEL =1,000 mg/kg bw/day, based on salivation.

Developmental NOAEL =1,000 mg/kg/day. This was the HDT; therefore, there is no LOAEL.

870.3700b Prenatal developmental toxicity in nonrodents (rabbit) 00131613 (1983) 93048024 (1990) Acceptable/guideline
0, 25, 100, or 400 mg/kg / day from days 6 through 18 of gestation. Maternal NOAEL =400 mg/kg bw/day This was the HDT; therefore, there is no LOAEL.

Developmental NOAEL =400 mg/kg bw/day. This was the HDT; therefore, there is no LOAEL.

870.3800 Reproduction and fertility

effects (rat) 41039505 (1987) Acceptable/guideline 0, 1,000, 5,000 and 10,000 ppm in the diet (equivalent to 0, 74.2,

380 .5, or 738 mg/kg bw/day for males and 0, 94.3, 471.2, or 933.3 mg/kg bw/day for females). Parental systemic, reproductive and offspring NOAEL =10,000 ppm (738 mg/kg bw/day in males 933.3 mg/kg bw/day in females). This was the HDT; therefore, there is no LOAEL.

870.4100a Chronic toxicity (rodent) NA; see 870.4300 NA

870.4100b Chronic toxicity (dog) 41039502 (1987) Acceptable/guideline
0, 1,000, 5,000 or 10,000 ppm (equivalent to 0, 25, NOAEL is =10,000 ppm (250 mg/kg/day)(HDT).

LOAEL. = None.

### Page 10 of 12

Table 3: Toxicity Profile of Imazapyr Technical.

Guideline No./ Study Type MRID No. (year)/

Classification/Doses Results

125 or 250 mg/kg/day) for 1 year.

870.4200a Carcinogenicity (rat) NA; see 870.4300

870.4200b Carcinogenicity (mouse) 41038505 (1988) 42774401 (1992) Acceptable/guideline
0, 1,000, 5,000 or 10,000 ppm (equivalent to 0, 126, 674 or 1,301 mg/kg /day in males and 0, 151,776 or 1,639 mg/kg /day in females) for 18 months. NOAEL =10,000 ppm (1,301 mg/kg/day in males and 1,639 mg/kg/day in females). This was the HDT; therefore, there is no LOAEL.

870.4300 Combined Chronic/Carcinogenicity (Sprague Dawley rat) 41039503 (1988) Acceptable/guideline 1
0, 100, 5000, 10000 ppm (M/F: 0/0, 49.9/64.2, 252.6/317.6, 503/638.6 mg/kg/day) NOAEL = 10000 ppm (M/F: 503/638.6 mg/kg/day.

LOAEL = None was shown, however a statistically significant (but within normal range) increase in BUN and a nominal decrease in body weight gain in males (2%)(may have approached a toxic dose) and a nominal increase (not statistically significant, pair wise) i n brain astrocytomas was seen in females, which the CARC classified as a “group E chemical”, no evidence of carcinogenicity in mice or rats. A 90

- day study in

rats showed no adverse effects at levels including the limit dose of 20,000 ppm (1000 mg/kg/day)

.

870.5100

Bacterial reverse mutation (Ames Assay) 00131615 (1983) 93048025 (1990) Acceptable /guideline Negative up to 5,000 μg/plate.

870.5300

In vitro mammalian cell gene

mutation 00151641 (1984) 93048028 (1990) Acceptable /guideline Negative up to cyto toxic doses (5,000 μg/m L ) with

and without activation.

870.5375

In vitro mammalian 00151640 (1984) 93048026 (1990) Negative up to cyto toxic doses (5,000 μg/m L ) with

and without activation.

### Page 11 of 12

Table 3: Toxicity Profile of Imazapyr Technical.

Guideline No./ Study Type MRID No. (year)/

Classification/Doses Results

chromosome aberration (CHO) Acceptable /guideline

870.5550 Unscheduled DNA synthesis (RPH) 00151639 (1984) 93048027 (1990) Acceptable /guideline Reported as negative (unacceptable, 1989), but considered acceptable in 1997. 2

870.5450

Rodent Dominant Lethal 00151638 (1985) Acceptable /guideline Reported as negative (unacceptable, 1989), but considered acceptable in 1997. 2

870. 62 0 0a Acute neurotoxicity screening battery (rat) 48469001 (2011) Acceptable /guideline 0, 200, 600 mg/kg NOAEL = ≥2000 mg/kg (HDT); therefore, there is

no LOAEL

870.6200b 90 Day neurotoxicity screening battery (rat) 48469001 (2011) Acceptable /guideline 0, 300, 1000 mg/kg/d (0, 89, 272, 924 mg/kg/d ♂; 0 92, 283, 933 mg/kg/d ♀) NOAEL ≥ 924 mg/kg/d (♂); ≥ 933 mg/kg/d (♀)
(HDT); therefore, there is no LOAEL

### Page 12 of 12

Table 3: Toxicity Profile of Imazapyr Technical.

Guideline No./ Study Type MRID No. (year)/

Classification/Doses Results

870.7485

Metabolism and pharmacokinetics (rat) 43861501 (1994) Acceptable

M&F: unlabeled or labeled imazapyr ~ 9.5 mg/kg or 924 mg/kg single gavage dose or as

14

- daily doses of unlabeled imazapyr followed by single labeled dose of 9.26 mg/kg.

M&F: 10 mg/kg labeled imazapyr single gavage

dose to measure excretion via expired air (pilot study).

M&F: 9.94 mg/kg labeled imazapyr by intravenous injection. No sex

- related differences in absorption were

apparent. Within 48 hours of treatment, >90% of

the administered dose was recovered in the excreta suggesting that elimination of the labeled test material was rapid. No specific sequestering tissues or organs were identified. Seven days after treatment, essentia lly all the test material had been eliminated. Rats that received the test material by intravenous injection excreted 87

- 95% of the administered dose in the urine and approximately 6% into the feces. This suggests that 15

- 28% if the

oral administered do se recovered in the feces represents unabsorbed material.

Metabolite characterization studies show that essentially all of the test material was excreted unchanged. Two minor metabolites CL 252,974 and CL 60,032 were detected in the urine or feces

of tr eated rats; however, their contribution

combined was < 0.5% of the administered dose. Up to 12 additional unidentified metabolites were isolated, but they constituted <3% of the administered dose. Based on the results, the study author suggests that what limited metabolism of CL 243,997 occurs, proceeds through hydrolysis to

form the 2

- carbonyl derivatives: CL 252,974 and
CL 60,032.

870.7600 Dermal penetration NA NA

870.7800 Immunotoxicity 48490102 (2011) Acceptable/guideline
0, 500, 1500, 5,000 ppm (equivalent to 0, 1 55

, 525 or 1, 668 mg/kg /day in

female mice ) NOAEL = ≥1,668 mg/kg/day; LOAEL was not

established.

1 The study is acceptable for regulatory purposes according to documentation in TXR# 0011692 (1995), TXR# 0051943 (2003), and TXR# 0011213 (1994).

2 Memorandum, dated 3/10/97, from Steve Robbins et al. of HED to Phillip Errico RD.