UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C
. 20460

MEMORANDUM Date : July 19, 2012 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

SUBJECT: Ethoprop, Immunotoxicity study in Rats PC Code: 041101 Decision No
. : 457676 Petition No. : N/A Risk Assessment Type: N/ A TXR No.: 0056382 MRID No.: 48632501 DP Barcode: 396215 Registration No. : N/ A Regulatory Action : N/A Submission No
. : N/ A CAS No.: 13194-48-4 40 CFR: N/A FROM: Y G Y PhD 

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- t¥ Risk Assessment Branch VI Health Effects Division (7509 P) THROUGH:

### F~**ecia** Fort, Chief 

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### ~'--..J! Risk Assessment Branch VI ..,.,...-**j....Jl}JICJ~Cfl..r** Health Effects Division (7509 P) TO: Monica Wait RMIB3 Pesticide Re-Evaluation Division (7508P) And Kit Farwell, DVM Risk Assessment Branch VII Health Effects Division (7509P) I. CONCLUSIONS The immunotoxicity study in rats for Ethoprop (MRID 48632501) has been reviewed. It is classified as acceptable/guideline and satisfies guideline requirements for an immunotoxicity study (OPPTS 870.7800)
.



### 1II. BACKGROUND and ACTION REQUESTED An immunotoxicity study on Ethopr op (MRID 48632501) has been subm itt ed. RAB VI was asked to review and prepare a DER for this study . III. RESULTS AND DISCUSSION The immunotoxicity study in rats for Ethoprop (MRID 4863250 1 ) has been reviewed. The DER is attached and an executive summary is as follows: EXECUTIVE SUMMARY: In an immunotox i city study (MRID 48632501), Ethoprop (96 .6% a.i., Batch no. PEA4000032) was administered to male Sprague-Daw le y (Crl:CD(SD)) rats (10/group) in diets at dose levels of 0, 5, 15, or 30 ppm (equivalent to 0.4, 1.2 , or 2.43 mg/kg/day, respectively) for 4 weeks. On Day 25, all anima l s in all groups received an intravenous injection of 2x 10 8 sheep red blood cells in 0.9% saline at the dose volume of 1.0 ml / animal. The positive control group consisted of 8 males received cyclophosphamide (50 mg/kg) by intraperitoneal i njec t ion on Day 27. The animals were monitored for mortality and for treatment related symp t oms twice daily. B ody weights were recorded on Day (-7) , Day ( -4 ), Day (1) and then twice weekly

until necropsy. Food consumption was recorded daily. Detailed clinical observations were done prior to the test s ub s tance administration and once every week till n ecropsy . During Week 4, blood samp le s were taken without fasting from the retro-orbital sinus from all animals under isoflurane anesthesia for blood (plasma and red b l ood cell)

cho lin esterase (ChE) analysis. On Day 29, animals were killed by carbon dioxide asphyxiation. All anjmals were subject to the detailed necropsy. Brains were processed and examined for cholinesterase activity. Spleens, thymus and brain from animals were weighed. Splenic tissues were used as the sources of splenocytes for conducting immunotoxicology investigations. There were no treatment related clinical signs, no effect on body weight a nd food and water consumption at dietary concentrations up to 30 ppm. However , t h ere were statistically significant reductions of erythrocyte acetylcholinesterase activity at 5 (p<0.05), 15 and 30 ppm (p<0.01). The percentage reduction for RBC ChE was 18%, 56% and 7 1 % at 5 , 15 and 30 ppm , respectively. There was a 1 3% reduction of brain acetylcholinesterase at 30 ppm. No treatment related effect on organ we i ghts and macroscopic pathology was found. The systemic toxicity LOAEL is 5 ppm (0.4 mg/kg/day) based on reduced red blood cell cholinesterase activity, the systemic toxicity NOAEL is not established(< 0.4 mg/kglday). Primary T-cell dependent antibody response to sheep RBC was ana l y z ed by modified Jeme P laque Forming Cell assay. There was no statistically significant decreased in both the specific activity (PFC / 1 0 6 cells) and total activity ( PFC / spleen) in treated groups when compared to the vehicle contro l group. There was a high inter-individua l variability noted in all the treatment groups as well as in the control group. Evaluation of individual 2animal data ofthis study did not show any trend or distribution that would demonstrate significant suppression ofanti-SRBC PFC response. Animals in positive control group, showed a statistically significant 

### (p<O.OO 1) decrease ofPFC response to a challenge with SRBCs in compared to the vehicle control group. This confirmed the ability ofthe test system to detect immunosuppressive effects and confirmed the validity ofthe study design. The Natural Killer (NK) cells activity was not evaluated in this study. The toxicology database for Ethoprop does not reveal any evidence of trea tment related effects on the immune system. The overall weight ofevidence suggests that the chemical does not directly target the immune system. Under HED guidance a NK cell activity assay is not required at this time. Under conditions of this study, the immunotoxicity NOAEL is 30 ppm (equivalent to 2.43 mg/kg/day), the highest tested dose. The LOAEL is not established (>2.43 mg/kg/day). This immunotoxicity study is classified acceptable/ guideline and satisfies the guideline requirement for an immunotoxicity study (OPPTS 870.7800) in rats.

3

### Etho ro I 

### 041101 Immunotoxicity (201 1) Page 1 of9 OPPTS 870.7800 I DACO 4.8 I OECD None 

### EPA Reviewer: Khin Swe Oo, MD. DABT 

### Signature:

_ __ """""''":----:---

- Toxicology and**Epi~emiology** 

### Branch, Health Effects Division (7509P)hte : 

## 7 j**~~ Jt** **ot'!J.** 

### . EPA Secondary Reviewer: Yung 

### G. Yang, PhD 

### Signature:**~** 

### 6:**~**-c:7 

### Risk Assessment Branch VI, Health Effects Division (7509P) Date: 

## 7 ;/l/ 2:9 1 

### vTemplate version 09/11 TXR #: 0056382 

### DATA EVALUATION RECORD STUDY TYPE: Immunotoxicity- 4 weeks Oral (Dietary) St udy; OPPTS 870.7800 

### PC CODE: 041 101 

### DP BARCODE: D 396215 

### TEST MATERIAL (PURITY) : Ethoprop (96.6% w/w) 

### SYNONYMS: Ethoprophos; 0-ethyl- S,S

-dipropyl phosphorodithioate. 

### CITATION: Arrowsmith W. (2011)
. Ethoprop: 4 -Week Dietary Immunotoxicity Study in Male Sprague

-Dawley Rat. Huntingdon Life Sciences, Woolley Road, Alconbury, Huntingdon, Cambridgeshire PE 28 4HS, UK. Project ID BDG0050. MRID 48632501, Unpublished. 

### SPONSOR: AMVAC Chemical Corporation, 4100 E. Washington Blvd., Los Angeles, CA 90023, USA. 

### EXECUTIVE SUMMARY: In an immunotoxicity study 

### (MRID 48632501), Ethoprop (96.6% a.i., Batch no. PEA4000032) was administered to male Sprague-Dawley (Crl:CD(SD)) rats (10/group) in diets at dose levels of 0, 5, 15, or 30 ppm (equivalent to 0.4, 1.2, or 2.43 mg/kg/day, respectively) for 4 weeks. On Day 25, all animals in all groups received an intravenous injection of2x108 sheep red blood cells in 0.9% saline at the dose volume of 1.0 ml/animal. The positive control group consisted of 8 males received cyclophosphamide (50 mg/kg) by intraperitoneal injection on Day 27
. The animals were monitored for mortality and for treatment related symptoms twice daily. Body weights were recorded on Day (

-7), Day (-4), Day (1) and then twice weekly until necropsy. Food consumption was recorded daily
. Detailed clinical observations were done pr ior to the test substance administration and once every week till necropsy. During Week 4, blood samples were taken without fasting from the retro-orbital sinus from all animals under isoflurane anesthesia for blood (plasma and red blood cell) cholinesterase (ChE) analysis. On Day 29, animals were killed by carbon dioxide asphyxiation. All animals were subject to the detailed necropsy. Brains were processed and examined for cholinesterase activity. Spleens, thymus and brain from animals were weighed. Splenic tissues were used as the sources of splenocytes for conducting immunotoxicology investigations. There were no treatment related clinical signs, no effect on body weight and food and water consumption at dietary concentrations up to 30 ppm. However, there were statistica lly significant reductions oferythrocyte acetylcholinesterase activity at 5 (p<0.05), 15 and 30 ppm (p<0.01). The percentage reduction for RBC ChE was 1 8%, 56% and 71% at 5, 15 and 30 ppm, respectively. There was a 13% reduction ofbrain acetylcholinesterase at 30 ppm. No treatmentEthoprop I 041101 Immunotoxicity (2011) Page 2 of 9 OPPTS 870.7800 I DACO 4.8 I OECD None related effect on organ weights and macroscopic patholog y was found . Th e systemic toxicity LOAEL is 5 ppm (0.4 mglkg/day) based on reduced red blood cell cholinesterase activity, the systemic toxicity NOAEL is not established(< 0.4 mglkg/day). Primary T-cell dependent antibody response to sheep RBC was analyzed by modified Jeme

Plaque Forming Cell assay. There was no statistically sign ificant decreased in both the specific activity (PFC/10 6 cells) and total activity (PFC/spleen) in tr ea t ed groups whe n compared to the vehicle control group. There was a high inter-individual variab ilit y noted in all the treatment groups as well as in the control group. Evaluation of individua l animal data of this s tudy did not

show any trend or distribution tha t would demonstrate significant s uppr ession of anti-SRBC PFC response. Animals in positive control group, showed a statist icall y significant (p<O.OOI) decre ase of PFC response to a cha llenge with SRBCs in compared to the veh icle control gro up. This confirmed the ability of the test system t o detect immunosuppressive effects and confirmed the validity of the study design. The Natural Killer (NK) cells activity was not evaluated in this study. The toxico lo gy database

for Ethoprop does not re vea l any evidence of treatment related effects on the immune system. The overall weight of evidence suggests that the chemical does not directly target the immune system. Under HED gu idanc e a NK cell activity assay is not required at thi s t ime. Under conditions of this study, the immunotoxicity NOAEL is 30 ppm (equivalent to 2.43 mglkglday), the highest tested dose. The LOAEL is not established (>2.43 mglkglday). Thi s immunotoxicity study is classified acceptable/ guideline and satisfies the guideline requirement for an immunotoxicity study (OPPTS 870.7800) in rats. COMPLIANCE : Signed and dated GLP, Quality Assurance, and Data Confidentiality s tat ements were provided.

### Ethoprop I 

### 041101 I. MATERIALS AND METHODS A. MATERIALS :
1. 

### Test material: Et hoprop 

### Immunotoxicity (2011) Page 3 of9 OPPTS 870
.7800 I DACO 4.8 I OECD None



### Description: Clear light yellow liquid 

### Lot/Batch#: PEA4000032 

### Purity: 96.6% (w/w) 

### Compound Stability: Stored deep frozen approximately at -20°C pending use. 

### CAS # 

### ofTGAI: 13194-48-4



### 2
. Vehicle and/or positive control: Rat and Mouse No.1 Maintenance Diet. Positive control group received cyclophosphamide monohydrate 50mg/kg, (Lot /Batch no. not reported), via intraperitonea l injection on Day 27 (2 days before termination).


### 3. Test animals : Species: Rats, male Strain: Sprague-Dawley Crl: CD(SD) Age/weight at the start oftreatment: 49-56 days; 233- 329 grams Source: Charles River (UK) Ltd
. Housing: Housed five animals per cage. Diet: Rat and Mouse No.1 Maintenance Diet, ad libitum Water: Public water supply ad libitum
Environmental conditions: Temperature: 19-23°C Humidity: 40-70%Ethoprop I 041101 Acclimation period: B. STUDY DESIGN:

Immunotoxicity (2011) Page 4 of9 OPPTS 870 . 7800 I DACO 4.8 I OECD None Air changes: Positive air pressure, not re-circulate 12 hrs dark/12 hrs light Photope r iod: 13 days 1. In life dates - Experiment Start: April1, 201 1 End: June 10, 2011 2. Animal assignment : Table 1. Study Design Group Dietary Treatment Dietary Cone. Achieved dosage No. of

No. (ppm) (m_glkglday) animals 1 Vehicle Control 0 0 10 2 Ethoprop 5 0.4 10 3 Ethoprop 15 1.2 10 4 Ethoprop 30 2.43 10 5 Positive control (CPH)b

-- 50° 8 • Data obtamed from pages 11 of the study report (MRID 48632501). • b Cyclophosphamide (CPH) was given to positive control group by intraperitonea l injection (50 mg/kg, 5mg/mL, lOmllkg) on Day 27. 3. Dose selection: It was reported tha t the dose levels were selected based on the findings from previous 28 day dietary toxicity studies (WIL-21199 and WI L -21200). In Project WIL -

21200, t he dietary concentrations used were 7.5, 15, and 30 ppm, and found low RBC ChE activity in males at 7. 5 ppm. I n Project WIL - 21199, the dietary concentrations were, 0 . 2, 0.5, and 1 ppm; and no treatment related findings at any dose l evel. 4 . Diet preparation and analysis: Diet was prepared week l y by preparing the premix and mixing it with an appropr i ate amount of basal diet to achieve the final concentrations. Prepared diet was stored deep frozen approximately at -20°C pending use. Resu l ts of Diet Analysis: Homogeneity analysis: CV <2%. Accuracy within 5% ofthe nomina l concentration Stability analysis: The mean analyzed concentration remained within 9% of the initial time zero. Concentration analysis: Concentration analysis showed ( + 10% to - 15%) of nominal concentrations. 5 . Statistics : It was reported that, treatment groups were compared using pairwise F isher's Exact tests (Fisher 1973) for each dose group against the control. If Bartlett's test for variance homogeneity (Bart l ett 1937) was not significant at the 1 %leve l , parametric _., . analysis (the FI approximate test) was app l ied. If the F 1 approximate test was significant, Dunnett's test (Dunnett 1955, 1964) was performed instead. If Bartlett's test was significant at the 1 % level, then logarithmic and square-root transformations were tried. If Bartlett's test was still significant, then non - parametric tests were applied. I f the HI approximate test for

### Ethoprop I 041101 

### Immunotoxicity (2011) 

### Page 5 of9 OPPTS 870.7800 I DACO 4.8 I OECD None monotonicity of dose-response was not significant at the 1 %level, Shirley's test for a monotonic trend (Shirley 1977) was applied. For organ weight data, analysis ofcovariance was initially performed using terminal bodyweight as covariate. If the within group relationship between organ weight and bodyweight was significant at the 10% level, then the treatment comparisons were made on adjusted group means in order to allow for differences in bodyweight which might influence the organ weights. Fisher's Exact tests (Fisher 1973) was performed for cholinesterase data if75% ofthe data (across all groups) were the same value. Treatment groups were compared with control group with pairwise comparisons. C. 

### METHODS: 1. 

### Observations : The animals were monit ored for morbidity and for treatment related symptoms twice daily. Detailed clinical observations were done before the test substance administration and once every week till necropsy. 

### 2
. Body weight: Body weights were recorded before test substance administration (Days -7 and

-4) and then twice weekly from Day 0 until necropsy. 

### 3
. Food/water consumption and compound intake: Food consumption was recorded weekly. Water consumption was observed daily. 

### 4. Sacrifice and pathology: On Day 29, animals were sacrificed by carbondioxide asphyxia tion.


### a. Gross necropsy: all animals were subjected to a necropsy; brain, spleen and thymus were weighed. Spleen samples were taken for immunotoxicology investigation and brain was processed and examined for cholinesterase activity. 

### b. Tissue preparation/histopathology: histology was not performed. 

### 5
. Immunotoxicitv:
a. Plague Forming Cell (PFC) Assay: T-lymphocyte-dependent antibody response to sheep red blood cells is evalua ted with PFC assay. Animals were exposed to the test substance for 4 weeks except vehicle control and positive control groups . On Day 25, all animals in all groups were injected intravenously into the tail vein with sheep red blood cell (2x 108 SRBC) in 09% saline (1.0 ml/animal). On Day 27, animals in positive control group were treated with immunosuppressant cyclophosphamide 50 mg/kg (5mg/ml solution at lOml/kg b.w.) via intraperitoneal injection. At termination, the spleens from the animals were removed and a single cell suspension was prepared from each animal by mechanical dissociation. Cells were counted and diluted to an appropriate concentration for the assay. The spleen cells were then mixed with an agar matrixEthoprop I 041101 Immunotoxicity (2011) Page 6 of9 OPPTS 870.7800 I DACO 4.8 I OECD None containing a suspension of the SRBC s and guinea pig serum complement. This mixture was poured into Petri dishes, allowed to set and incubated for up to 3 hours. Individual B lymphocytes s ecreting antibodies to SRBCs formed smal l foci where antibody-dependent, complement-mediated lysis occurred. The number of lytic plaques for ea ch animal was determined and g r o up mean responses calculated. b. Na tural Killer (NK) Cells Activity Assay: N K cells assay was not p er formed. II. RESULTS: A. OBSERVATIONs: 1. Clinical signs of toxicity: There w e re no treatment related signs and sym ptoms in treated grou ps. 2. Mortality: Ther e were no premature death s. B. Body weight and weight gain: No treatment related effects o n body weight and body weight gain (Table 2). TABLE 2. Average body weights and body weight gains during 28 days of treatment Ethoprop Body weights (g ± SD) Dose (ppm) D ay 1 Da yl5 0 ( vehicle control ) 272±20. 8 373±27.4 5 274±2 6.1 376±40.1 IS 28 8 ± 23 .2 381±35.9 30 245± 14.5 370 ± 20.3 Data obtamed from page 33 m the study report . n = l 0 anima ls per gr oup .

D ay22 410±32. 1 414±4 8.5 420±4 0.6 406±24 . 0

Da y29 43 8 ±33.3 446 ± 50 . 0

45 1 ± 44.4 433±26.1 C. FOOD/WATER CONSUMPTION AND COMPOUND INTAKE: 1. Food consumption: No differences in food co n sum p t ion in al l g r o up s.

Total weight gain (g ± SD) (Days 1- 29) 1 65 ±23.9 172±29.0 163±25.5 153 ± 15.3 2. Water consumption: There was no effect of treatment on water consump tion. 3. Compound consumption: includ ed in Table 1. 4. Food efficiency: Did not report. D. GROSS NECROPSY: N o treatment r elated macroscopic changes at n ec rops y . 1. Organ weight: Th ere we re no brain , th y mu s an d sp leen weight d i fferences in treated groups when compared to the vehi c le control group ( Tab l e 3).Ethoprop I 041101 Immunotoxicity (2011) Page 7 of9 OPPTS 870.7800 I DACO 4.8 I OECD None Table 

### 3. Mean terminal body weight and Organ weights, Mean±SD Dose Group Body weight (g) Brain (g) Spleen (g) Thymus (g) (ppm) Vehicle Control 436±33 2
.04±0
.09 0.862±0.197 0.489±0.138 5 445±50 2
.00±0.07 0.915±0.192 0.481±0.163 15 449±45 2.07±0.08 0.952±0.145 0.454±0.109 30 433±26 2.17±0.3 0.850±0.136 0.465±0.111 InformatiOn was obtamed from page 36 ofthe study report 2. Histology: No report on histology 

### 3. Blood and brain cholinesterase: Erythrocyte acetylcholinesterase activity was statistica lly significantly reduced in a dose

-related manner in all treated groups when compared to the vehicle control group (18%, 56% and 71% reduction at 5, 15 and 30 ppm groups, respectively). Brain acetylcholinesterase activity was significantly reduced at 30 ppm (p<O.O l ) (Table 4). Table 4. Blood and brain cholinesterase (ChE) activities

Dose Group (ppm) Blood ChE (U/L) 0 1832.5*±364.2 5 1497.5±496.3 15 797
.5**±272.7 30 522
.5**±248.7 Data extracted from page 35 ofthe study (n= l O) *P<0
.05; ** p<O.Ol E
. IMMUNOTOXICITY TESTS: Brain ChE (U/kg) 24155±907.2 23425± 1109.1 23260±984.3 21 090**±1013.5



### 1. Plague forming cell assay (PFC) : There were no stat istically significant changes in the PFC response to sheep red blood cells, in all treated groups when compared to the vehicle control group (Table 5). There was a high inter

-individual variability noted in all the treatment groups as well as in the control group. Evaluation ofindividual animal data ofthis study did not show any trend or distribution that would demonstrate significant suppression ofanti-SRBC PFC response (Figures 1 and 2). Treatment with cyclophosphamide resulted in almost complete reduction ofthe PFC response, both as PFC/106 cells or PFC/spleen (p<O.OOl). Table 

### 5
. Results of plaque forming cell assay (mean± SD) Group (ppm) Cells/spleen (107) PFC/106 cells PFCispleen 0 37 .94± 16.94 657.8±217.2 251642±128579 5 33.89±17
.76 611.8±611.8 193082±114327 15 4 1.13±17.1 6 826
.3±733
.9 269062±116755 30 33 .61± 12.45 525.0±296.0 193996±165671 Positive control 9.89
.. .±3.28 23.8
. .. ±17.7 2231'"±1576 Data extracted from page 115 ofstudy report.

.. p<O.Ol. ••• p< O

.OOI.Ethoprop I 041101 Immunotoxicity (2011) Page 8 of 9 OPPTS 870.7800 I DACO 4 . 8 I OECD None Fieu re 1: Individual animal data of specific activity ( PFC/10 6 cells) 3000.0 2500.0 .. 'ii Q 2000.0**~** i 1500.0 u ... 0.. 1000 .0 500.0 0.0 0 Key :

G r oup I • Conlrol, 0 ppm Group 2**~** ETHOI>KOP. S ppm Group 3 = ETiiOPROP, 15 ppm Group 4**~** E ' IHOPROP, JO ppm

• • . T • Group S - Cyclophosphamide, SO mt/k{'.

• • • • • • • • T l .L • • • .... 2 3 Mole group 4 5 Data extracted from page 113 of the study report. Fieure 2: Individual animal data of total activity (PFC/spleen) 600000 500000 c : 400000 ii. .. ! 300000 u ... 0.. 200000 100000 0 0 Key : Group 1 - Conrr<>l, 0 ppm Gr<>up 2 = ETHOPROP , S prm Group 3 • ETHOPROP, 15 ppm Group 4 = ETHOPROP, 30 ppm

• • • • • • • • • Group S = Cyc l ophos p hamide , SO mglkg

• • • • • • • • ... • • f • • 2 3 M .. •group Data extracted from page 114 of the study report.

• • • - • i • 4 5 2. NK cell activity assay: Did not perform NK cell assay. III.DISCUSSION AND CONCLUSIONS: A. INVESTIGATORS' CONCLUSIONS: It is concluded that dietary administration of Ethoprop to male Sprague -Da wley r ats at 5, 15 and 30 ppm for four weeks ca u sed no to xicologically significant findings. There was no suppress ion of imm une func t ion . The NOAE L for immunotoxicity was greater than 30 ppm (> 2.43 mg/kg/day).

### Ethoprop I 

### 041101 Immunotoxicity (2011) Page 9 of9 OPPTS 870
.7800 I DACO 4.8 / OECD None


### B. REVIEWER COMMENTS: In an immunotoxicity study (MRID 48632501), Ethoprop (96.6% a.i., Batch no. PEA4000032) was administered to male Sprague-Dawley (Crl:CD(SD)) rats (10/group) in diets at dose levels ofO , 5, 15 , or 30 ppm for 4 weeks. On Day 25, all animals in all groups received an intravenous injection (by bolus) of2x108 sheep red blood cells in 0.9% saline at the dose volume of 1.0 ml/animal. The positive control group consisted of 8 males received 50 mglkg cyclophosphamide (CPH) by intraperitoneal injection on Day 27. The re were no treatment related effects on clinical signs, body weight, food, and water consumption at dietary concentrations up to 30 ppm. However, there were statistically significant reductions oferythrocyte acetylcholinesterase activity at 5 ( p<0 .05 ), 15 and 30 ppm (p<O.Ol). The percentage reduction for RB C ChE was 18%, 56% and 71% at 5, 15 and 30 ppm, respectively. There was a 13% reduction ofbrain acetylcholinesterase activity at 30 ppm. No treatment related effect on organ weights and macroscopic pathology was found. 

### The systemic toxicity LOAEL is 5 ppm (0.4 mg/kg/day) based on reduced red blood cell cholinesterase levels , the systemic toxicity NOAEL is (<0.4 mglk
. g/day). Primary T-cell dependent antibody response to sheep RBC was analyzed by modified Jeme Plaque Forming Cell assay. There was no stati stica lly significant decreased in both the specific activity (PFC/ 1 06 cells) and total activity (PFC/spleen) in treated groups when compared to the vehicle control group. There was a high inter-individual variability noted in all the treatment groups as well as in the control group. Animals in positive control group , showed a statistically significant (p<O.OOl) decreased PFC response to a challenge with SRBCs in compared to the vehicle control group. This confirmed the ability ofthe test system to detect immunosuppressive effects and confirmed the validity ofthe study design. The Natural Killer (NK) cells activity was not evaluated in this study. The toxicology database for Ethoprop does not reveal any evidence oftrea tment related effects on the immune system. The overall weight ofevidence suggests that the chemical does not directly target the immune system. Under HED guidance a NK cell activity assay is not required at thi s time. 

### Under conditions of this study, the immunotoxicity NOAEL is 30 ppm (equivalent to 2.43 mglkglday), the highest tested dose
. The LOAEL is not established (>2.43 mglkglday)
. C. STUDY DEFICIENCIES: Body weight, body weight changes, and organ weights of the positive control (cyclophosphamide) group was not reported.