Document ID: EPA-HQ-OPP-2012-0128-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-10-16T04:00Z

Powdered corn cobs								
								DP Number(s): 394414
PC Code: 006154 cellulose
(corn cob doesn't have PC code) 						EPA Reg. or File Symbol No: 84889-E
      	
   
       UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
       		     WASHINGTON, D.C. 20460
      
	OFFICE OF CHEMICAL SAFETY AND POLUTION PREVENTION/OFFICE OF PESTICIDE PROGRAMS        	

MEMORANDUM

DATE:		4/25/12

SUBJECT:	Science review of Rodetrol performance against rats and mice.  The active ingredient in the product is powdered corn cobs, containing 45.1% w/w cellulose. 

            
            Decision Number: 	447148
            DP Number: 	394414			
            EPA File Symbol Number: 	84889-E
            Chemical Class: 	Biochemical			
            PC Code: 006154 cellulose (corn cob doesn't have PC code)				
            CAS Number:  9000-11-7 cellulose (corn cob doesn't have CAS No.) 				
            Active Ingredient: powdered corn cobs			
            Tolerance Exemptions: Non-food	
				MRID Numbers: 484335-05; 484335-17 to 484335-24, and 484335-39
                                                                  
FROM:		Clara Fuentes, Ph.D. Entomologist 	
            Biochemical Pesticides Branch
            Biopesticides & Pollution Prevention Division (7511P)

TO:			Leonard Cole, Regulatory Action Leader
            Biochemical Pesticides Branch
            Biopesticides & Pollution Prevention Division (7511P) 

ACTION REQUESTED

Rodetrol, LLC. is requesting registration of Rodetrol to be used as a rodenticide against rats and mice.  In support of registration, the registrant has submitted summaries of product performance 

studies in MRIDs 484335-17 in 484335-24, conducted on the same formulation under laboratory conditions to support indoor use of the product.

RECOMMENDATIONS AND CONCLUSIONS

Product Performance:  Acceptable.  Sufficient information is provided in MRIDs 484335-17 to  484335-24 showing that the proposed product kills rats and mice when fed exclusively on the product for a period of approximately 7 days for rats and 3 days for mice.  The submitted efficacy data are summary of laboratory studies conducted on the same formulation under different trade names.  The product causes physical disruption of the feeding mechanism in rats and mice.  Mortality is caused by dehydration and malnutrition, however, several postulated pathological pathways were investigated and none were established as the physiological mechanism leading to these lethal outcomes.  It is unknown how normal food consumption in addition to Rodetrol would have influenced product performance since the mortality effects of Rodentrol were tested by feeding the rodents exclusively on the product. 

MRIDs 484335-39 and 484335-05 are supplemental.
 
Note to RAL:   

Label language restrictions concerning efficacy claims supported by data:

Experimental results correspond to experimental conditions of feeding caged rodents exclusively on the product over different periods.  In reality, free rodents are most likely to feed on additional food items so, the minimum periods for maximum efficacy reported on label and supported by data are the outcome of artificial rather than real conditions.  Therefore, it is uncertain whether the minimum period of 8 and 3 days for maximum efficacy on rats and mice, respectively, reflect actual performance of the product on free rodents.  The label should clarify that those measures of efficacy reflect ideal conditions and that optimal product performance may differ under actual conditions of food consumption by free rodents.  Due to the above explanation plus results from supplemental field tests in MRIDs 484335-39 and 484335-05, the word "control" should not be allowed on the label.  Data indicates that the product reduces rodent population in infested areas but there is no conclusive proof that it kills 100% of free rats or mice infesting structures within 8 or 3 days, respectively.  To test that, the researcher would have to conduct a different experiment designed to determine the optimal consumption level of Rodetrol in a mixed diet.

STUDY SUMMARIES

MRID484335-17:  Efficacy of Eradirat against Sprague-Dawley laboratory rats and Assessment of mode of Action and Effects.

The report is a summary of a lab test conducted to assess the effectiveness of the Eradirat in causing mortality inlaboratory rats, and to investigate its mode of action.  Eradirat formulation is substantially similar to the proposed product, Rodetrol.  The test organism was the Sprague-Dawley rat, Rattus norvegicus. Twenty two rats of equal sex ratio were acclimated for 2 weeks prior to study initiation.  The rats were 6 weeks old when testing began.  A group of 16 rats, 8 males and 8 females, were fed Eradirat for 8 days in the absence of other food.  A control group of 6 rats, half males and half females, were fed with rodent diet for the same time period.  Consumption was measured daily.  Body weight was recorded following treatment.  Blood samples were collected daily and analyzed for haematological and biochemical paramaters used in clinical diagnosis.   All rats fed Eradirat died within 6 days (ranging between 4 to 8 days) of treatment.  Consumption of the product was  low relative to consumption of rodent diet by rats in the control group.  Treatment rats lost an average of 34.8% body weight following treatment while control rats gained 20.5% on average.  Haematological analyses indicated elevated concentrations of red blood cells and haemoglobin, and decreasing concentrations of other blood parameters (mean cell volumes, white blood cells, and mean corpuscular haemoglobin.  Biochemical analyses of serum samples indicated elevated concentration of other parameters in treated rats.  Treated rats dehydrated and emaciated, with evidence of internal haemorrhage.  Bladder contained no urine, and small intestine contained undigested solid material from bait.  The researchers concluded that consumption of the bait caused dehydration through several proposed and unconfirmed mechanisms.  Dehaydration triggers a cascade of physiological events that culminate in death by heart failure.
The report includes a list of references from the scientific literature.  No information on animal husbandry and ambient laboratory conditions is provided.   The report includes post mortem reports of pathology, and a couple of diagrams describing postulated lethal physiological pathways.  Treatment means, with their associated standard deviations, for haematological parameters, body mass, food and water consumption are presented in graphs.

MRID 484335-18:  Efficacy of Eradirat against Sprague-Dawley Rats

This is a laboratory study designed to determine the effectiveness of Eradirat in causing mortality in laboratory-reared Sprague-Dawley rat, Rattus norvegicus.  The study is a duplicate of another study conducted by Celsis Laboratory Group (Kable, 2002) designed to meet the same objective.
Twenty four rats, half males and half females, 4 weeks old and weighing approximately 123 g. that ranged from 108 to 136 g, were received from Hercus Taeri Resource Unit in New Zealand, and acclimated for 7 days prior to test initiation.  Rats were caged individually in rack-mounted cages of 1,400 cm[2] area.  The animals were maintained at temperature of 21.6 C° +- 2 C°, RH 27-48 % and light cycle of natural photoperiod.   All rats were fed Purina Lab Diet and provided with water at libitum.  Eighteen rats, half males and half females, were randomly divided into treatment and control groups. Twelve rats were assigned to treatment group, and 6 others to control (50:50 sex ratio).  Treatment rats were fed exclusively on Eradirat until death of all rats, which took 5 days for the last rat in the treatment group.  Control rats were fed Purina lab diet throughout the test period.  
The following parameters were measured to assess efficacy: mortality, behavior, body weight, food and water consumption, and pathology.  Observations were recorded twice daily, in the morning and afternoon always at the same time.  Body weights were recorded on days 1, 2, 4 and 7 during acclimatization and at the end of study.  Food and water consumption were measured daily from third day of study initiation and always at the same time.  All treated, plus one pair of male and female control rats were autopsied for determination of gross pathology.  The data was analyzed by comparison of treatment means.  Standard deviations of the means were reported.   All rats died between 3.5 and 5 days.of daily feeding exclusively on Eradirat.  The average for both sexes was 4 days.  The time period between the first symptoms and death was 12 hours.  The symptoms were piloerection followed by progressive lethargy and deteriorating coordination.  At death, most rats had traces of blood aroud snout and urogenital area.  There was no mortality or abnormal behavior among control group rats.  All treatment rats experienced 20 to 25% weight loss while control rats increased their weights 10 to 20% in 5 days.  Rats in treatment group showed an abrupt decline in food consumption of 5 to 7 g. while food consumption remained stable among controls, 20 g. for males and 15 g. for females throughout the test.  The same trend was observed among treated and control rats regarding water consumption.  Pathological examination revealed poor conditions among treated rats.  Visible behavioral symptoms appear only at the final half day before death.  The researchers concluded that the product caused rat mortality most likely from dehydration.  The study reports a couple of minor deviations from the Celsis (Kable, 2002) study regarding rats mean body weights, controlled temperature and RH that are unlikely to compromise test results.  Raw data are not included in the study report.  The study report provides identification of the test substance as Eradirat, a pellet bait consisting of plant material with no conventional pesticides.  

MRID 484335-19:  Confirming Effects of Eradirat on Rats when Fed ad libitum  

The study was conducted under laboratory conditions to confirmed the performance of Eradirat, formulation 3, on Sprague Dawley rats fed at libitum with the product for a period of 14 days.  Test animals were individually caged and fed Purina Rodent Chow for 7 days acclimatization period.  Animals were observed daily for general health, food consumption.  Twenty and 10 healthy rats (50:50 sex ratio) were randomly assigned to the treatment and control groups, respectively.   Rats age are not reported.  Initial weights ranged from 115 to 132 g. in females, and 99 to 123 g. in males.  Observations included food and water consumption and body weights, recorded daily.  Clinical and behavioral observations were recorded twice daily.  Dead or euthanized rats were examined for gross necropsis.  Results show that all 20 rats died in the treatment group after 5 days of treatment.   Only data summaries are reported.  Treatment means were not subject to statistical analysis for comparison.  

MRID 484335-20:  Efficacy of Eradimouse against Norway Rats

This is a laboratory study to assess the effectiveness of Eradimouse against non-acclimatized feral Norway rats; specifically, the project is designed to investigate the mode of action of the product through pathological observations and microbiological cultures.  It is postulated that certain type of bacteria might be involved in the cause of death.  In particular, Clostridium perfringes was identified by Coerze (1999) as a possible mortality agent.  The test material used was Eradimouse, `formulation 3,' which is the same formulation as Eradirat in smaller pellet.  Wild-trapped rats were caged in 1,400 m[2] metal cages in the lab and kept at 20 to 25 C°,  RH = 30 to 35 %, and natural summertime photoperiod.  Twenty five wild rats were brought into captivity but not acclimatized before testing to avoid the possibility that key intestinal bacteria may be lost during acclimation to the sterile conditions of the laboratory environment.  Twenty rats were randomly assigned to treated and control groups. The treatment group consisted of 20 rats, 12 males and 8 females.  The control group consisted of 5 rats, 4 males and 1 female.  Treatment rats were fed exclusively on Eradimouse while control rats were fed on rodent diet pellets.  Daily food consumption was estimated to the nearest 0.1 g.  from the weight of food remaining after each 24 hours period.   Body weights were recorded at beginning of trial and on death or end of testing.  Doses of ingested product were calculated dividing total consumption (corrected for weight changes in control samples) by mean values of beginning and ending body weights.  Post-mortum examination was conducted for gross pathology and bacterial cultures.  Sixteen rats died after consuming doses from 0.05 to 0.34 g of product/g of body weight.  There was no mortality among control rats.  Control rats consumed on average five times more food than treated rats.  Wild rats showed considerable variability in their susceptibility to the Eradimouse.  Blood loss from the stomach was the only consistent symptom.  Gross pathology and intestinal micro-organisms were normal.  Eradimouse killed most rats in less than 14 days, approximately within 5.6 days of treatment.  On average, treatment rats weighed less than controls (start weight of treated rats = 153  +- 15.1g., n = 20; start weight of controls = 203.6 +- 22.6 g., n = 5).  Average final weight among treated rats = 121.9 +- 12.8 g.  Average final weight among controls = 237.3 +- 26.7 g.  On average, treated rats lost 21.4% of their initial weight by the end of the trial while controls gained 10. 9% by end of trial.  Average food consumption among controls was 169.2 (average dose = 0.75 g/g).  Average food consumed among treated rats was 18.7 g (average dose = 0.14g/g).  Minimum lethal dose ranged from 0.2 to 0.3 g/g b.w.  The lethal mechanism of the product remains unclear.  Rats ate very little of the product and loss considerable weight.  Use of wild rats did not result in unusual proliferation of intestinal bacteria.  

MRID 484335-21:  Efficay of Eradimouse against Wild House Mice

This is a laboratory study to assess the efficacy of Eradimouse pellets against wild house mice, Mus musculus; specifically, the project is designed to investigate the mode of action of the product through pathological observations and microbiological cultures.  It is postulated that certain type of bacteria might be involved in the cause of death.  In particular, Clostridium perfringes was identified by Coerze (1999) as a possible mortality agent.  Thirteen wild caught mice were acclimatized for 4 weeks in captivity.  Mice were caged individually in 1,400 cm[2] area cages and maintained at temperature ranging from 20 to 25 °C, RH = 30  -  50%, and light cycle of natural summertime photoperiod.   All mice were fed on standard rodent diet during acclimatization period.  Ten mice, half male and half female, were randomly assigned to the treatment group and fed exclusively on Eradimouse for 14 days trial.  The control group consisted of 3 female mice fed on rodent dietary pellets throughout the trial.  Daily food consumption was estimated to the nearest 0.1 g. from the weight of food remaining in feeding containers every 24 hours.  Body weights were recorded at beginning of trial and at the end.  Doses of ingested product were calculated dividing total consumption (corrected for weight changes in control samples) by mean values of beginning and ending body weights.  Post-mortum examination was conducted for gross pathology and bacterial cultures.  Mortality was 100% among treated mice.  The lowest lethal dose was 0.3 g/g body weight.  There was no mortality among the control mice.   On average, control mice consumed about 3 to 6 g. of food daily while treated mice consumed approximately 1 to 3 g of product daily.  Treated mice lost 28.8% of body weight in around 3.8 days from beginning of trial while controls lost 5.5% body weight over 14 days since test initiation.   The lethal mechanism of the product was not established without indication of Clostridium perfringes as a possible mortality agent.

MRID 48433522:  Effects of Eradimouse on Mice when Fed ad libitum

The study was conducted under laboratory conditions to confirm the effectiveness of the product to cause mortality on lab-reared mice, Non-Swiss Albino, fed on the product for 14 days.  Ambient laboratory conditions are not reported.  The report indicates that the animals were maintained according to the Guide for the Care of Laboratory Animals (NRC, 1996).  Twenty mice, half male and half females were randomly assigned to the treatment group.  The control group consisted of 10 mice, half males and half females.  Treated mice were fed exclusively on the product while control mice were fed Purina Rodent Chow throughout the test.  All mice were individually caged and fed on certified Purina Rodent Chow for 7 days prior to beginning of testing.  During the acclimatization period, food and water consumption were monitored daily.  All mice were observed daily for health and suitability to testing.   After the acclimatization period, the initial body weight of female mice ranged from 24 to 30 g. and from 26 to 32 g. for males.  Feed and water consumption were estimated daily throughout the test period.  From day 1 to day 7 of testing, mice were observed towice a day for pathological and behavioral symptoms.  From day 7 of testing, control mice were observed once daily.  Body weight was recorded daily.  Post-mortum examination for gross necropsy was conducted on all mice at the end of the test.  No Microbiology or histology was performed for this study.  Death occurred within 7 days among treated mice.  Necropsy observations were normal among test and control animals.  Data on body weights, food and water consumption, were summarized and tabulated.  No statistical analysis for comparison of treatment means is reported.  

MRID 484335-23:  Efficacy of Eradimouse against Feral House Mice

The test was conducted in the laboratory to assess the efficacy of Eradimouse against feral house mice, Mus musculus, and investigated the mode of action of the product through pathological observations and microbiological cultures.  Thirteen wild trapped mice were acclimatized to captivity for 4 weeks.  They were  individually caged in 1,400 cm[2] area cages at ambient controlled temperature ranging from 20 to 25 °C, RH = 30 to 50%, and natural summer time photoperiod.  Ten mice, half male and half female, were randomly assigned to the treatment group.  The control group consisted of 3 males.  Treated mice were fed exclusively on the product.  Control mice were fed rodent dietary pellets.  The trial lasted 14 days.  Daily food consumption was estimated daily from the weight of food remaining after each 24 hour period.  Body weights were recorded at beginning and end of trial or upon death.  Doses of product were estimated by dividing the total consumed (corrected for weight changes in control samples) by the mean value of beginning and ending body weights.  Two dead mice from treatment group were submitted to post-mortum examination for gross pathology and bacterial cultures from the upper and lower intestine.  Mortality was 100% among treated mice.  The lowest lethal dose was 0.3 g/g body weight (about 6 g/20 g body weight).  There was no mortality among controls.  Control mice consumed an average of 3 to 6 g of food daily.  Treated mice consumed an average of 1 to 3 g of product per day.  Control mice lost an average of 5.5 % body weight during 14 days of trial.  Treated mice died around 3.8 days post treatment, and lost 28.8% body weight.  Cause of death was not established.  

MRID 484335-24:  Trials to Support Registration of Rode-Trol Time to Death Efficacy (Rats and Mice)

This is a laboratory test conducted on rats and mice to determine the time it takes for the product to cause mortality in rats and mice when fed exclusively Rodettrol followed by rodent food pellets.
 The species of rats tested was Ratus norvegicus obtained from lincesed supplier Harlam, USDA.  The mice were not derived from a  specific strain, and no information is provided about their source.  The same husbandry procedures were followed for rats and mice.  Only healthy young adult rats, never tested before, were selected for the experiment.  Their initial weight ranged from 115-125 for males, and 115-125 for females  (+- 20% of average weight).   Upon their arrival to the test facility, the rats were paired with others of the same sex, and assigned to clean stainless steel wire mesh cages in a temperature controlled room. No information is provided on the size of the cages or ambient conditions such as temperature, light cycle, and relative humidity.  

The rats were allowed to acclimate to the testing facility for 10 days prior to test initiation.  The control group was fed Purina rodent feed (guinea pig pellets), and the experimental group was fed on Rodetrol Rat pellets.  Water was available at libitum.  The experimental design is described as having 5 treatments, replicated 4 times.  Each replicate consisting of  2 cages, each cage containing 1 pair of male and female rats per cage for a total of 16 rats (8 males and 8 females).  The total number of male and female rats employed in the experiment was 80; 40 of either sex.  Treatments from 1 to 5 differ in number of days rats were fed Rodetrol.  Rats in treatment 1 were fed Rodetrol for 6 days.  Rats in treatments 2, 3, 4, and 5 were fed Rodetrol daily for 7, 8, 9 and 10 days, respectively.  There were 2 controls.  One control was fed Purina rodent pellets, and the other was kept unfed.  Observation lasted for 20 days.

The same experimental procedure was conducted on mice weighing approximately 30 grams (+- 10%) at beginning of the experiment.  No information is provided on the source of the mice, their age or health status.  Each experimental and control group was replicated 4 times as described on the above paragraph.  Each replicate consisted of 1 cage housing 1 pair of same sex mice per cage.  As described, individual pairs of same sex mice per cage were randomly assigned to each treatment replicate for a total of 8 mice (4 of either sex) per control treatment. Experimental treatments 1, 2, 3, 4, and 5consisted of mice fed daily on Rodentrol for 1, 2, 3, 4 and 5 days, respectively.

Results are tabulated on separate tables for time to death for rats and mice.  Rat mortality was the highest, around 100%, at treatments 3, 4, and 5 for rats fed daily on Rodetrol for 8, 9 and 10 consecutive days.  There was no mortality among control rats fed on Purina rodent pellets.  Mortality was 50% among unfed control rats.  

Experimental and control mice show the comparable results.  Mortality was the highest, around 100%, at treatments 3, 4, and 5 for rats fed daily on Rodetrol for 3, 4 and 5 consecutive days.  There was no mortality among control mice fed on Purina rodent pellets.  Mortality was 50% among unfed control mice.  

The researcher concludes that Rodetrol induces mortality in cage rats and mice over time of consecutive feeding exclusively on the product.  It takes a minimum of 8 and 3 days of continuous feeding to induce mortality in rats and mice, respectively.  

cc: Clara Fuentes, RAL , BPPD Chron File, IHAD/ARS
	FT, PY-S: 4/25/12