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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

OFFICE OF PREVENTION, PESTICIDE

 AND TOXIC SUBSTANCES

MEMORANDUM

Date: December 23, 2009

SUBJECT: Fluopyram - ToxSAC Meeting on July 16, 2009

PC Code: 080302 DP Barcode: NA

Decision No.: NA Registration No.: NA

Petition No.: NA Regulatory Action: NA

Risk Assessment Type: Single Chemical Aggregate Case No.: NA

TXR No.: NA CAS No.: NA

MRID No.: NA 40 CFR: NA

 

FROM: Jessica Kidwell, ToxSAC Executive Secretary

Health Effects Division (7509P)

THROUGH: Elizabeth Méndez, ToxSAC Chair

Health Effects Division (7509P)

TO: Myron Ottley, Toxicologist

RAB III, Health Effects Division (7509P)

ToxSAC Meeting Notes for 7/16/09 Meeting on Fluopyram

Team Members: Myron Ottley, Toxicologist

ToxSAC Members: Judy Facey, Jessica Kidwell, Marquea King, Elizabeth Mendez, Whang 

Phang, Elissa Reaves, Jessica Ryman, Ed Scollon

Other Attendees: Marion Copley (HED/SIMB), Barry O’Keefe, Paula Deschamp
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A. ENDPOINT SELECTION

The ToxSAC was requested to provide comments on the points of departure selections and 

proposed Endpoints for the fluopyram risk assessment.

ToxSAC Response: The ToxSAC recommendations for endpoint selection are below.

Dietary Exposure Endpoints

Acute Dietary (General Population, including infants and children): The acute neurotoxicity

study in rats was selected for the acute dietary exposure scenario for the general population, 

including infants and children. The point of departure (POD) was a NOAEL of 50 mg/kg/day. 

The LOAEL of 125 mg/kg/day was based on decreased motor and locomotor activity in female 

rats. This acute endpoint is appropriate for the route and duration of exposure as well as for the 

population of concern. 

An overall safety factor of 1000 should be applied (100X for inter- and intra-species variability, 

The FQPA safety factor of was retained in the form of a database uncertainty factor (UFdb) of 

10X for lack of a comparative thyroid assay. 

aRfD= 50 mg/kg/day = 0.050 mg/kg/day

1000 (includes UFdb of 10x)

aRfD = aPAD

Acute Dietary (Females 13-49 years old): An acute dietary endpoint for females 13-49 years 

old was not identified. No prenatal or fetal toxicity was observed in developmental or 

reproductive animal studies that could be attributed to a single dose. In the absence of a hazard 

for this population, risk estimates need not be conducted for this exposure scenario.

Chronic Dietary (all populations): The chronic toxicity/carcinogenicity study in rats was 

selected for the chronic dietary exposure scenario for all populations. The POD was a NOAEL of 

1.2 mg/kg/day. The LOAEL of 6 mg/kg/day was based on nephropathy, follicular cell 

hypertrophy in the thyroid, and increased liver weight with gross pathological histopathological 

findings. This endpoint is appropriate for the duration and population of concern. The POD from 

the rat will be protective of thyroid effects (thyroid hyperplasia and thyroid follicular cell 

tumors) seen in mice.

An overall safety factor of 1000 should be applied (100X for inter- and intra-species variability, 

and a database UF of 10X for a lack of a comparative thyroid assay. The FQPA safety factor 

was retained in the form of a database uncertainty factor (UFdb) of 10X for lack of a 

comparative thyroid assay. 
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cRfD= 1.2 mg/kg/day = 0.0012 mg/kg/day

 1000

cRfD = cPAD

Residential Exposure Endpoints

Incidental Oral Exposures (Short and Intermediate term): The 2-generation reproduction study 

in rats was selected for the incidental oral exposure scenarios (short- and intermediate-term). 

The POD was an offspring NOAEL of 14.5 mg/kg/day. The offspring LOAEL of 82.8 

mg/kg/day was based on decreased pup body weight and body weight gain and decreased spleen 

and thymus weight. This endpoint is appropriate for the population of concern (children) since 

this body weight/body weight gain effect occurred post-natally and is not an in utero effect.

The residential level of concern for MOE is 1000 (100X for inter- and intra-species variability, 

and a database UF of 10X for a lack of a comparative thyroid study).

Occupational and Residential Exposure Endpoints

Dermal Exposure (short- and intermediate-term):

The 28-day dermal toxicity study in rats was selected for both the short- and intermediate-term 

dermal exposure scenarios. The POD was a NOAEL of 300 mg/kg/day. The LOAEL of 1000 

mg/kg/day was based on increased cholesterol in females, increased prothrombin time in males, 

increased liver weight (both sexes) and liver hypertrophy. The 28-day dermal toxicity study in 

rats is the appropriate route of exposure and measures all endpoints of concern. An oral study 

was not chosen for a dermal endpoint since no increased sensitivity was seen in the 

developmental rat or rabbit studies or in the 2-generation reproduction study in rats. The dermal 

endpoint is protective of effects from any in utero exposure. This 28-day dermal toxicity study

is appropriate for both the short- and intermediate-term exposures. Since dermal absorption is so

low (<1% in humans for the concentrate), it is unlikely that the internal dose would lead to a 

progression of toxicity.

The residential level of concern for MOE is 1000 (100X for inter- and intra-species variability, 

and a database UF of 10X for a lack a comparative thyroid study). The occupational LOC for 

MOE is 1000 (100X for inter- and intra-species variability and 10X for a lack of a comparative 

thyroid study to protect the pregnant female worker).

Inhalation Exposure (short- and intermediate-term): The 2-generation reproduction study in rats 

was selected for the inhalation exposure scenarios (short- and intermediate-term). The POD was 

an offspring NOAEL of 14.5 mg/kg/day. The offspring LOAEL of 82.8 mg/kg/day was based on 

decreased pup body weight and body weight gain and decreased in spleen and thymus weight.

An oral study was not chosen for a dermal endpoint since no increased sensitivity was seen in the 

developmental rat or rabbit studies or in the 2-generation reproduction study in rats. This 

endpoint is appropriate for the population of concern (children).
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The residential level of concern for MOE is 1000 (100X for inter- and intra-species variability, 

and a database UF of 10X for a lack of a comparative thyroid study). The occupational LOC for 

MOE is 1000 (100X for inter- and intra-species variability and 10X for a lack of a comparative 

thyroid study to protect the pregnant female worker).

B. ToxSAC Comments on DERs

1. Pharmacokinetic studies: The ToxSAC recommended that the evidence of sex differences (3-

4 fold) which were seen in the pharmacokinetic studies should be discussed in the hazard 

characterization. The ToxSAC suggested that the toxicologist build a story tying together the 

ADME data and the toxicology data. It should include that absorption is very rapid, and that the 

sex differences seen in the ADME data are also reflected in the ACN study results. 

2. Acute Neurotoxicity (ACN) Study: There was some discussion of whether the effects seen in 

the ACN study were neurotoxic or systemic. Several members of the ToxSAC pointed out that 

the transient but marked effect on motor and locomotor activity are reminiscent of effects seen 

after exposure to sedatives or anesthetics. Thus, they considered the effects in the ACN to be 

indicative of a potentially neurotoxic effect which was supported by findings in the long term 

cancer study in rats. The chronic toxicity/carcinogenicity study in rats showed possible clinical

signs of neurotoxicity including limited use of hind limbs, reduced motor activity, and lethargy at 

the high dose. Other members of the committee, however, viewed these effects as indications of 

generalized toxicity and not necessarily directly related to effects on the nervous system. 

Regardless, of the etiology of the effect there was consensus that the decrease in motor and 

locomotor activity (↓70% ) seen on Day 0 in the ACN study was considered to be adverse and 

appropriate to establish an acute reference dose for the general population. 

3. Dermal Absorption Factor (DAF): It was suggested that the DAF for humans be incorporated 

into the hazard characterization. The ToxSAC concluded that the Triple Pack dermal absorption 

studies (i.e., parallelogram approach) were well conducted and that the calculations and the 

underlying assumptions were correct. The hazard characterization should give more emphasis to

the Triple Pack and should specifically state the dermal absorption factor for use in humans. 

Contact Jessica Ryman for specific language to use.

4. 2-Generation Reproduction Study: The ToxSAC was in general agreement with this DER, but 

had several comments: a) For the parental systemic LOAEL, do not include decreased body

weight as part of the LOAEL since the decrease is too minimal (5-6%) (a 10% decrease is the cut 

off used for adverse effects for decreases in parental body weight); b) Since the basis of the 

LOAEL statement is cholesterol, hemoglobin, and hematocrit etc., it would be helpful to have 

that actual data in the DER. This information should be added in table format so the magnitude 

of the changes can be presented; c) In the DER it was suggested that a table of the organ weight 

changes for the spleen and thymus be added to see the magnitude of changes. This is important 

to include since Germany feels that a DIT study is needed; d) The ToxSAC recommends that 

PPS not be included in the LOAEL statement since the values are well within the historical 

control range for the laboratory.
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5. Developmental Rat DER: DER says LOAEL is highest dose tested. Ureter effects should not 

be counted as a compound-related at any dose level since these effects are commonly seen in rats 

and are considered a normal aspect of renal development in late gestation of rats.1 Thus only one 

visceral finding the thymic remnant present remains as part of LOAEL. 

5. Developmental Rabbit DER: The ToxSAC recommended that the body weight information, 

not just the body weight gain information, be added to the text as well as to the maternal LOAEL

statement. 

C. Is there a need for a Developmental Immunotoxicity (DIT) study?

ToxSAC Response: The ToxSAC agrees that a DIT study is not required at this time pending the 

results of the adult immunotoxicity study which is currently being conducted. The 9-16% 

decreases in the spleen and thymus weights seen in the 2-generation reproduction study were not 

considered to be a sufficiently robust response to trigger a DIT study. (See table below).

The effects of the test substance on spleen and thymus weights were not compelling. The 

ToxSAC recommended that the data presentation in the DER could be improved with the 

addition of standard deviations (if available), however, statistically significant differences were 

observed for the majority of the data, and presentation will not change that. The ToxSAC also 

recommended additional characterization of the data. For example, if there were no correlating 

histopathological changes in the spleen or the thymus, then a decrease in the weights is not 

compelling, since there is no histopathological evidence that these statistically significant 

changes were of biological importance. In addition, there were no indications in hematology

parameters that would lead us to believe the mouse system is compromised. Pending the results 

of the immunotoxicity study, it is recommended that the DIT issue be revisited.

Spleen Thymus

Adult Adult

P female -12% abs (p<0.05) P female -9% abs (p<0.05) 

F1 female -12% abs (p<0.05) F1 male -14% abs (p<0.05) 

21-day pup 21-day pup

F2 (M+F) -14% abs F2 (M+F) -16% abs (p<0.01)

F2 (M+F) -9% rel F2 (M+F) -9% rel (p<0.01)

D. Is there a need for a Comparative Thyroid Assay in the rat?

ToxSAC Response: The ToxSAC determined that a comparative thyroid assay in the rat was 

needed. In the fluopyram database, the thyroid was the target organ. Thyroid effects were seen 

in the 28-day rat (increased thyroid weight), 90-day rat (changes in thyroid hormones and thyroid 

follicular cell hypertrophy), chronic rat (thyroid follicular cell hypertrophy), and the 

carcinogenicity study in the mouse (thyroid follicular cell hyperplasia and thyroid follicular cell 

tumors). The thyroid effects may be more sensitive. The benefits of a comparative thyroid assay

 

1 DC Woo and RM Hoar (1972). "Apparent hydronephrosis" as a normal aspect of renal development in late 

gestation of rats: the effect of methyl salicylate. Teratology 6(2):191-196
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are two fold: 1) the results would give information on thyroid toxicity and whether or not 

fluopyram is a direct acting thyroid toxicant; and 2) it would cover the neurotoxic type effects

seen because thyroid hormone homeostasis is a precursor of developmental neurotoxicity in 

thyroid toxicant compounds. The thyroid is critical for fetal development, particularly for brain 

development.