Page 1 of 6 **UNITED STA TES ENVIRONMENTA**  **L PROTECTION A GENCY** 

**WA SHINGTON, D.C. 20460**  **OFFICE OF PREVENTION, PESTICIDE AND TOXIC SUBSTANCES**  **MEMORANDUM Date:**  December 23 , 2009 **SUBJECT: Flu**  **o pyram**  **-** 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 T **XR No.:** NA **CAS No.: NA**  **MRID No.:** NA **40 CFR:** NA **FROM:** Jessica Kidwell, ToxSAC Executive Secretary

Health Effects Division (7509P) **THROUGH:** Elizabeth M é ndez, T oxSAC Chair

Health Effects Division (7509P) **TO:** My

ron Ottley , Toxicologist RA B III , Health Effects Division (7509P) **ToxSAC Meeting Notes for 7/16/09**  **Meeting on**  **Fluopyram** Team Members : My ron Ottley , Toxicologist ToxSAC Members : Judy Facey , Jessica Kidwell, Marquea King, Elizabeth Mendez, Whang Phang, Elissa Reaves, Jessica Ry man , Ed Scollon Other Attendees : Marion Copley (HED/SIMB), Barry

O’Keefe, Paula DeschampPage 2 of 6

**A. ENDPOINT SELECTION**  The ToxSAC was requested to provide comments on the p oint s of d eparture selections and proposed Endpoints for th e fluopy ram risk assessment. ToxSAC Response: The ToxSAC recommendations for endpoint selection are below. **Dietary Exposure Endpoints**  Acute Dietary (General Population, including infants and children) : The a cute 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 safet y factor of 1000 should be applied (100X for inter - and intra - species variability , The FQPA safet y factor of was retained in the form of a database uncertainty factor (UFdb ) of 10X for lack of a comparative thy roid assay . aRfD = 50 mg/kg/day = 0. 0 5 0 mg/kg/day 1 00 0 (includes UFdb of 10x) aRfD = aPAD Acute Dietary (

Females 13 - 49 years old

): An acute dietary

endpoint for females 13 - 49 y ears old was not identified . No prenatal or fetal toxicity was observed in developmental or reproductiv e 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 /carcinogenicit y 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 LOAELof 6 mg/kg/day was based on nephropathy , follicular cell hy pertrophy in the thy

roid, and increased liver weight with gross pathological histopathol og ical findings. This endpoint is appropriate for the duration and population of concern . The POD from the rat will be protective of thy roid effects (th yroid hyperplasia and th yroid follicular cell tumors) seen in m ice. An overall safet y 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 thy roid assay . The FQPA safet y factor was retained in the form of a databa se uncertaint y factor ( UFdb ) of 10X for lack of a comparative th yr o id assay .Page 3 of 6 cRfD= 1.2 mg/kg/day = 0.0 0 12 mg/kg/day

100 0 c RfD = c PAD **Residential Exposure Endpoints**  I ncidental Oral Exposures (Short and Intermediate term ): The 2 - generation reproduction stud y in rats was selected for the incidental oral exposure scenarios (short - and intermedi ate - term). The POD was an offspring NOAEL of 14.5 mg/kg/day . The offspring LOAELof 82.8 mg/kg/day

was based on decreased pup bod y weight and body weight gain and decreased spleen and thy mus 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 thy roid study). **Occupational and Resident i** **al 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 NOAELof 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 hy pertrophy . The 28 - day

de rmal toxicity

study in rats is the appropriate route of exposure and measures all endpoints of concern. An oral stud y 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 an y in utero exposure. This 28 - day dermal toxicity

study is appropriate for both the short - and intermediate - term expos ures . Si nce dermal absorption is so low (<1% in humans for the concentr ate), 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 thy r oid study). The occupational LOC for MOE is 100 0 (100X for inter - and intra - species variability and 10X for a lack of a comparative thy roid 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 bod y weight and body weight g ain and decreased in spleen and thy mus 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 p opulation of concern (children).Page 4 of 6

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 thy roid study). The occupational LOC for MOE is 100 0 (100X for inter - and intra - species variability and 10X for a lack of a comparative thy roid study

to protect the pregnant female worker). **B. ToxSAC**  **Comments on DERs**  1 . Pharmacokinetic studies : The ToxSAC recommended that the e vidence of s ex 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 . A cute Neurotoxicity (ACN) Study : There was some discussion of whether the effects seen in the ACN study

were neurotoxic or sy stemic. Several memb ers 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 n eurotoxic effect which was supported by findings in the long term cancer stud y 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 necessaril y directl y related to effects on the nervous s ys tem. Regardless, of the etiology of the effect there was con sensus 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 assumpt ions were correct. The hazard characterizat ion should give more emphasis to the Triple Pack and should specificall y state the dermal absorption factor for use in humans . Contact Jessica Ry

man for specific language to use . 4. 2 - Gen e ration Reproduction Study : The ToxSAC was i n general agreement with this DER, but had several comm ents : a) For the parental sy stemic 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 effect s for decreases in pare ntal body weight) ; b) Since the basis of the LOAEL statement is cholester o l , hemoglobin , and hematocrit etc. , i t 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 thy mus 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 .Page 5 of 6

5. Developmental Rat DER : DER say s LOAEL is highest dose tested. Ureter effects should not be counted as a compound - related at an y 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 thy

mic 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 currentl y being conducted. The 9 - 16% decreas es in the spleen and thy mus 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). T he effects of the test substance on spleen and thy mus weights were not compelling. The ToxSAC recommended that the d ata presentation in the DER could be improved with the addition of standard deviations (if available), however, s t atisticall y significant differences were observed for the majorit y of the data, and pres entation wi ll not change that. The ToxSAC also recommend ed additional characterization of the data. For example, if there were no correlating histopathological changes in the spleen or the th ymus, then a decrease in the weights is not compelling, since there is no h istopathological 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 sy stem 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 thy roid assay

in the rat was needed. In the fluop yram database, the thy roid was the target organ. Thy roid effects were seen in the 28 - day

rat (increased thy

roid weight), 90 - day

rat (changes in thy

roid hormones and thy

roid follicular cell h ypertrophy), chronic rat (th yroid follicular cell h ypertroph y) , and the carcinogenici ty

study in the mouse (thy

roid follicular cell hy

perplasia and thy

roid follicular cell tumors). The thy

roid effects may

be more sensitive. The benefits of a comparative th yroid 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 - 196Page 6 of 6

are two fold: 1) the result s would give information on thy roid toxicity

and whether or not fluopy ram is a direct acting thy

roid toxicant; and 2) it would cover the neurotoxic ty pe effects seen because th yroid hormone homeostasis is a precursor of developmental neurotoxicity in thy roid toxicant compounds. The thy roid is critical for fetal development, particularl y for brain development.