2 II. BACKGROUND and ACTION REQUESTED

An immunotoxicity study on Propoxur (MRID# 48759401) has been submitted. RAB VI was asked to review and prepare a DER for this study.

III. RESULTS AND DISCUSSION

The immunotoxicity study in rats for Propoxur (MRID# 48759401) has been reviewed. The DER is attached and an executive summary is as follows:

EXECUTIVE SUMMARY : In an immunotoxicity study (MRID #48759401), Propoxur Technical (99.1% a.i., Batch no. KP074PF 436-1-00006-2) was administered to male and female Wistar (Hsd Cpb:Wu) rats (8/dose/se x) in the diet at dose levels of 0, 1250, 2500, or 5000 ppm (equivalent to 0, 88.9, 175.5, or 362.6 mg/kg/day for males and 0, 103.7, 177.5 or 342.7 mg/kg/day for females, respectiv ely) for at least 32 days. During the study, clinical condition, bodyw eight, food and water consum ption, organ weight, macro and histopathology were evaluated. Five days before sacrifice, all animals in all groups received a single intravenous dos e of sheep red blood cell (SRBC, 1x10 9 SRBC/mL in BSS, 100 μL/animal). At sacrifice on Da y 28, selected organs were removed and weighed (brain, spleen, and thymus). The anti-SRBC antibody response was measured with a modified plaque forming cell (PFC) a ssay. In addition, flow cytometric analysis for subpopulation of the spleen cells and antibod y (IgG, IgM, and IgA) titers with ELISA were measured. Positive controls were perf ormed previously with cyclophosphamide at 40 or 80 mg/kg/day for reliability check of these assays.

There were no premature deaths, and no trea tment-related clinical signs. Body weights were statistically significantly reduced since Day 14 in all treated groups in males. At Day 32, the differences of mean body weights in treated groups compared to the control

were 8.4%, 8.9% and 10.8% for males and 4.3%, 9.5% and 12.6% in females (for groups 1250 ppm, 2500 ppm and 5000 ppm, respectivel y). There was persistently low food consumption in the mid and high dose groups when compared to the vehicle control group. The decreases of body weight and food consumption were considered toxicologically significant at 5000 ppm fo r both sexes. The organ weights (spleen, thymus and brain) were not significantly different from the vehicle control group. Histopathology of these organs and mese nteric lymph nodes gave no evidence of

treatment related effects.

The systemic LOAEL was 5000 ppm (equival ent to 362.6 mg/kg/day in males and 342.7 mg/kg/day in females) based on reduced body weight gain and food consumption. The systemic toxicity NOAEL was 2500 ppm (175.5 mg/kg/day for males and 177.5 mg/kg/day for females).

There were no significant treatment-rela ted effects on the sp ecific anti-SRBC PFC response as measured by total activity (PFC/10 6 viable cells) or total activity (PFC/spleen). High inter-indivi dual variability was noted in all the treatment groups as well as in the control group. Evaluation of the individual animal data of this study did3 not show any trend or distri bution that would de monstrate significant suppression of antiSRBC antibody response.

There were no significant treat ment-related effects on antibody (IgG, IgM, or IgA) titers, and splenic cell subpopulations. In the flow cytometric analysis, females at 5,000 ppm showed statistically significan t decrease in NK cells (CD 161 + ). However, this decrease was within the normal range of variance for this parameter; and it was not observed in males. NK cell activity assay was not performed. The overall weight of evidence suggests that the chemical does not directly target the immune system. Under HED guidance a NK cell activity assay is not re quired at this time.

The NOAEL for immunotoxicity was 5000 ppm (equivalent to 362.6 mg/kg/day for males, and 342.7 mg/kg/day for females), th e highest dose tested; the LOAEL for immunotoxicity was not established.

This immunotoxicity study is classified acceptable/guideline and satisfy the guideline requirement for an immunotoxicity study (OPPTS 870.7800) in the rats

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