Sethoxydim Risk Assessment

both 360 and 1080 ppm, histopathologic signs of liver toxicity were also observed - i.e., fatty 
degeneration and swelling of the liver. 
A one-year feeding study in dogs has also been conducted in which doses were administered as 
rates of 0, 8.86/9.41, 17.5/19.9, and 110/129 mg/kg/day to males/females (IRDC 1984). At 
8.86/9.41 mg/kg/day no adverse effects were observed.  At a dose of 17.5 mg/kg/day, mild 
anemia was observed in male dogs and this dose level was classified by the U.S. EPA as a 
LOAEL.  The NOAEL of 8.86/9.41 mg/kg/day was selected by the U.S. EPA as the basis for the 
Agency RfD (U.S. EPA/IRIS 1989). 
No standard 90-day subchronic toxicity studies have been encountered.  The only other repeated 
dose studies involve assays for reproductive or teratogenic effects (Section 3.1.4) and a dermal 
toxicity study (Section 3.1.7). 
3.1.4.  Reproductive and Teratogenic Effects.  Sethoxydim has been tested for its ability to 
cause birth defects (i.e., teratogenicity) as well as its ability to cause reproductive impairment. 
Teratogenicity studies typically entail gavage administration to pregnant rats or rabbits on specific 
days of gestation.  Two such studies (each of which is detailed in Appendix 1) were conducted on 
sethoxydim: one in rats and one in rabbits.  Both of these studies are reported in  Nisso Inst. 
(1980a). 
In the rat study, which involved daily gavage dosing on days 7 to 17 of gestation, the maternal 
NOAEL was 40 mg/kg/day with decreased body weight observed at 100 mg/kg/day. No effects 
on fetuses were noted at the highest dose tested, 250 mg/kg/day.  In the rabbit study, which 
involved daily gavage dosing on days 6 to 28 of gestation, the highest dose tested ( 480 
mg/kg/day) resulted in toxic effects to the dams (decreased weight gain) and fetuses (decreased 
number of viable fetuses and decreased fetal weight).  Thus, the maternal and fetal NOAEL was 
160 mg/kg/day with a corresponding LOAEL of  480 mg/kg/day. 
Another type of reproduction study involves exposing more than one generation of the test animal 
to the compound in the diet.  No such studies were encountered in the literature or in the initial 
search of the FIFRA/CBI files.  U.S. EPA/OPP (1998a) summarizes the results of a two 
generation reproduction study in which rats were fed diets containing 0, 150, 600, and 3,000 ppm 
which resulted in daily doses of approximately 0, 7.5, 30, and 150 mg/kg.  No effects were 
observed in dams or offspring. 
3.1.5.  Carcinogenicity and Mutagenicity.  The two-year feeding studies in rats and mice, 
discussed in Section 3.1.3 and summarized in Appendix 1, involved complete histopathology in 
order to assess the potential carcinogenicity of sethoxydim.  Only one of the studies, the study 
with the high dose group of 3,000 ppm has been accepted by the U.S. EPA based on the criteria 
that a cancer study should involve at least one dose level at which adverse effects are observed ­
i.e., some evidence that the maximum tolerated dose was encompassed by the study.  In this high 
dose study, as well as in the other lower dose studies, no evidence for carcinogenicity was noted 
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(U.S. EPA/OPP 1998a).  The U.S. EPA/OPP (1998a) has not classified sethoxydim for 
carcinogenicity and the earlier review by the U.S. EPA/OPP (U.S. EPA/IRIS 1989) indicates that 
this compound has not been evaluated for carcinogenicity by the agency. 
Several standard assays for mutagenicity, reviewed by the U.S. EPA/OPP (1998a), have been 
negative.  These assays included an Ames assay for gene mutation, Chinese hamster bone marrow 
cytogenetic assay, as well as recombinant assays and forward mutation assays in Bacillus subtilis, 
Escherichia coli, and Salmonella typhimurium.  Thus, based on a review of the available 
information, there appears to be no basis for asserting that sethoxydim is likely to pose any cancer 
risk. 
3.1.6.  Effects on the Skin and Eyes. Sethoxydim failed to cause any evidence of primary skin 
irritation in a standard rabbit assay (Toxicity Category IV; no irritation).  A standard assay for 
dermal sensitization in the guinea pig was waived by the U.S. EPA/OPP (1998a) because no 
sensitization was seen in guinea pigs dosed with the end-use product, Poast (18% active 
ingredient).  The MSDS for Poast, however, states that Poast is moderately irritating to the skin 
of rabbits (BASF 2000).  In addition, the U.S. EPA/OPP (1998a) reports that slight epidermal 
hyperplasia was observed in rats after a daily dermal dose of 1,000 mg/kg/day over a 21-day 
period. 
The U.S. EPA/OPP (1998a) also states that no primary eye irritation was observed in the rabbit 
and classifies sethoxydim as Toxicity Category IV (no irritation).  The basis for this classification 
is unclear.  As summarized in Appendix 1, sethoxydim has been shown to cause eye irritation in 
rabbits in two studies that have been submitted to the U.S. EPA (Souma et al.  1981; Kirsch and 
Hildebrand 1983).  In addition, the  MSDS for Poast states that Poast is moderately irritating to 
the eyes of rabbits (BASF 2000), a statement that is consistent with the studies summarized in 
Appendix 1. 
3.1.7.  Systemic Toxic Effects from Dermal Exposure.  Most of the occupational exposure 
scenarios and many of the exposure scenarios for the general public involve the dermal route of 
exposure.  For these exposure scenarios, dermal absorption is estimated and compared to an 
estimated acceptable level of oral exposure based on subchronic or chronic toxicity studies.  Thus, 
it is necessary to assess the consequences of dermal exposure relative to oral exposure and the 
extent to which sethoxydim is likely to be absorbed from the surface of the skin. 
The available toxicity studies summarized in Appendix 1 indicate that dermal exposures to single 
acute doses of up to 5000 mg/kg sethoxydim were below the LD
50
 for rabbits (Bio-Medical 
Research Laboratories Co, Ltd. 1979, 1980).  While no mortality was seen in any of the exposed 
rats or mice, signs of neurotoxicity (i.e., decreased motor activity, ataxia and tremors) were 
apparent, similar to but less severe than the effects noted after oral administration.  Thus, as with 
many chemicals (e.g. Gaines 1969), sethoxydim can cause toxic effects after dermal exposure but, 
in terms of mg/kg dose, sethoxydim appears to be less potent after dermal exposure compared to 
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