CALIFORNIA ENVIRONMENTAL PROTECTION AGENCY
DEPARTMENT OF PESTICIDE REGULATION
MEDICAL TOXICOLOGY BRANCH
SUMMARY OF TOXICOLOGY DATA
Indoxacarb
Chemical Code # 5331, Tolerance # 52425
SB 950: not assigned
Original date 3/11/99
Revised: 9/17/04
I. DATA GAP STATUS
Chronic toxicity, rat: No data gap, no adverse effect
Chronic toxicity, dog: No data gap, no adverse effect
Oncogenicity, rat: No data gap, no adverse effect
Oncogenicity, mouse: No data gap, possible adverse effect (non-neoplastic)
Reproduction, rat: No data gap, no adverse effect
Teratology, rat: No data gap, no adverse effect
Teratology, rabbit: No data gap, no adverse effect
Gene mutation: No data gap, no adverse effect
Chromosome effects: No data gap, no adverse effect
DNA damage: No data gap, no adverse effect
Neurotoxicity: No data gap, no adverse effect
Toxicology one-liners are attached.
All record numbers for the above study types through 204672 (Document no. 52425-0135) were
examined.
** indicates an acceptable study.
Bold face indicates a possible adverse effect.
Indoxacarb technical is a mixture of two optical isomers, namely DPX-KN128 (the insecticidally
active isomer) and DPX-KN127 (insecticidally inactive) and is referred to as either DPX-MP062 or
DPX-JW062, based on the ratio of isomers used.
File name: T040917
T. Moore, 9/17/04.
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II. TOXICOLOGY ONE-LINERS AND CONCLUSIONS
These pages contain summaries only. Individual worksheets may contain additional effects.
COMBINED, RAT
**52425-054 162226 鈥滳ombined Chronic Toxicity/Oncogenicity Study with DPX-JW062-106 (50%
DPX-KN128, 50% DPX-KN127) Two-Year Feeding Study in Rats鈥? (Frame, S. 835-E. I. du Pont de
Nemours and Company, Haskell Laboratory, Elkton Road, Newark, Delaware, Study HLR 1174-
96, 11/19/97). DPX-JW062-106 technical (Batch DPX-JW062-106, 47.5% DPX-KN128) was
given in the diet daily to males at 0, 20, 40, 60, 125 or 250 ppm and females at 0, 10, 20, 40, 60
or 125 ppm for 24 months. Deaths of one female at 60 ppm and seven at 125 ppm during the first
year were associated with bone marrow atrophy, splenic lymphoid depletion and thymic necrosis.
Decreases in mean body weight/weight gain in males at 125 and 250 ppm and females at 60 and
125 ppm correlated with decreased food consumption. Hemolytic anemia at 60 ppm and above
(males) and 40 ppm and above (females): RBC mass, hemoglobin and hematocrit were
decreased and linked with increased reticulocyte counts and increased MCV. Bone marrow
regenerative response was increased bone marrow hyperplasia in the one-year interim sacrifice
125 ppm females. Spleen weights were increased in both sexes at the respective high-dose levels
and other non-neoplastic changes were secondary physiological responses to test substance-
related hemolysis; increased pigment observed within the Kupffer cells of female livers (125 ppm)
and the macrophages of the spleen (both sexes at 60 ppm and above) indicated increased RBC
turnover. Increased hematopoiesis was reported in the spleen of interim sacrifice males at 125
ppm and above and in the bone marrow of high-dose males and females. After two years,
secondary changes were seen in the liver, spleen, bone marrow, kidneys and thymus in high dose
groups. Increased pigment was observed in the Kupffer cells of female livers at 40 ppm and
above; in males, increases were noted at 250 ppm only. Increased splenic pigment was seen in
all compound-treated male groups and in females at 60 ppm and above; a slight increase in
splenic congestion was seen in 250 ppm males. No evidence of an oncogenic effect was
reported. NOEL(M)= 40 ppm; (F)=20 ppm (M: 1.59 mg/kg/day; F: 1.04 mg/kg/day based on
hemolytic anemia). Acceptable. Kellner, 1/29/99.
CHRONIC TOXICITY, DOG
**52425-047 162215 鈥淐hronic Toxicity Study of DPX-JW062-106 (50% DPX-KN128, 50% DPX-
KN127) One Year Feeding Study in Dogs鈥? (Mertens, J. 831-WIL Research Laboratories, Inc.
Ashland, Ohio. Study HLO 885-96, 11/19/97). DPX-JW062-106 technical (Batch DPX-JW062-
106, 47.5% DPX-KN128) was administered orally (via the feed) to 5 Beagle dogs/sex/dose at
levels of 0, 40, 80, 640 and 1280 ppm for 52 weeks. There was a treatment-related decrease in
body weight, body weight gain and food consumption in 1280 ppm dogs during the first three
months of the study. Reduced mean hemoglobin, RBC count and hematocrit was noted in the 80,
640 and 1280 ppm groups during all periods tested; increased Heinz bodies in these groups
indicated hemolysis. Increased mean reticulocyte counts and MCV and decreased corpuscular
hemoglobin concentration, erythrocyte morphologic changes and increased mean platelet counts
indicated responses to hemolytic anemia. Significantly decreased RBC counts were also reported
in 40 ppm males at week 25 and 51. Females at 40 ppm also showed reductions in RBC, but the
differences were not statistically significant. Mean liver weights were increased in males (640 and
1280 ppm groups) and females (1280 ppm only). Microscopic changes in groups 40 ppm and
above included increased pigment (hemosiderin) in liver Kupffer cells, kidney tubule epithelium,
spleen and bone marrow and increased extramedullary hematopoiesis in the spleen and bone
marrow hyperplasia. NOEL (M/F)=40 ppm (males: 1.1 mg/kg/day; females: 1.3 mg/kg/day based
on biologically significant hemolytic anemia at 80 ppm and above). Acceptable. Kellner, 1/12/99.
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ONCOGENICITY, RAT
See Combined Toxicity, Rat
ONCOGENICITY, MOUSE
**52425-040 162205 鈥淥ncogenicity Study with DPX-JW062-106 (50% DPX-KN128, 50% DPX-
KN127) Eighteen-Month Feeding Study in Mice鈥? (Frame, S. 832-E. I. du Pont de Nemours and
Company, Haskell Laboratory, Elkton Road, Newark, Delaware, Study HLR 799-96, 3/24/97).
DPX-JW062-106 technical (Batch DPX-JW062-106, approximately 48% DPX-KN128) was given
in the diet daily to 70 Crl:CD庐-1(ICR)BR mice/sex/dose at 0, 20, 100, or 125/150/200 ppm for 18
months (200 ppm level reduced to 150 ppm on day 126 and to 125 ppm on day 287 due to
excessive mortality). The cause of death was either central nervous system disorder (determined
from clinical signs of abnormal gait/mobility and head tilt) or heart inflammation/ necrosis (males
only). Significant decreases in mean body weight were seen in both sexes at 100 ppm and at the
high-dose (most severe during the 200 ppm exposure). Clinical signs suggesting neurotoxic
activity were reported in high-dose mice at early stages of study (e.g., abnormal gait/mobility, tilted
head and weakness) with symptoms decreasing as dose levels were reduced to 125 ppm.
Females at 100 ppm also showed increased abnormal gait and head tilt. Red fluid in plural cavity
noted after gross necropsy corresponded with heart lesions in high-dose males (e.g., necrosis,
hemorrhage and inflammation). No Adverse Neoplastic Effects. Non-neoplastic changes were
noted in the brain of both sexes and in the heart of males only of mice that died or were sacrificed
in extremis. Neuronal necrosis was reported in two high-dose males and two females and in one
female at 100 ppm. Both high-dose males were sacrificed in extremis, one while receiving the 150
ppm diet (day 133) and the other while receiving the 125 ppm diet (test day 302). The two affected
females died or were killed in extremis (day 83 and 108, respectively) while receiving 200 ppm.
Residual vacuolation of the piriform cortex was observed in 2 female high-dose mice that survived
to the 18-month scheduled sacrifice. NOEL(M/F)=20 ppm (M: 2.63 mg/kg/day based on
neurotoxicity, heart lesions at 125 ppm and decreased body weight gain at 100 ppm; F: 3.99
mg/kg/day based on neurotoxicity at 100 and 125 ppm). Acceptable. Kellner, 2/9/99.
REPRODUCTION, RAT
**52425-046 162214 鈥淭wo Generation Reproduction/Fertility Study with DPX-JW062-106 in Rats鈥?
(Breslin, W. 834-MPI Research, Mattawan, MI, Report# HLO 115-96, 11/3/97). DPX-JW062-106
(Batch no. DPX-JW062-106, 47.7% DPX-KN128, dissolved in acetone) was administered orally
via the feed to 26 Crl:CD庐 VAF/Plus 庐 rats/sex/dose at levels of 0, 20, 60, 100 ppm beginning 70
days prior to mating and continuing until euthanasia for 2 generations. There were no apparent
dose-related increases in the frequency or severity of clinical observations for the treated F0 or F1
groups compared to control. Body weight changes (in F0 dams only) included decreased body
weights in 100 ppm F0 males throughout the dosing period and decreased weight in 60 and 100
ppm F0 females during premating, gestation and lactation. Food consumption was significantly
reduced in 100 ppm F0 males and in 60 and 100 ppm F0 females. Necropsy findings included
increased spleen weights in the F0 and F1 males at 100 ppm and in the F0 and F1 females at 60
and 100 ppm. Maternal NOEL= 20 ppm (0.856-4.141 mg/kg/day, based on increased spleen
weights in females at 60 and 100 ppm). There were no apparent compound-related effects on
gonad function, estrous cycling or mating behavior in either the F0 or F1 animals. In F1 females
at 100 ppm, slight decreases in fecundity and fertility index were noted. While mean F1 pup
weights in the 60 and 100 ppm groups were statistically reduced during the lactation period,
corresponding weights in the F2 generation showed no compound-related effect. Developmental
NOEL= 20 ppm (based on decreased F1 pup weights during lactation at 60 and 100 ppm). No
Adverse Effects; decrease in F1 fecundity and fertility indices were not statistically significant, not
seen during F0 mating and not accompanied by effects in sperm or estrous cycle evaluations.
Reproductive NOEL= 60 ppm (1.734-11.610 mg/kg/day; based on slight reduction in F1 fertility
index at 100 ppm). Acceptable. Kellner, 12/17/98.
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TERATOLOGY, RAT
**52425-042, -044 162207 162212 鈥淒PX-JW062-112 (50% DPX-KN128, 50% DPX-KN127):
Developmental Toxicity Study in Rats鈥? (Munley, S. 833-E. I. du Pont de Nemours and Company,
Haskell Laboratory for Toxicology and Industrial Medicine, Newark, Delaware, Report# HL-1997-
00049, 3/31/97). DPX-JW062-112 (Batch no. DPX-JW062-112, 47.4% DPX-KN128) was
administered via oral gavage (dissolved in 0.5% methyl cellulose) to 25 mated Crl:CD 庐(SD)BR
female rats/dose at levels of 0, 10, 100, 500 or 1000 mg/kg, with cesarean sectioning on day 22 of
gestation. Prior to scheduled sacrifice, 4, 17 and 15 rats died in the 100, 500 and 1000 mg/kg
groups, respectively. Clinical signs in 100 mg/kg dams included abnormal gait/mobility and at 500
mg/kg, increased abnormal gait/mobility, alopecia, hunched posture and general weakness were
noted. At 1000 mg/kg, all these signs plus stained fur and inability to stand were seen. Among
surviving rats at 100 mg/kg and above, there were significant reductions in mean maternal body
weights, weight changes and food consumption. Necropsy of the G.I. tract revealed distended
stomach with unusual contents (white, yellow, or orange-colored pasty contents), hemorrhage or
ulcerated areas, and lack of formed feces in some dams at 100 mg/kg and above. Maternal
NOEL= 10 mg/kg/ day (based on body weight, food consumption, clinical signs and necropsy
findings). Litter data showed no apparent differences in the number of corpora lutea, implants,
early resorption, or sex ratio. A slight increase was noted in the incidence of late resorptions per
litter at 1000 mg/kg and mean fetal weight was significantly reduced at 500 and 1000 mg/kg.
There were no compound-related effects on the incidence of fetal malformations or variations. No
Adverse Effects. Developmental NOEL= 10 mg/kg (based on significantly reduced fetal viability
at 100 mg/kg and above). Acceptable. Kellner, 11/19/98.
**52425-043, -044 162209 162211 鈥淒PX-MP062 (Approximately 75% DPX-KN128, 25% IN-
KN127): Developmental Toxicity Study in Rats鈥? (Munley, S. 833-E. I. du Pont de Nemours and
Company, Haskell Laboratory for Toxicology and Industrial Medicine, Newark, Delaware, Report#
HL-1997-00202, 11/5/97). DPX-MP062 (Batch no. DPX-MP062-51A, 79% DPX-KN128,
dissolved in PEG 400) was administered via oral gavage to 25 mated Crl:CD 庐(SD)BR female
rats/dose on days 7-21 of gestation at levels of 0, 0.5, 1.0, 2.0 or 4.0 mg/kg, with cesarean
sectioning on day 22 of gestation. Increased alopecia was noted at 2.0 and 4.0 mg/kg. Mean
maternal body weight, body weight gain and food consumption was significantly reduced in high-
dose dams. One dam died (gavage trauma) and another was killed in extremis prior to scheduled
sacrifice; both were considered not compound-related. At the scheduled necropsy, one high-dose
dam had a thick, yellow residue in the stomach and another had numerous, pinpoint stomach
ulcers. Maternal NOEL= 2.0 mg/kg (based on body weight, food consumption, clinical signs and
necropsy findings at 4.0 mg/kg). Litter data showed no apparent differences in the number of
corpora lutea, implants, resorptions or sex ratio. Mean fetal weight was significantly reduced at
the high-dose level. An increase in fetal variations in the form of wavy ribs at the high-dose level
No Adverse Effects. Developmental NOEL= 2.0 mg/kg (based on wavy rib and significantly
reduced mean fetal weight at 4.0 mg/kg). Acceptable. Kellner, 12/1/98.
**52425-043 162210 鈥淒evelopmental Toxicity Study of DPX-JW062-106 in Rats鈥? (Munley, S.
833-E. I. du Pont de Nemours and Company, Haskell Laboratory for Toxicology and Industrial
Medicine, Newark, Delaware, Report# HLR 558-95, 11/5/97). DPX-JW062-106 (Batch no. DPX-
JW062-106, 47.5% DPX-KN128, dissolved in acetone) was administered orally via the feed to 25
mated Crl:CD 庐BR female rats/dose on day 7-22 of gestation at levels of 0, 20, 40, 80 or 120 ppm
(equivalent to 0, 1.1, 2.2, 4.1 and 5.7 mg/kg/day) with cesarean sectioning on day 22 of gestation.
Increased alopecia was noted at 120 ppm and mean maternal body weight, body weight gain and
food consumption was significantly reduced in 40, 80 and 120 ppm dams. Maternal NOEL= 20
ppm (based on body weight and food consumption findings at 40 ppm and above). Litter data
showed no apparent differences in the number of corpora lutea, implants, resorptions or sex ratio.
Mean fetal weight was significantly reduced at 80 and 120 ppm. No Adverse Effects.
Developmental NOEL= 40 ppm (based on significantly reduced mean fetal weight at 80 and 120
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ppm). Acceptable. Kellner, 12/8/98.
TERATOLOGY, RABBIT
**52425-042 162208 鈥淒evelopmental Toxicity Study of DPX-JW062-112 in Rabbits鈥? (Munley, S.
833-E. I. du Pont de Nemours and Company, Haskell Laboratory for Toxicology and Industrial
Medicine, Newark, Delaware, Report# 587-95, 11/29/95). DPX-JW062-112 (Batch no. DPX-
JW062-112, 47.4% DPX-KN128) was administered via oral gavage (dissolved in 0.5% methyl
cellulose and 1% Tween庐 80) to 23 inseminated Hra:(NZW)SPF rabbits/dose at levels of 0, 250,
500 or 1000 mg/kg from day 7-28 of gestation, with cesarean sectioning on day 29G. There were
no dose-related deaths at any level, however, five rabbits died prior to the scheduled sacrifice
from mechanical (gavage) trauma. Green-colored stools were seen in the high-dose group. Mean
maternal body weight changes were significantly reduced at 1000 mg/kg/day over days 21-23G;
mean body weight gain from day 7-29G was also reduced. Mean maternal food consumption was
significantly reduced at this dose level. Maternal NOEL= 500 mg/kg/ day (based on body weight,
food consumption, clinical signs). Litter data showed no apparent differences in the number of
corpora lutea, implants, early/late resorption, or sex ratio. There were no compound-related
effects on the incidence of fetal malformations. Mean fetal weight was significantly reduced and
variations in the form of increased incidence of retarded ossification of sternebra was reported at
1000 mg/kg. No Adverse Effects. Developmental NOEL= 500 mg/kg (based on significantly
decreased mean fetal weight and retarded ossification of sternebra at 1000 mg/kg). Acceptable.
Kellner, 11/23/98.
GENE MUTATION
**52425-051 162220 鈥淒PX-MP062 (Approximately 75% DPX-KN128, 25% DPX-KN127): In Vitro
Mammalian Cell Gene Mutation Test with an Independent Repeat Assay鈥? (San, R. and Clarke, J.
842- Microbiological Associates, Inc., Rockville, MD. DuPont Study #1997-00030, 4/17/97).
DPX-MP062 (batch #DPX-MP062-51A, 70.9% DPX-KN128) was tested for mutagenic potential in
Chinese hamster ovary cells using the CHO/HGPRT mutation assay with and without metabolic
activation (Aroclor 1254-induced rat liver S-9 fraction) in four trials at dose levels of 3.1, 6.3, 12.5,
25, 100 and 250 碌g/ml (5 hr incubation). None of the treated cultures exhibited mutant
frequencies of more than 40 mutants per 106 clonable cells, indicating that the test article was
negative for mutagenicity. Acceptable. Kellner, 12/22/98.
**52425-051 162222 鈥淒PX-MP062 (Approximately 75% DPX-KN128, 25% DPX-KN127):
Mutagenicity Testing in the Salmonella typhimurium and Escherichia coli Plate Incorporation
Assay鈥? (Mathison, B. 842-E. I. du Pont de Nemours and Company, Haskell Laboratory for
Toxicology and Industrial Medicine, Newark, Delaware, Study #HLR 831-96, 3/19/97). DPX-
MP062 (batch #DPX-MP062-51A, 70.9% DPX-KN128) was tested for mutagenic potential in the
Salmonella, E. coli/Mammalian-Microsome Mutagenicity Assay at levels of 0, 10, 50, 100, 250,
500, 1000, 2500 and 5000 ug/plate (triplicate plating) using Salmonella strains TA100, TA97a,
TA98, TA1535 and E. coli strain WP2 uvrA with and without metabolic activation (Aroclor 1254-
induced rat liver S-9 fraction) in two trials. All colony counts indicated that the test article was
negative for mutagenicity. Acceptable. Kellner, 1/3/99.
CHROMOSOME EFFECTS
**52425-051 162221 鈥淒PX-MP062 (Approximately 75% DPX-KN128, 25% DPX-KN127): Mouse
Bone Marrow Micronucleus Assay鈥? (Cox, L. , 843; E. I. du Pont de Nemours and Company,
Haskell Laboratory for Toxicology and Industrial Medicine, Newark, Delaware, Report HLR 1046-
96, 7/10/97). DPX-MP062 (batch #DPX-MP062-51A, 70.9% DPX-KN128) was tested for
clastogenic activity in polychromatic erythrocytes from bone marrow in vivo after 5 or 6 Crl:CD庐-
1(ICR)BR mice/sex/dose/sacrifice time were administered the test compound by oral intubation at
levels of 0, 3000 or 4000 mg/kg (males) and 0, 1000 or 2000 mg/kg (females); 2000 polychromatic
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erythrocytes/animal were scored for the presence of micronuclei. Clinical signs included
convulsions, ataxia, tremors, vocalization, lethargy, ruffled fur, salivation, abnormal gait, and/or
hunched posture in 16 of 18 males at 3000 mg/kg and all males at 4000 mg/kg; one 3000 mg/kg
male was found dead at 24 hrs post dosing. Clinical signs persisting to 48 hrs included diarrhea,
stained underbody and enophthalmus in addition to earlier signs. At 72 hrs, ruffled fur was seen in
about half of the males. In females at 1000 and 2000 mg/kg, clinical signs were similar to that of
males, although these persisted to 72 hrs in only 1 female. Significant mean body weight losses
were noted at 24, 48 and 72 hrs in 3000 and 4000 mg/kg males. No Adverse Effects: There
were no dose-related increases in the number of micronucleated polychromatic erythrocytes in
bone marrow cells compared to control. Acceptable. Kellner, 12/30/98.
**52425-048 162216 鈥淒PX-MP062 (Approximately 75% DPX-KN128, 25% DPX-KN127): 鈥淚n Vitro
Mammalian Cytogenetic Test Using Human Peripheral Lymphocytes鈥? (Gudi, R. and Schadly, E.
843-Microbiological Associates, Inc., Rockville, Maryland, Study HLO 979-96, 12/17/96). DPX-
MP062 (batch #DPX-MP062-51A, 70.9% DPX-KN128, with DMSO vehicle) was tested for
clastogenic potential in primary human peripheral lymphocytes at concentrations ranging from
15.7 to 1000 ug/ml (initial assay) and 0, 250, 500, 750 or 1000 ug/ml (independent repeat assay),
each with and without metabolic activation (Aroclor 1254-induced rat liver microsomal enzyme).
Exposure to test chemical was 4 hours and harvest time was after 24 h (initial and repeat assay)
or 48 h (repeat only). Lymphocytes [whole blood] were from a female and a male donor in each
trial. One-hundred metaphase spreads/duplicate culture were scored for chromosomal
aberrations. In culture media, the test article was in suspension at 1000 ug/ml and soluble but
cloudy at stock concentrations of 250, 500 and 750 ug/ml. Microscopic examination revealed 82%
reduction of mitotic index at 1000 ug/ml (without S-9) in the initial assay. No Adverse Effects;
the percentage of cells with structural aberrations at 1000 ug/ml or lower concentrations of DPX-
MP062 was not significantly increased above that of the solvent control. Similar negative findings
were reported in the treated cells in the presence of metabolic activation and the percentage of
polyploid cells was not significantly increased above that of the solvent control at the 48 hour
harvest at any dose level. Acceptable. Kellner, 1/7/99.
DNA DAMAGE
**52425-049 162217 鈥淒PX-MP062 (Approximately 75% DPX-KN128, 25% DPX-KN127):
Unscheduled DNA Synthesis in Mammalian Cells In Vitro with an Independent Repeat Assay鈥?
(San, R. and Sly, J., 844; Microbiological Associates, Inc., Rockville, MD., Study HLO-1997-
00033, 5/16/97). DPX-MP062 (batch #DPX-MP062-51A, 70.9% DPX-KN128) was tested for
potential DNA damage in primary rat liver cell cultures (from adult male Fischer F344 rats) using
concentrations of 0, 1.56, 3.13, 6.3, 12.5, 25, 50, 100 and 200 碌g/ml with 3 plates/dose being
exposed to the test article for 18-20 hours in two independent trials. Nuclear grains were counted
in 50 cells in each of three cultures/dose. No Adverse Effects. The mean net nuclear grains per
nucleus (grand mean) for the 12.5, 25, 50, 100, 200 碌g/ml groups in the initial assay were -1.8, -
1.8, -1.4, -2.0 and -1.7 respectively. These values were comparable to the mean control values of
-1.7 (1% DMSO) and similar data were obtained in the repeat assay. Acceptable. Kellner,
1/28/99.
NEUROTOXICITY
**33; 162198; 鈥淎cute Oral Neurotoxicity Study with DPX-MP062 (Approximately 75% DPX-KN128,
25% DPX-KN127) in Rats鈥? (Christoph, G.R., Haskell Laboratory for Toxicology and Industrial
Medicine, E.I. du Pont de Nemours and Company, Newark, DE, Haskell Laboratory Report No.
1117-96, 4/29/97). 818. DPX-MP062 (Batch No. 51A, 74.7% DPX-KN128), prepared in 99.575%
polyethylene glycol, 0.050% 3-t-butyl-4-hydroxyanisole, and 0.375% L-ascorbic acid 6-palmitate,
was administered by gavage in a single dose at concentrations of 0 (vehicle), 12.5 (females only),
25 (males only), 50 (females only), 100, or 200 (males only) mg/kg to 12 Crl:CD庐BR rats per sex
per dose level. One female at 100 mg/kg died on test day 12. Treatment-related pallor (at 100
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mg/kg) and alopecia (at 50 and 100 mg/kg) were observed in females. Treatment-related
decreased mean body weight was observed in females at 50 and 100 mg/kg. Treatment-related
reduced mean body weight gain was observed in males at 200 mg/kg and in females at 50 and
100 mg/kg. Treatment-related decreased mean forelimb strength and mean hindlimb foot splay
were observed in males at 200 mg/kg. FOB assessments revealed no treatment-related effects.
Motor activity assessments revealed no treatment-related effects in the mean total duration of
movements and mean total number of movements. Necropsy and microscopic examination
revealed no treatment-related abnormalities. No adverse effects. NOEL (M)=100 mg/kg (based
on reduced mean body weight gains, and decreased mean forelimb strength and hindlimb foot
splay) and NOEL (F)=12.5 mg/kg (based on clinical signs, decreased mean body weight, and
reduced mean body weight gain). Acceptable. (Corlett and Leung, 12/17/98)
**38; 162203; 鈥淎cute Oral Neurotoxicity Study of DPX-JW062 in Rats鈥? (Mikles, K.A., Haskell
Laboratory for Toxicology and Industrial Medicine, E.I. du Pont de Nemours and Company,
Newark, DE, Haskell Laboratory Report No. 477-95, 3/13/96). 818. DPX-JW062 Technical (Batch
No. DPX-JW062-112, 45.5% DPX-KN128), prepared in corn oil, was administered by gavage in a
single dose at concentrations of 0 (vehicle), 500, 1000, or 2000 mg/kg to 12 Crl:CD庐BR rats per
sex per dose level. 2 females at 1000 mg/kg and 2 females at 2000 mg/kg were sacrificed in
extremis. FOB assessments (open field) revealed treatment-related slow righting reflex on test
day 8 (at all dose levels) and on test day 15 (at 500 mg/kg and 2000 mg/kg), and treatment-related
low arousal on test day 1 (1 to 3 hours after dosing), on test day 8, and on test day 15 at all dose
levels in females. Treatment-related increased mean hindlimb strength was observed in females
at 1000 and 2000 mg/kg 1 to 3 hours after dosing. FOB assessments on males revealed no
treatment-related effects. Motor activity assessments revealed treatment-related increases in both
the mean total number of movements and the mean total duration of movements at 500, 1000,
and 2000 mg/kg 1 to 3 hours after dosing in females; motor activity assessments revealed no
treatment-related effects in the mean total duration of movements and mean total number of
movements in males. Necropsy and microscopic examination revealed no treatment-related
abnormalities. No adverse effects. NOEL (M)=2000 mg/kg (based on no treatment-related
effects at HDT) and NOEL (F)< 500 mg/kg (based on effects observed during open field FOB
assessments). Acceptable. (Corlett and Leung, 12/30/98)
** 41; 162206; 鈥淪ubchronic Oral Neurotoxicity Study with DPX-MP062 Technical (Approximately
75% DPX-KN128, 25% DPX-KN127) in Rats鈥? (Malley, L.A., Haskell Laboratory for Toxicology and
Industrial Medicine, E.I. du Pont de Nemours and Company, Newark, DE, DuPont HLR 1116-96,
3/7/97). 827. DPX-MP062-51 Technical (Batch No. DPX-MP062-51A, 74.7% DPX-KN128) was
admixed to the feed at concentrations of 0, 10, 50 (females only), 100, or 200 (males only) ppm (0,
0.569, 5.62, or 11.9 mg/kg/day, respectively, for males and 0, 0.685, 3.30, or 6.09 mg/kg/day,
respectively, for females) and fed to 12 Crl:CD庐BR rats per sex per dose level for approximately
90 days. 3 females at 100 ppm died or were sacrificed in extremis. No dose-related clinical signs
were observed. Treatment-related decreased mean body weight, decreased mean body weight
gain, and decreased mean daily food consumption were observed at 100 and 200 ppm in males
and at 50 and 100 ppm in females. FOB assessments revealed no treatment-related effects.
Motor activity assessments revealed no treatment-related effects. Necropsy and microscopic
examination revealed no treatment-related abnormalities. No adverse effects. NOEL (M)=0.569
mg/kg/day (10 ppm) and (F)=0.685 mg/kg/day (10 ppm) (based on treatment-related decreased
mean body weight, decreased mean body weight gain, and decreased mean daily food
consumption). Acceptable. (Corlett and Leung, 1/6/99)
------------------------------------------------------------------------------------------------------------------------------
SUBCHRONIC STUDIES
050; 162218; 鈥淩epeated Dose Oral Toxicity: 28-Day Feeding Study with DPX-JW062-34 in Male
and Female Rats鈥? (Reynolds, V.L., Haskell Laboratory for Toxicology and Industrial Medicine, E.I.
du Pont de Nemours and Company, Newark, DE, Laboratory Report No. 403-93, 7/21/93). DPX-
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JW062-34 Technical (47.3% DPX-KN128) was admixed to the feed at concentrations of 0, 8/400
(started at 8 ppm and increased to 400 ppm on Day 17), 12, 29, 59, 118, or 235 ppm (0,
0.713/23.4, 1.02, 2.47, 5.89, 8.85, and 20.6 mg/kg/day, respectively, for males and 0,
0.0.738/14.0, 1.08, 2.61, 4.72, 9.29, or 23.5 mg/kg/day, respectively, for females) and fed to 5
Crl:CD庐BR rats per sex per dose level for at least 28 consecutive days. No males died; 2 females
at 235 ppm and 3 females at 8/400 ppm died with the mortalities occurring on Days 27-28 in the
8/400 ppm group. Treatment-related ruffled fur (at 235 ppm in males and females), and
dehydration, weakness, pallor, and abnormal gait or mobility (at 235 and 400 ppm in females)
were observed. Statistically significant and treatment-related decreased mean body weights were
observed in males at 235 ppm and above and in females at 118 ppm and above. No adverse
effects. NOEL (M)=5.89 mg/kg/day (118 ppm) and (F)=2.61 mg/kg/day (59 ppm) (based on
statistically significant and treatment-related decreased mean body weights). Supplemental
study (animals were dosed for only 28 days, no clinical chemistry on the test animals was
conducted, and no histopathology on the test animals was performed). (Corlett, 1/7/99)
050; 162219; 鈥淩epeated Dose Oral Toxicity: 28-Day Feeding Study with DPX-JW062-34 in
Male and Female Mice, Revision I鈥? (Reynolds, V.L., Haskell Laboratory for Toxicology and
Industrial Medicine, E.I. du Pont de Nemours and Company, Newark, DE, Laboratory Report No.
406-93, 12/3/93). DPX-JW062-34 Technical (47.4% DPX-KN128) was admixed to the feed at
concentrations of 0, 12, 29/400 (started at 29 ppm and increased to 400 ppm on Day 8 of feeding),
59, 118, 235, 1225, or 2450 ppm (0, 2.06, 5.23/60.3, 10.8, 17.9, 34.0, not determined, and not
determined mg/kg/day, respectively, for males, and 0, 2.52, 6.83/56.0, 11.8, 21.5, 35.3, not
determined, and not determined mg/kg/day, respectively, for females) and fed to 10 Crl:CD庐-
1(ICR)BR mice per sex per dose level for at least 28 consecutive days. Mortalities (including
animals sacrificed in extremis) occurred as follows- males: 0/10, 0/10, 1/10, 0/10, 0/10, 1/10,
10/10, 10/10, respectively; females: 0/10, 0/10, 0/10, 0/10, 0/10, 1/10, 10/10, 10/10, respectively.
Treatment-related impaired gait or mobility, ataxia, dehydration, enophthalmus, head tilt, and
tremors at 235 ppm and above were observed in both males and females. Statistically significant
and treatment-related decreased mean body weights, mean body weight gains, and mean daily
food consumption were observed in males at 118 ppm and above and in females at 235 ppm and
above. No adverse effects. NOEL (M)=10.8 mg/kg/day (59 ppm) and (F)=21.5 mg/kg/day (118
ppm) (based on statistically significant and treatment-related decreased mean body weights, mean
body weight gains, and mean daily food intake). Supplemental study (animals were dosed for
only 28 days, no clinical chemistry on the test animals was conducted, and no histopathology on
the test animals was performed). (Corlett, 1/11/99)
** 045; 162213; 鈥淩epeated Dose Dermal Toxicity: 28-Day Study with DPX-MP062 Technical
(Consisting of Approximately 75% DPX-KN128 and 25% DPX-KN127) in Rats鈥? (Mertens,
J.J.W.M., WIL Research Laboratories, Inc., Ashland, OH, Haskell Laboratory Project ID: HLO 747-
96, Performing Laboratory Project ID: WIL-189027, 11/19/97). 822. DPX-MP062-51 Technical
(Batch No. DPX-MP062-51A, 74.7% DPX-KN128), moistened with deionized water to form a
paste, was applied to the shaved skin of 5 Crl:CD庐BR (Sprague-Dawley) rats per sex per dose at
concentrations of 0, 50, 500, 1000, or 2000 mg/kg/day for 6 hours per day 7 days per week for 4
consecutive weeks using an occlusive wrap. No animals died. Dried yellow staining of the
urogenital, anogenital, and hindlimb areas in males beginning at 1000 mg/kg/day and in females
beginning at 500 mg/kg/day was observed. Treatment-related decreases in mean red blood cell
(in both males and females), in mean hemoglobin (in females only), and mean hematocrit (in
females only) levels at 2000 mg/kg/day were observed. Treatment-related increases in mean cell
volume and in mean cell hemoglobin in both males and females at 2000 mg/kg/day were
observed. Treatment-related focal eschar was observed at all dose levels. Necropsy and
microscopic examination revealed no treatment-related abnormalities. No adverse effects. NOEL
(systemic, M/F)=1000 mg/kg/day (based on a treatment-related decrease in mean red blood cell
levels and treatment-related increases in mean cell volume and mean cell hemoglobin levels in
males and females and on treatment-related decreases in mean hemoglobin and mean hematocrit
levels in females), NOEL (dermal, M/F)< 50 mg/kg/day (based on treatment-related focal eschar).
DPR MEDICAL TOXICOLOGY
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Acceptable. (Corlett, 2/17/99)
52425-0135; 204672; 鈥淒PX-MP062 Technical: Repeated-Dose Dermal Toxicity 28-Day Study in
Rats鈥?; (S.A. MacKenzie; E.I. du Pont de Nemours & Co., Haskell Laboratory for Toxicology and
Industrial Medicine, Newark, DE; Project ID. DuPont-2813; 10/18/99); The skin of 10
Crl:CD(SD)IGS BR rats/sex/group was treated with 0, 50, 500, 1000 or 2000 mg/kg/day of DPX-
MP062 Technical (batch no. DPX-MP062-216; purity: 95.83% (DPX-KN128 (active isomer, S-(+)
enantiomer, 75%), IN-KN127 (inactive isomer, R-(-) enantiomer, 25%)) 6 hours/day for 28 days.
Three females in the 2000 mg/kg group were euthanized in extremis; two on study day 7 and one
on study day 11. Two of these deaths were considered to be treatment-related. The mean body
weights of the females in the 500 mg/kg group and above were less than that of the females in the
control group by the end of the study (p<0.05). The mean body weight gains for these females
and for the 2000 mg/kg males were less than those of the control group (p<0.05). The mean food
consumption for the 500 mg/kg and above females and for the 1000 mg/kg and above males was
less than that of the control at various times during the study (p<0.05). Both sexes in the 500
mg/kg group and above exhibited an increased incidence of stained perineum and/or underbody in
comparison to the controls (stained perineum: (M) 0: 4/10 vs. 500: 10/10, 1000: 10/10, 2000:
10/10, (F) 0: 1/10 vs. 500: 10/10, 1000: 10/10, 2000: 8/10; stained underbody: (M) 0: 0/10 vs. 500:
6/10, 1000: 10/10, 2000: 10/10, (F) 0: 0/10 vs. 500: 2/10, 1000: 10/10, 2000: 10/10). In the
hematology evaluation, the mean red blood cell count and hemoglobin concentration for both
sexes in the 500 mg/kg group and above were lower than those of the controls (p<0.5). The mean
MCV values for the 1000 mg/kg males and above and for the 500 mg/kg females and above were
greater than those values for the controls (p<0.05). The mean MCHC values were
correspondingly lower for these same animals (p<0.05). The mean percentage of
methemoglobinemia was increased for the males in the 500 mg/kg group and above and for the
1000 mg/kg females and above (p<0.05). The males in the 500 mg/kg group and above and the
females in the 50 mg/kg group and above demonstrated an increase in the number of
reticulocytes over that of the controls (p<0.05). Among the clinical chemistry parameters
examined, the mean serum bilirubin was increased for the 1000 and 2000 mg/kg males (p<0.05).
The mean creatinine levels were increased for the males in the 500 mg/kg group and above
(p<0.05). The mean inorganic phosphate level for the 2000 mg/kg males was greater than that of
the controls (p<0.05). The mean cholesterol levels for the females in the 500 mg/kg group and
above were increased above that of the control (p<0.05). In the necropsy examination, the mean
absolute and relative spleen weights for the 500 mg/kg males were greater than those of the
controls (p<0.05). The mean relative spleen weight of the 2000 mg/kg females was greater than
that of the controls (p<0.05). The histopathology examination revealed the incidence of increased
extramedulallary hematopoiesis in the spleen of both sexes in the 50 mg/kg group and above ((M)
0: 0/10 vs. 50: 6/10, 500: 10/10, 1000: 10/10, 2000: 10/10; (F) 0: 0/10 vs. 50: 3/10, 500: 9/10,
1000: 7/10, 2000: 6/10) (note: 3 females in the 2000 mg/kg group were euthanized by day 11).
Pigmented macrophages were evident in the spleens of the males in the 500 mg/kg group and
above and the females in the 50 mg/kg group and above ((M) 0: 0/10 vs. 500: 10/10, 1000: 10/10,
2000: 10/10; (F) 0: 0/10 vs. 50: 7/10, 500: 10/10, 1000: 10/10, 2000: 8/10). In the 2000 mg/kg
group, a fatty change in the median cleft of the liver of 2 females was noted. Focal necrosis in the
liver of one of these females was also evident. Possible adverse effect: anemia; Subchronic
dermal toxicity NOEL: (M/F) < 50 mg/kg/day (based upon increased extramedullary
hematopoiesis in the spleen and an increase in reticulocyte number noted for the 50 mg/kg
group); Study acceptable. (Moore, 8/23/04)
52425-0134; 203322; 鈥淒PX-MP062 Manufacturing Use Product: Four-Week Inhalation Toxicity
Study in Rats鈥?; (A.J. O鈥橬eill; E.I. du Pont de Nemours and Co., Haskell Laboratory for Health and
Environmental Sciences, Newark, DE; Project ID. DuPont-10222; 2/21/03); Ten Crl:CD(SD)IGS
BR rats/sex/group were exposed nose-only to 0, 4.6, 23, or 290 mg/m3 (gravimetric) of DPX-
MP062 (batch no. DPX-MP062-89A; DPX-MP062: 70%; DPX-KN128: 51.9%, DPX-KN127: 18.1%)
6 hours/day, 5 days/week for 4 weeks. An additional group of 5 females was exposed in the
same manner to 82 mg/m3 of the carrier alone (designated H-25232). The mean MMAD (GSD)
DPR MEDICAL TOXICOLOGY
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values for the 4.6, 23 and 290 mg/m3 exposures were 1.30 (2.10), 1.25 (2.30) and 1.30 (2.10) um,
respectively; the mean MMAD value for the carrier was 1.20 um (no GSD was calculated because
the distribution was not log-normally distributed). The mean body weights for the 23 and 290
mg/m3 males were lower than those of the controls over the course of the study (p<0.05). Food
consumption was lower for the males in the 23 mg/m3 group and for both sexes in the 290 mg/m3
group at various times during the study (p<0.05). Clinical signs of stained fur were evident for both
sexes in the 290 mg/m3 group ((M) 0: 0/10 vs. 290: 3/10, (F) 0: 0/10 vs. 290: 9/10). An increasing
number of animals exhibited nasal/ocular discharge in all of the test material exposure groups ((M)
0: 3/10 vs. 4.6: 8/10, 23: 9/10, 290: 10/10, (F) 0: 4/10 vs. 4.6: 10/10, 23: 8/10, 290: 10/10)
(p<0.05). In the hematology evaluation, the 290 mg/m3 females demonstrated treatment-related
effects of lower red blood cell count, hemoglobin concentration, and hematocrit (p<0.05). Both of
the sexes in the 290 mg/m3 group had elevated reticulocyte counts (M: NS, F: p<0.05). The 290
mg/m3 females as well as the females exposed to the carrier had increased neutrophil counts
(p<0.05). In the clinical chemistry results, both sexes in the 290 mg/m3 group and the females in
the 23 mg/m3 group had elevated serum creatinine levels. The serum cholesterol concentration
was elevated for the 290 mg/m3 females (p<0.05). The females exposed to the carrier had an
increased serum alkaline phosphatase activity level (p<0.05). Both of the sexes in the 290 mg/m3
group had an increased level of serum bilirubin (M: p<0.05, F: NS). In the urinalysis, both of the
sexes in the 290 mg/m3 group excreted greater urine volumes with concomitant decreases in
osmolality (p<0.05). In the necropsy examination, the mean absolute and relative lung weights for
the 23 and 290 mg/m3 females and the mean relative lung weights for the 23 and 290 mg/m3
males were greater than those of the controls (p<0.05). The mean absolute and relative spleen
weights were greater for both sexes in the 290 mg/m3 group. The mean absolute kidney weights
for the 23 mg/m3 females and the mean absolute and relative kidney weights for the 290 mg/m3
females were less than those of the control (p<0.05). The mean relative testes weights for the 23
and 290 mg/m3 males were greater than that of the control (p<0.05). The mean relative
epididymides weight for the 290 mg/m3 males was also greater than that of the control (p<0.05).
In the histopathology examination, the lungs, liver and spleen were the apparent target organs. In
the lungs, both sexes in the 23 and 290 mg/m3 groups and the females exposed to the carrier
exhibited minimal subacute/chronic inflammation ((M) 0: 0/10 vs. 23: 3/10, 290: 8/10; (F) 0: 1/10
vs. 23: 7/10, 290: 10/10, 82: 5/5). Minimal hyperplasia/squamous metaplasia in the bronchioles
and alveolar ducts was noted for these animals as well ((M) 0: 0/10 vs. 23: 6/10, 290: 10/10; (F) 0:
0/10 vs. 23: 5/10, 290: 10/10, 82: 5/5). In the pharynx/larynx region, minimal or mild squamous
metaplasia was evident for animals in the same groups ((M) 0: 0/10 vs. 23: 3/10, 290: 9/10; (F) 0:
0/10 vs. 23: 2/10, 290: 6/10, 82: 5/5). Females in the 290 mg/m3 group exhibited focal necrosis in
the liver (0: 0/10 vs. 290: 2/10). In the spleen, a minimal or mild increase in pigmentation was
evident for both sexes in the 290 mg/m3 group ((M) 0: 0/10 vs. 290: 10/10, (F) 0: 0/10 vs. 290:
10/10). Increased extramedullary hematopoiesis was also noted in the spleen of these animals
((M) 0: 0/10 vs. 290: 9/10, (F) 0: 0/10 vs. 290: 8/10). The females in the 290 mg/m3 group also
exhibited atrophy of the thymus (0: 0/10 vs. 290: 2/10). Possible adverse effects: pulmonary
squamous metaplasia and focal necrosis in the liver. Subacute NOEL: (M/F) 4.6 mg/m3 (based
upon the incidence of inflammation in the lungs and squamous cell metaplasia in the lungs and
pharynx of the 23 mg/m3 exposure group). Study supplemental (non-guideline study). (Moore,
8/19/04)
** 034; 162199; 鈥淪ubchronic Oral Toxicity:90-Day Study with DPX-MP062 (Approximately 75%
DPX-KN128, 25% DPX-KN127) Feeding Study in Rats鈥? (MacKenzie, S.A., Haskell Laboratory for
Toxicology and Industrial Medicine, E.I. du Pont de Nemours and Company, Newark, DE,
Laboratory Project ID DuPont HL-1997-00056, 3/24/97). 821. DPX-MP062 (Batch No. DPX-
MP062-51A, 74.7% DPX-KN128) was admixed to the feed at concentrations of 0, 10, 25 (females
only), 50, 100, or 200 (males only) ppm (0, 0.620, 3.09, 6.01, or 15.0 mg/kg/day, respectively, for
males and 0, 0.760, 2.13, 3.78, or 8.94 mg/kg/day, respectively, for females) and fed to 10 Crl:CD庐
(SD)BR rats per sex per dose level for approximately 90 days. 5 females at 100 ppm died or were
sacrificed in extremis. No dose-related clinical signs were observed in males; among females at
100 ppm, ataxia (in 2 of the mortalities), weakness (in 4 animals), and tremors (in 1 of the
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mortalities) were observed. Treatment-related decreased mean body weight and decreased mean
body weight gain in males at 200 ppm and in females at 50 and 100 ppm were observed.
Statistically significant and dose-related decreases in mean red blood cell, hemoglobin, and
hematocrit levels in males beginning at 100 ppm, 50 ppm, and 100 ppm, respectively, and in
females beginning at 25 ppm, 10 ppm, and 10 ppm, respectively, were observed. Microscopic
examination revealed treatment-related increased pigment and increased extramedullary
hematopoiesis in the spleen in males at 50, 100, and 200 ppm, and in females at all dose levels.
No adverse effects. NOEL (M)=0.620 mg/kg/day (10 ppm) and (F)< 0.760 mg/kg/day (10 ppm)
[based on treatment-related decreased mean hemoglobin (males and females) and hematocrit
(females) levels and histologic effects in the spleen). Acceptable. (Corlett, 1/19/99)
** 035; 162200; 鈥淪ubchronic Oral Toxicity:90-Day Study with DPX-JW062-34 (50% DPX-KN128,
50% DPX-KN127) Feeding Study in Mice鈥? [Malek, D.E., Haskell Laboratory for Toxicology and
Industrial Medicine, E.I. du Pont de Nemours and Company, Newark, DE, Haskell Laboratory
Report No. 750-93 (Revision No. 1), 1/22/97]. 821. DPX-JW062-34 Technical (Batch No. DPX-
JW062-34, 47.4% DPX-KN128) was admixed to the feed at concentrations of 0, 10/300 (started at
10 ppm and increased to 300 ppm on Day 42 of feeding), 35, 75, or 150 ppm (0, 1.7/44, 5.5, 12, or
23 mg/kg/day, respectively, for males and 0, 2.1/51, 7.0, 16, or 30 mg/kg/day, respectively, for
females) and fed to 10 Crl:CD-1庐(ICR)BR mice per sex per dose level for approximately 90 days.
One male at 300 ppm was found dead on day 85. Treatment-related clinical signs included
animals leaning to one side (in males at 300 ppm and in females at 150 and 300 ppm), abnormal
gait or mobility (in females at 300 ppm), and tremors (in one male at 300 ppm). Treatment-related
decreases in mean body weight (in males at 300 ppm), mean body weight gain (in males at 300
ppm), and mean daily food consumed per mouse (in males at 300 ppm and in females at 150 and
300 ppm) were observed. Treatment-related increases in mean reticulocyte (in males and
females at 300 ppm), mean cell volume (in males at 300 ppm and in females at 150 and 300
ppm), and mean white blood cell (in males and females at 300 ppm) levels, and the treatment-
related presence of Heinz bodies (in males and females at 150 and 300 ppm) were observed.
Microscopic examination revealed treatment-related increased pigment in the spleen in males and
females beginning at 75 ppm. No adverse effects. NOEL (M)=5.5 mg/kg/day (35 ppm) and
(F)=7.0 mg/kg/day (35 ppm) (based on treatment-related increased pigment in the spleen).
Acceptable. (Corlett, 1/28/99)
** 036; 162201; 鈥淪ubchronic Oral Toxicity:90-Day Study with DPX-JW062-106 (Approximately
50% DPX-KN128, 50% DPX-KN127) Feeding Study in Dogs鈥? (Mertens, J.J.W.M., WIL Research
Laboratories, Inc., Ashland, OH, Haskell Laboratory Project ID: HLO 494-95, Performing
Laboratory Project ID: WIL-189016, 11/19/97). 821. DPX-JW062 Technical (Batch No. DPX-
JW062-106, 47.5% DPX-KN128) was admixed to the feed at concentrations of 0, 40, 80, 160, or
640 ppm (0, 1, 2, 5, or 18 mg/kg/day, respectively, for males, and 0, 1, 3, 5, or 17 mg/kg/day,
respectively, for females) and fed to 4 outbred beagle dogs per sex per dose level for 13 weeks.
No animals died during the study interval. No treatment-related clinical signs were observed.
Statistically significant and treatment-related decreases in mean red blood cell and hemoglobin
levels in males at 160 and 640 ppm, and females at 640 ppm and statistically significant and dose-
related increases in mean cell volume in males beginning at 160 ppm and in females beginning at
80 ppm and percent reticulocytes in males at 640 ppm and in females at 160 and 640 ppm were
observed. Treatment-related increases in Heinz bodies and mean total bilirubin levels were
observed in males and females at 160 and 640 ppm. Microscopic examination revealed a
treatment-related increase in pigment in the spleen beginning in males at 40 ppm and in females
at 80 ppm, increased extramedullary hematopoiesis in the spleen beginning in males and females
at 160 ppm, treatment-related erythrocytic hyperplasia and an increase in pigment in the bone
marrow in males beginning at 80 ppm and in females beginning at 40 ppm, and a treatment-
related increase in pigment in the liver in males and females beginning at 80 ppm. No adverse
effects. NOEL (M/F)< 1 mg/kg/day (40 ppm) (based on a treatment-related increase in pigment in
the spleen in males, and on a treatment-related increase in extramedullary hematopoiesis in the
spleen, and treatment-related erythrocytic hyperplasia and a treatment-related increase in pigment
DPR MEDICAL TOXICOLOGY
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in the bone marrow in females). Acceptable. (Corlett, 2/10/99)
** 037; 162202; 鈥淪ubchronic Oral Toxicity:90-Day Study with DPX-JW062-34 (50% DPX-KN128,
50% DPX-KN127) Feeding Study in Rats鈥? [Malek, D.E., Haskell Laboratory for Toxicology and
Industrial Medicine, E.I. du Pont de Nemours and Company, Newark, DE, Haskell Laboratory
Report No. 751-93 (Revision No. 2), 11/17/97]. 821. DPX-JW062-34 Technical (Batch No. DPX-
JW062-34, 47.4% DPX-KN128) was admixed to the feed at concentrations of 0, 15 (females only),
30, 60, 125, or 250 (males only) ppm (0, 1.92, 3.91, 7.95, or 16.1 mg/kg/day, respectively, for
males and 0, 0.992, 2.30, 4.59, or 9.48 mg/kg/day, respectively, for females) and fed to 10 Crl:CD
庐
BR rats per sex per dose level for approximately 90 days. One female at 125 ppm was found
dead on test day 26. No dose-related clinical signs were observed. Treatment-related decreases
mean body weight, mean body weight gain, and mean daily food consumed per rat in males at 250
ppm and in females at 125 ppm were observed. Statistically significant and dose-related
decreases in mean red blood cell and hemoglobin were reported in males and females at 30 ppm
and higher. An increase in mean reticulocyte (in males at 250 ppm and in females at 125 ppm)
and mean cell volume (in males at 250 ppm and in females at 60 and 125 ppm) levels were
observed. Microscopic examination revealed treatment-related and dose-related increases in the
incidence of pigment in the spleen in males and females beginning at 30 ppm and of erythrocytic
hyperplasia in the spleen in males and female beginning at 60 ppm, and treatment-related
increased incidences in pigment in Kupffer cells in the liver and in bone marrow hyperplasia in
males at 250 ppm and in females at 125 ppm. No adverse effects. NOEL (M)<30 ppm and
(F)=0.992 mg/kg/day (15 ppm) [based on treatment-related decreased mean red blood cell and
hemoglobin levels (males and females), decreased mean hematocrit level (males only), and an
increase in incidence of pigment in the spleen)]. Acceptable. (Corlett, 1/22/99)
** 039; 162204; 鈥淪ubchronic Oral Toxicity:90-Day Study with DPX-JW062-69 (99.7% DPX-
KN128) Feeding Study in Rats鈥? [Malek, D.E., Haskell Laboratory for Toxicology and Industrial
Medicine, E.I. du Pont de Nemours and Company, Newark, DE, Haskell Laboratory Report No.
301-94 (Revision No. 2), 11/17/97]. 821. DPX-JW062-69 Technical (Batch No. DPX-JW062-69,
purity=91.2%) was admixed to the feed at concentrations of 0, 3 (females only), 8, 20, 50, 100, or
200 (males only) ppm (0, 0.56, 1.4, 3.2, 6.6, or 14 mg/kg/day, respectively, for males and 0, 0.25,
0.68, 1.7, 4.1, or 8.5 mg/kg/day, respectively, for females) and fed to 10 Crl:CD 庐BR rats per sex
per dose level for approximately 90 days. One male at 200 ppm was sacrificed in extremis on test
day 87. No dose-related clinical signs were observed. Dose-related and statistically significant
decreases in mean body weight and mean body weight gain at 200 ppm in males and at 50 and
100 ppm in females, and in mean daily food consumed per rat in males at 200 ppm and in females
at 100 ppm were observed. Biologically significant decreases in mean red blood cell and
hemoglobin levels in males beginning at 100 ppm and in females beginning at 20 ppm were
observed. Microscopic examination revealed treatment-related and dose-related increases in the
incidence of pigment in the spleen in males beginning at 50 ppm and females beginning at 20
ppm. No adverse effects. NOEL (M)=1.4 mg/kg/day (20 ppm) and (F)=0.68 mg/kg/day (8 ppm)
[based on a treatment-related increase in incidence of pigment in the spleen (males and females)
and biologically significant decreases in mean red blood cell and mean hemoglobin levels
(females)]. Acceptable. (Corlett, 2/2/99)
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