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EC number: 266-582-5
CAS number: 67124-09-8
toxicologically significant test article-related lesions were noted in
the tissues examined.
kidney observations are listed separately under left and right kidneys,
findings are presented as combined data for both kidneys. Minimal to
mild hyaline droplet accumulation was present in 27 Group 4 males (96%).
Other prominent renal changes including tubular epithelial
degeneration/regeneration, tubular dilatation and inflammation were
noted in males and females from Groups 1and 4. The incidences of these
lesions varied by sex and dose group.
nephroblastoma was noted in the left kidney of a Group 4 female (1353).
The mass was approximately 5 x 8 mm, was well-delineated and occupied
the cortical and medullary space at one pole of the kidney, well within
the limits of the normal structure.
dermal mass observed grossly in a Group 4 female (1403) was diagnosed as
a mammary carcinoma.
renal lesions noted in the control and treated animals represent changes
associated with hyaline droplet nephropathy (HDN) and/or chronic
progressive nephropathy (CPN).
droplets, as noted in the Group 4 males, can be induced by a variety of
chemical compounds in certain strains of male rats and is frequently
associated with the accumulation of a2m-globulin within the hyaline
droplets. A progressive nephropathy accompanies hyaline droplet
accumulation, highlighted early on by tubular epithelial
degeneration/regeneration and tubular dilatation with granular casts.
Although histological findings in this study are consistent with a2m
-globulin, specific identification of a,,-globulin has not been done.
Definitive diagnosis of a2m - globulin is academic in that its presence
and the associated nephropathy (HDN) In male rats is not considered
toxicologically significant for humans according to Environmental
Protection Agency Risk Assessment Forum (Baetck K.P, et al 1991).
renal tubular degeneration/regeneration, tubular dilatation and
inflammation, as observed in control animals and Group 4 females, are
consistent with the constellation of lesions representing early signs of
Chronic Progressive Nephropathy (CPN), a spontaneous, progressive,
age-related entity. CPN is most common and prominent in male rats, as
noted in this study.
increased incidence of tubular changes and inflammation in Group 4 males
is interpreted and the dual expression of both HDN and CPN.
occur rarely in young adult rats, with an incidence of 0 -0.4% (Mesfin,
G.M. 1999). This was interpreted as an incidental finding and not
considered treatment related.
most common spontaneous neoplasm in aged Sprague-Dawley females are of
mammary gland origin. Incidence of mammary carcinomas is 8.8% according
to Chandra, et. al.(Chandra M, 1992). This lesion was interpreted as
spontaneous and was not considered test article related.
changes noted were considered to be normal findings in rats of this age
study was conducted to evaluate the potential effects of oral
administration of HPV-1 (CAS #67124-09-8) on the integrity and
performance of the reproductive system in male and female rats,
including gonadal function, mating behavior, conception, gestation,
parturition, lactation and weaning. This study was also conducted to
provide preliminary information concerning the effects of the test
substance on neonatal moribundity, mortality and postnatal developmental
toxicity. This standardized procedure was conducted according to OECD
study consisted of a vehicle control and three treatment groups, with 28
males and 28 females in each group. HPV-1 (CAS #67124-09-8) was
dissolved in corn oil and administered at dosage levels of 50, 167 and
500 mg/kg/day, by once daily oral gavage, to F0 parental animals. All
doses were given at a constant volume of 2.5 mL/kg. Control animals were
administered corn oil under the same experimental conditions at an
equivalent dose volume.F0 males were treated for a minimum of 70 days
prior to mating and until completion of parturition. F0 females were
treated for a minimum of 14 days prior to mating through lactation day
F0 parental animals and F1 offspring were closely examined for
indications of toxicity. Experimental endpoints for F0 animals included
clinical observations, body weights, food consumption, mating,
parturition, lactation, hematology determinations and offspring growth
and viability. All F0 and F1 animals were subjected to a gross necropsy
examination at the time of death or terminal euthanasia.
administration of the test substance to F0 male rats for a minimum of 70
days prior to mating and until completion of parturition produced
clinical signs including salivation prior to dosing and a dose-related
increase in post-dose salivation in the 167 and 500 mg/kg/day groups and
lower mean body weights (reduced approximately 5-7 % compared to
controls) in the 500 mg/kg/day group.
food consumption of F0 males in the 50, 167 and 500 mg/kg/day groups was
comparable to controls throughout the study. There were no
toxicologically meaningful differences between the control, 50, 167 and
500 mg/kg/day groups with respect to the F0 male mating and fertility
indices. The F0 male hematology parameters, F0 male gross necropsy
observations, F0 male absolute or relative organ weights or the F0 male
sperm parameters were evaluated and no statistically significant
differences were observed. In addition, no toxicologically meaningful
microscopic lesions were observed in any of the F0 male tissues/organs
examined from this study.
administration of the test substance to F0 female rats for a minimum of
14 days prior to mating and throughout lactation produced clinical signs
for F0 females in the 50, 167 and 500 mg/kg/day groups. The clinical
signs included a low incidence of reddish vaginal discharge, swelling
(mammary glands), dark material around the eyes and dark material around
the nose in the 50, 167 and 500 mg/kg/day groups; a low incidence of
salivation prior to dosing, an increased incidence of urine stain and a
dose-related increase in post-dose salivation in the 167 and 500
mg/kg/day groups; and a low incidence of ocular discharge in the 500
were no toxicologically meaningful differences between the control, 50,
167 and 500 mg/kg/day groups with respect to F0 female mean body
weights, body weight change, food consumption, mating and fertility
indices, precoital intervals, gestation lengths or the hematology
parameters evaluated. Gross necropsy findings for one F0 female in the
500 mg/kg/day group euthanized on post breeding day 25 included dark
brownish-red fluid in the uterus and vagina and one small placenta and
two nonviable pups in the vagina. No other remarkable findings were
noted in the F0 females at necropsy and no toxicologically meaningful
microscopic lesions were observed in any of the F0 female tissues/organs
examined from this study.
toxicologically meaningful differences were noted in F1 pup viability
during lactation. Mean F1 pup weights were statistically lower than
controls in the 167 mg/kg/day group on lactation day 14 and in the 500
mg/kg/day group on lactation days 14 and 21; however, mean F1 pup
weights in these groups remained within the range of the test laboratory
historical control data. With the possible exception of a slight
increase in the incidence of pups cool to the touch, no remarkable F1
pup observations were noted during lactation. No remarkable findings
were noted at necropsy for F1 pups stillborn, found dead, culled on day
4 or euthanized on lactation day 21.
of all observed toxicological effects were summarized in the following
F0 – Systemic Effects
F0 - Reproduction
F1 - Development
Live born pups is lower
Post dosing salivation, urine stain
Mean pup weights were lower (P < 0.05), but remained within the range of the test facilities historical control data.
Post dosing salivation, lower body weight, oculars discharge
Mean pup weights were lower (P < 0.05), but remained within the range of the test facilities historical control data
to the study director, a dosage level of 50 mg/kg/day was considered to
be the no-observed-adverse-effect level (NOAEL) for parental (FO)
toxicity. There were no indications of impaired fertility or other
reproductive effects in the F0 males or females at dosage levels up to
500 mg/kg/day. A dosage level of 50 mg/kg/ay was considered the
no-observed-adverse-effect level (NOAEL) for developmental effects, as a
result of decreased pup weights noted for the 167 and 500 mg/kg/day
group pups during the latter half of lactation.
The study results were re-examined and new
NOAELs for for parental and developmental toxicity were determined.
Comparing to 50 mg/kg/day, the additional clinical observations included
salivation and urine stain in females treated with 167 mg/kg/day test
substance. Because 1) salivation was considered to be a reflex to
administration of the test substance, 2) urine staining did not
correlate with urination pattern or kidney gross necropsy, and 3) the
severity of the effects is limited.
on the decreased body weight gains in F0 animals treated with 500
mg/kg/day, a dosage level of 167 mg/kg/day was considered to be the
NOAEL for parental (F0) toxicity.
dosage level of 167 mg/kg/day was considered the NOAEL for developmental
effects, since the decreased pup weights noted for the 167 and 500
mg/kg/day group pups during the latter half of lactation were within the
range of historical control data.
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