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EC number: 266-582-5
CAS number: 67124-09-8
significant test article-related lesions were noted in the tissues
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.
A 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.
A dermal mass observed
grossly in a Group 4 female (1403) was diagnosed as a mammary carcinoma.
The renal lesions
noted in the control and treated animals represent changes associated
with hyaline droplet nephropathy (HDN) and/or chronic progressive
Hyaline 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).
The 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.
incidence of tubular changes and inflammation in Group 4 males is
interpreted and the dual expression of both HDN and CPN.
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
The 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.
Other changes noted
were considered to be normal findings in rats of this age and strain.
This 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 HPV-1 (CAS #67124-09-8) on
neonatal moribundity, mortality and postnatal developmental toxicity.
The 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, toF0parental 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.F0males 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
Both 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.
Oral administration of 1-(tert-dodecylthio)propan-2-ol
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/ay group.
Mean food consumption
of F0 males in the 50, 167 and 500 mg/kg/day groups was comparable to
controls throughout the study and 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 evaluated, F0 male gross necropsy
observations, F0 male absolute or relative organ weights or the F0 male
sperm parameters evaluated. In addition, no toxicologically meaningful
microscopic lesions were observed in any of the F0 male tissues/organs
examined from this study.
Oral administration of 1-(tert-dodecylthio)propan-2-ol
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 mg/kg/day group.
There 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.
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 testing 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
According to the study
director, a dosage level of 50 mg/kg/day was considered to be the NOAEL
for parental (F0) 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 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. The doses level of 167 mg/kg/days
was determined to be the NOAEL for parental toxicity.
For F1 generation, the decreased mean pup
weight that was observed at 167 mg/kg/day and 500 mg/kg/day were within
historical range of the test laboratory. However, because the decrease
in pup weights at the high dose was highly significant, the LOAEL for
fetotoxicity was determined to be 500 mg/kg/day. The NOAEL was
determined to be 167 mg/kg/day because 1) the decrease in pup weights
were within the historical control range and were not highly significant
and 2) the pups gained weight at comparable rate comparing to the
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