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EC number: 265-078-2
CAS number: 64741-77-1
A complex combination of hydrocarbons from distillation of the products from a hydrocracking process. It consists predominantly of saturated hydrocarbons having carbon numbers predominantly in the range of C10 through C18, and boiling in the range of approximately 160°C to 320°C (320°F to 608°F).
OBJECTIVE AND METHODS
objective of this study was to characterize the effects of 'Distillates
(Fischer - Tropsch), heavy, C18-50 – branched, cyclic and linear' on the
integrity and performance of the male and female reproductive systems,
including gonadal function, the estrus cycle, mating behavior,
conception, gestation, parturition, lactation, and weaning of the F0 and
F1generations, as well as the neonatal survival, growth, and development
of the F1and F2offspring.
groups of male and female Crl:CD(SD) rats (25 or 26/sex/group for the
F0generation and 25/sex/group for the F1generation) were administered
the test item, daily by oral gavage for at least 70 consecutive days
prior to mating. Dosage levels were 50, 250, and 1000 mg/kg/day for the
F0and F1generations. A concurrent control group of 25 or 26/sex and
25/sex for the F0 and F1generations, respectively, received the vehicle,
corn oil (CAS No. 8001-30-7), on a comparable regimen. F0animals were
approximately 6 to 7 weeks (42 to 46 days) of age at the initiation of
test item administration. The test item was administered to offspring
selected to become the F1parental generation following weaning,
beginning on postnatal day (PND) 22. The F0 and F1males continued to
receive the test item throughout mating and through the day prior to
euthanasia. The F0 and F1females continued to receive the test item
throughout mating, gestation, and lactation, and through the day prior
were observed at least twice daily for mortality. Clinical observations,
body weights, and food consumption were recorded at appropriate
intervals for males throughout the study and for females prior to mating
and during gestation and lactation. Vaginal smears were performed daily
for determination of estrous cycles beginning 21 days prior to pairing.
All F0 and F1females were allowed to deliver and rear their pups until
weaning on lactation day (LD=PND) 21. Clinical observations, body
weights, and sexes for F1and F2pups were recorded at appropriate
intervals. For both generations (F1and F2), 10 pups per litter (5 per
sex, when possible) were arbitrarily selected on PND 4 to reduce the
variability among the litters.
(25/sex/group) from the pairing of the F0animals were selected on PND 21
to constitute the F1generation. Developmental landmarks (balanopreputial
separation and vaginal patency) were evaluated for the selected F1rats.
Nonselected F1pups were necropsied on PND 21, and F2pups were necropsied
on PND 21. Selected organs (brain, spleen, and thymus) were weighed from
1 pup/sex/litter (when possible) from both F1and F2pups that were
necropsied on PND 21. Each F0and F1parental animal received a complete
detailed gross necropsy (the surviving female parental animals were
necropsied on LD 21), and selected organs were weighed. Spermatogenic
endpoints [sperm motility (including progressive motility), morphology,
and number] were recorded for F0and F1males as appropriate, and ovarian
primordial follicle counts and the corpora lutea counts were recorded
for all F1females in the control and high-dose groups. Designated
tissues from the F0 and F1parental animals were examined microscopically.
OF RESULTS AND CONCLUSION
of the test material 'Distillates (Fischer-Tropsch), heavy, C18-50 -
branched, cyclic and linear' to male and female rats at dosages up to
1000 mg/kg/day had no effect on reproductive performance or gestation
length and parturition of both the F0and F1parental generations. In
addition, there were no test item-related effects on F1and F2litter
parameters, postnatal survival, physical condition/mortality, or pup
body weights. Vaginal patency of F1females and balanopreputial
separation in F1males were unaffected by test item administration.
Andrology parameters were unaffected by test item administration.
there were 8 unscheduled deaths of parental animals (1 F0female, 4
F1males, and 3 F1females). None of the deaths were directly attributed
to the test item. Based on macroscopic (and in some cases microscopic)
findings, 3 of the deaths (all F1males; 1 in Group 3 and 2 in Group 4)
were likely due to gavage error and/or aspiration of the dose
formulation into the lungs.
relatively low viscosity nature of the test item (kinematic viscosity at
40 ºC of 22.7 cSt) and the use of corn oil as the vehicle, aspiration
events were not unexpected. One F1female (Group 3) was injured by her
mating partner and euthanized for humane reasons. One F1female (Group 3)
was euthanized following a self-inflicted injury (it had caught its
head/jaw in the cage lid). One F0(Group 2) and one F1(Group 1) females
with dystocia were also euthanized. The cause of death for one F1male
(Group 4) was unable to be definitively determined at necropsy.
no adverse test item-related effects on F0and F1parental body weights,
body weight changes, feed consumption, and food efficiency. Test
item-related histopathological lesions were identified in the lungs of
both males and females of the F0and F1generations. There was an
increased incidence and severity of chronic interstitial/alveolus
inflammation in the F0and F1males and females given 1000 mg/kg/day; this
microscopic finding correlated with macroscopic observations in F0males
and females, as well as increased absolute and/or relative lung weights
in F0and F1males and females. As these lung lesions were considered to
be secondary to aspiration of the dose formulation, and the chronic
interstitial/alveolus inflammation finding was not unanticipated based
on a previous 90-day, repeat-dose study with this test item, the lungs
from the low- and mid-dose animals were not evaluated. A test
item-related, slight increase in the incidence of renal tubule hyaline
droplets was seen in the F1males given 1000 mg/kg/day; however, only
kidneys with gross lesions were examined in this study. The morphologic
appearance of these droplets suggested hydrocarbon-induceda2µ-globulin
male rat nephropathy, an anticipated outcome of this study. No
degenerative/necrotic renal tubule changes were observed in association
with the hyaline droplets.
distance (AGD) for female F1, but not F2, pups was statistically
significantly decreased to a similar level in all test item-treated
groups and in groups given 250 and 1000 mg/kg/day when adjusted for body
weight compared with the control group. However, these changes were not
considered adverse, as the AGD and adjusted AGD values for all groups
spanned a range similar to the historical control range for AGD in
F2pups and fell within the range noted for the F2females on this study.
(Note: F1pup AGD is a nonstandard endpoint, not required by the OECD 416
guidelines; therefore, no historical control ranges exist at this test
facility.) Other female parameters such as vaginal patency and estrous
cyclicity were unaffected by test item administration. A decrease in AGD
values in females is generally not considered toxicologically relevant.
In addition, the biological meaning of this small change in AGD is not
clear, as hyperfeminization was not apparent based on other endpoints,
and since there were no adverse effects on the F1 reproductive
parameters or the F2 pup parameters. An equivocal, nonadverse, slight
decrease in F2pup brain weights was noted. Macroscopic and microscopic
findings in PND 21 pups were not test item related.
substance [0 (vehicle), 50, 250, or 1000 mg/kg/day)] was given orally to
F0and F1parental male and female rats for at least 70 days prior to
mating and throughout the 14-day mating, postmating holding (for males),
and gestation and lactation (for females) periods. There was a test
item-related, nonadverse decrease in AGD in F1females born from dams
given 250 and 1000 mg/kg/day. Test item-related histopathological
lesions were identified in the lungs (chronic interstitial/alveolus
inflammation) of both males and females of the F0and F1generations with
corresponding macroscopic findings and/or increased lung weights and the
kidneys (renal tubulehyaline droplets likely representinga2µ-globulin)
of the F1males only. The lung lesions were most likely secondary to
aspiration of the test material and therefore not relevant for human
risk assessment. The renal effects are a well known male rat specific
effect which is induced by hydrocarbons and has no relevance for humans.
An equivocal, nonadverse slight decrease in F2pup brain weights was
noted. Based on the absence of adverse, test item-related findings on
the integrity and performance of the male and female reproductive
systems, the absence of adverse findings directly attributable to the
test item in nonreproductive tissues, and the absence of adverse effects
on in-life parameters (such as body weight, feed consumption, and
clinical observations), a dosage level of 1000 mg/kg/day was considered
to be the no-observed-adverse-effect level (NOAEL) for reproductive and
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