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EC number: 216-600-2
CAS number: 1623-05-8
Two repeat dose studies were conducted with PPVE. The
results of the studies were:
The No Observed Adverse Effect Concentration (NOAEC) is 43.89 mg/L (4034
ppm) when tested according to OECD 422 (2016).
The No Observed Adverse Effect Concentration (NOAEC) is 54.4 mg/L (5000
ppm) when tested according a custom protocol.
The repeat dose and reproductive and developmental toxicity potential of
the test article was evaluated when administered by whole body
inhalation to male and female Sprague Dawley rats for 28 days. The
potential for the test article to affect male and female reproductive
performance such as gonadal function, mating behavior and conception
through day 13 of postnatal life was evaluated followed by a 14 -day
recovery period. The study was conducted in compliance with OECD GLP
(1997). The test was conducted according to OECD Guideline 422
(2016).The test substance was administered as a 6-hour, whole-body
inhalation exposure daily to 3 groups of male and female Crl:CD(SD)
rats. The low- and mid-exposure groups (Groups 2–3) each consisted of 10
rats/sex and the high-exposure group (Group 4) consisted of 15 rats/sex.
Target exposure levels were 300, 1000, and 4000 parts per million (ppm).
A concurrent control group of 15 rats/sex was exposed to humidified,
filtered air on a comparable regimen. Overall mean exposure
concentrations were 300, 1004, and 4034 ppm for the 300, 1000, and 4000
ppm groups, respectively. Males and females were approximately 10 weeks
of age at the beginning of test substance exposure. Males were exposed
to the test substance for 14 days prior to mating. Males continued to be
exposed throughout the mating period through 1 day prior to euthanasia
for a total of 28 days. Females were exposed to the test substance for
14 days prior to pairing and were exposed through Gestation Day 20.
Exposure was suspended from Gestation Day 21 through Lactation Day 4 to
avoid potential confounding effects on nesting and nursing behavior
caused by separation of dams from their litters. Exposure of the F0
females with evidence of mating was re-initiated on Lactation Day 5 for
females that delivered and continued through the day prior to euthanasia
(Lactation Day 13) for a total of 50–53 days; females that failed to
deliver were exposed through the day prior to euthanasia (Post-Mating
day 25) for a total of 35–38 days. The extra 5 males and 5 females in
the control and high-exposure groups that were not used for mating were
exposed beginning on Study Day 0; following 28 days of exposure for
males and 49 days of exposure for females, these animals were assigned
to a 15-day nonexposure recovery period.
All animals were observed twice daily for mortality and moribundity.
Clinical observations, body weights, and food consumption were recorded
at appropriate intervals. FOB and motor activity data were recorded for
5 males/group on Study Day 27 and for 5 females/group on Lactation Day
13. All F0 females selected for pairing were allowed to deliver and rear
their pups until Lactation Day 14. F1 clinical observations, body
weights, and sexes were recorded at appropriate intervals and anogenital
distance was recorded on PND 1. To reduce variability among the litters,
8 pups/litter, 4 pups/sex when possible, were randomly selected on PND
4; blood samples for possible thyroid hormone analysis were collected
from the culled pups (1/sex/litter). All F1 male pups were evaluated for
areolae/nipple anlagen on PND 13. Remaining F1 pups were euthanized on
PND 13; blood samples for thyroid hormone analysis were collected and
selected organs were weighed from 1 pup/sex/litter. Clinical pathology
evaluations (hematology, coagulation, and serum chemistry) were
performed on 5 F0 animals/sex/group at the primary necropsy and 5
animals/sex in the control and high-exposure groups at the recovery
necropsy. Blood samples for thyroid hormone analysis were collected from
F0 males and females at the primary necropsy; only male samples were
analyzed. F0 males were euthanized following completion of the mating
period or 15-day recovery period and F0 females were euthanized on
Lactation Day 14 for females that delivered, Post-Mating Day 25 for
females that failed to deliver, or following the 15-day recovery period.
Complete necropsies were conducted on all F0 animals, and selected
organs were weighed. Selected tissues were examined microscopically from
all F0 animals in the control and high-exposure groups at the primary
necropsy. In addition, the kidneys and nasal level II were identified as
potential target tissues in males and were examined from all males in
all groups at the primary and recovery necropsies.
There was no test substance-related mortality noted at any exposure
level. One F0 female in the 300 ppm group was found dead on Lactation
Day 0; this death was attributed to dystocia and was considered
unrelated to test substance exposure. In addition, 1 male in the 4000
ppm group was found dead on the day of the recovery necropsy; the cause
of death was undetermined due to the lack of necropsy findings or
relevant histopathological changes and therefore was not attributed to
test substance exposure. All other F0 and F1 males and females survived
to the scheduled necropsies. Test substance-related red material around
the nose was noted for F0 males and females in the 1000 and 4000 ppm
groups approximately 1 hour following exposure generally throughout the
exposure period. This clinical observation generally did not persist to
the daily examinations on the following day and was; therefore, not
considered adverse. A test substance-related lower mean body weight gain
was noted for F0 males in the 4000 ppm group compared to the control
group for the overall exposure period (Study Days 0–27) due to a lower
mean body weight gain in this group during the first week of exposure.
However, mean absolute body weights in the 4000 ppm group F0 males were
similar to the control group throughout the study. Therefore, the lower
mean body weight gains observed in this group were not considered
adverse. Mean body weights and body weight gains in the 4000 ppm group
F0 males were similar to the control group during the recovery period.
Mean body weights and body weight gains in the 4000 ppm group F0 females
were unaffected by test substance exposure during the premating,
gestation, and lactation periods. Mean body weights in the 4000 ppm
group F0 females were similar to the control group throughout the
recovery period. Mean body weights and body weight gains in the 300 and
1000 ppm group F0 males and females and mean food consumption in all
test substance-exposed groups were unaffected by test substance exposure
throughout the study. Mean F0 male and female mating and fertility
indices, F0 male copulation indices, and F0 female conception indices in
the 300, 1000, and 4000 ppm groups were unaffected by test substance
exposure. The mean number of days between pairing and coitus, gestation
length, and the process of parturition were unaffected by test substance
exposure. There were no test substance-related effects noted on mean
estrous cycle lengths or the mean numbers of implantation sites and
unaccounted-for sites in F0 females at any exposure level. No test
substance-related effects were noted during the FOB or motor activity
evaluations at any exposure level in the F0 generation. There were no
test substance-related gross necropsy observations or alterations in
clinical pathology parameters (hematology, coagulation, and serum
chemistry) were noted for F0 males and females at any exposure level
during the primary and recovery evaluations. Mean serum T4 levels in the
F0 males were unaffected by test substance exposure. Test
substance-related higher mean absolute and relative (to final body
and/or brain weight) lung weights were noted for F0 males and females in
the 4000 ppm group at the primary necropsy. There were no microscopic
correlates for the higher lung weights and the values were generally
within the Charles River Ashland historical control data ranges;
therefore, the higher mean lung weights were not considered adverse.
Mean lung weights in the 4000 ppm F0 males and females were similar to
the control group at the recovery necropsy, indicative of complete
recovery. At the primary necropsy, lower incidences of tubular
basophilia and higher incidences of chronic progressive nephropathy
(CPN) were observed in the 4000 ppm group F0 males. As tubular
basophilia is the precursor change to the common background finding and
spontaneously developing CPN, these incidences demonstrated a
non-adverse test article-induced exacerbation in the development of CPN.
1 In addition, CPN and tubular basophilia in the control group males
tended to be unilateral while CPN was predominantly bilateral in the
4000 ppm group. In nasal level II, higher incidences of mixed cell
inflammation were seen in the 4000 ppm group F0 males at the primary
necropsy. The distribution of the inflammation was most commonly
associated with the transitional epithelium and in this study the
inflammation likely represented non-adverse local irritation directly
attributed to test article inhalation. At the recovery necropsy, test
article-related CPN persisted in the 4000 ppm group F0 males which was
expected considering the progressive nature of this spontaneously
developing degenerative condition while, nasal inflammation was observed
in a single male indicative of a complete recovery. There were no test
substance-related histologic changes noted for F0 males in the 300 and
1000 ppm groups or F0 females at any exposure level. Mean numbers of F1
pups born, live litter size, percentage of males at birth, postnatal
survival, the general physical condition of the F1 pups, pup body
weights and body weight gains, anogenital distance, and
areolae/nipple anlagen counts (males only) in the 300, 1000, and 4000
ppm groups were unaffected by parental test substance exposure. Necropsy
findings for F1 pups that died were not suggestive of any association
with maternal administration of the test substance. There were no test
substance-related changes in mean serum T4 levels or mean
thyroid/parathyroid weights in F1 males and females on PND 13.
Based on the results of the study, the No Observed Adverse Effect
Concentration for the test article is 43.89 mg/L (4034 ppm).
The repeat dose inhalation toxicity of the test article was evaluated in
Alderley Park SPF Albino rats. The study was not conducted in compliance
with GLP regulations. The test method was based on a custom protocol.
Rats (4/sex/group) were exposed to 0 (control), 2500, or 5000 ppm (0,
27.2, and 54.4 mg/L, respectively) test article for 6 hours a day, 5
days a week, for 3 weeks (15 total exposures). Clinical signs (daily)
and body weights (daily) were recorded. Following the final exposure, 18
hour urine samples were collected and analyzed for protein, glucose and
bilirubin content. Blood was also collected and examined for urea,
sodium, potassium and ALT. Animals were subject to gross necropsy one
day after the last exposure. Histopathological examination of the lungs,
liver, kidneys, heart, gonads, spleen, epididymis or uterus, thymus and
trachea were performed. No mortality occurred during the study
period. Rats exposed to 5000 ppm of the test article had slight
irritation to the eyes and nose. Some signs of CNS depression were
evident. Body weight gain and food consumption in the animals exposed to
5000 ppm test article was reduced compared to control animals. No
significant differences were observed in the hematological indices,
clinical chemistry parameters, urinalysis, gross pathological and
histopathological findings of treated animals when compared with
controls. Based on the results of the study, the No Observed Adverse
Effect Level (NOAEL) of the test article is 5000 ppm (54.4 mg/L).
The results of the studies do not meet the classification criteria for
target organ toxicity in a repeated dose study.
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