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EC number: 259-134-5
CAS number: 54381-16-7
maternal and developmental toxicity potential of N,N-bis
(2-hydroxyethyl)-p-phenylenediamine sulfate was determined following the
OECD Guideline 414 (Prenatal Developmental Toxicity Study).
purpose of this study was to evaluate the developmental toxicity
(embryo-fetal toxicity and teratogenic potential) of N,N-bis
(2-hydroxyethyl)-p-phenylenediamine sulfate when administered to female
Crl:CD (SD)IGS BR VAF/Plus rats (presumed pregnant) by oral gavage at
dose levels of 0, 5, 20 and 50 mg /kg bw/day for a period of gestation
Day 6 through 20.
hundred female Crl:CD (SD)IGS BR VAF/Plus rats of 68 d age (Source:
Charles River Laboratories, Inc., Raleigh, North Carolina, USA) weighing
219 - 247 g were housed individually in stainless steel, wire-bottomed
cages. The animals were maintained under standard laboratory conditions
(temperature: 20.6-26.7°C, humidity: 39.0-57.2%, minimum of 10 air
changes/h, 12 h light/12 h dark cycle per d) and fed on Certified Rodent
Diet #5002; ad libitum. The animals were acclimatized for 6 d prior to
6 d of acclimation, 140 virgin female rats were placed into cohabitation
with 140 breeder male rats, one male rat per female rat for a 4 d
cohabitation period. Female rats with spermatozoa observed in a smear of
the vaginal contents and/or a copulatory plug observed in situ were
confirmed pregnant (The day pregnancy was confirmed was designated as
gestation Day 0). Post-coitum,
mated females were randomly divided into 3 different treatment groups
consisting of 25 animals/dose group. A similar sized group of animals
that received 0.2% w/v erythorbic acid in R.O. deionized water (vehicle)
served as control. Solutions of the test substance and/or the vehicle
were administered orally (gavage) once daily from Days 6 through 20 of
presumed gestation. The dosage volume was 10 mL/kg, adjusted daily on
the basis of the individual body weights recorded immediately before
administration of the test substance.
clinical observations, body weights and feed consumption values were
recorded. All surviving rats were sacrificed on gestation Day 21. The
gravid uterus was excised, weighed and subsequently examined for the
number and distribution of corpora lutea, implantation sites and uterine
contents. A gross necropsy was performed. Fetuses were weighed and
examined for gross external, soft tissue and skeletal alterations and
sex. To minimize bias, Caesarean-sectioning and subsequent fetal
observations were conducted without knowledge of dosage group.
dam in the high dose group was found dead on gestation Day 18. No other
mortality or any clinical necropsy observations related to the test
substance occurred. Maternal body weight gains were reduced in the mid
dose group and significantly reduced in the high dose group during the
entire dosage period (calculated as gestation Day 6 -21). The gravid
uterine weights were reduced in the mid and high dose groups, as
compared to the control group value. Although not always dosage
dependent, these reductions reflected a slightly smaller litter size
that occurred spontaneously in the mid and high dose groups (13.3 and
13.6, respectively) compared to the 0 (Vehicle) and low dose groups
(15.0 and 15.2, respectively). Corrected maternal body weights
(gestation Day 21 body weight minus the gravid uterine weight) and
corrected body weight changes were comparable among the groups.
Corresponding to reductions in body weight gain, absolute (g/day) and
relative feed consumption values (g/kg/day) were significantly reduced
in the mid and high dose groups for the dosage interval of gestation Day
6 -9 (92.2% and 92.5%, respectively, of the control group absolute
treatment related effects were noted in caesarean-sectioning or litter
observations. The litter averages for corpora lutea, implantations,
litter sizes, live fetuses, early and late resorptions, fetal body
weights, percent resorbed conceptuses and percent live male fetuses were
comparable among the four dosage groups and did not differ significantly.
significant increases (p<=0.05 to p<=0.01) in the number of litters with
fetuses with alterations, the number of fetuses with alterations and the
percentage of fetuses with alterations per litter were not considered
related to the test substance as the increases were not dosage dependent
and the increases reflected low values in the control group.
There was a
significant (p≤0.05) decrease in the number of ossified hindlimb
phalanges in the 50
mg/kg/day dosage group; however, this was not considered toxicologically
important since there was no other adverse effect on fetal weights or
fetal alterations. No other gross external, soft tissue or skeletal
fetal alterations (malformations or variations) were attributable to
treatment with the test substance.
on the above observations, the maternal
no-observable-adverse-effect-level (NOAEL) was 5 mg/kg/day. Dosages of
20 and 50 mg/kg/day produced reductions in body weight and feed
consumption. The developmental NOAEL was determined by the study authors
to be 50 mg/kg/day. No developmental toxicity was produced at dosages as
high as 50 mg/kg/day, the highest dose tested.
teratogenicity study is classified as acceptable, and satisfies the
guideline requirements of the OECD 414 method.
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