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EC number: 233-520-3
CAS number: 10213-78-2
attached (0142-0417) Tables, Figures, Appendices, Addenda and Statistics.
following results refer to the Fourteen
day Repeated Dose Oral (Gavage) Range-Finding Toxicity Study in the Rat
(Part 2) with Assessment of Maximum Tolerated Dose (Part 1)
1: Maximum Tolerated Dose Results:
500 mg/kg/day female was found dead on Day 3 and the two remaining
females were killedin extremison Day 3. There were no further
clinical observations were detected at 50 mg/kg/day and at 00 mg/kg/day
findings were confined to one instance of transient increased
salivation. At 200 mg/kg/day, increased salivation was detected in all
animals. At 500 mg/kg/day, increased salivation was detected and
accompanied on occasions by hunched posture and pilo-erection, tiptoe
gait and ano-genital staining, lethargy and ptosis. All animals then
showed a decline in general condition leading to the death of one animal
and a decision was then taken on humane grounds to sacrifice the two
surviving animals. Animals subsequently treated at 350 mg/kg/day
displayed findings of increased salivation, diuresis, hunched posture,
pilo-erection, decreased respiration, emaciation, ptosis, lethargy and
pallor and diarrhoea.
gains were evident for females treated with 50 mg/kg/day. One female
treated with 100 mg/kg/day showed a bodyweight loss of 1g on Day 3
although all females showed bodyweight gains on Day 5. One female
treated with 200 mg/kg/day showed an 8g bodyweight loss on Day 3 and
another female treated with 200 mg/kg/day showed a bodyweight loss of 5g
on Day 5. Bodyweight gains at this dose level were less than those
observed at 50 and 100 mg/kg/day. Bodyweight gains were evident for two
females treated with 350 mg/kg/day on Day 3 and the bodyweight for one
female was unchanged on Day 3 compared to the Day 1 bodyweight.
Bodyweight losses of 3g and 29g were evident for two females treated
with 350 mg/kg/day on Day 5. At 500 mg/kg/day, all females showed
bodyweight losses of between 6 and 16g prior to treatment on Day 3, and
further bodyweight losses of 1g and 6g were evident for the remaining
two females prior to termination.
female treated with 500 mg/kg/day found dead on Day 3 showed a distended
stomach, and sloughing of the glandular and non-glandular gastric
epithelia. Gaseous distension was also observed in the small and large
intestines. The remaining two females treated with 500 mg/kg/day and
terminated on Day 3 showed gaseous distension of the gastro-intestinal
tract. Females treated with 350 mg/kg/day were terminated following five
days of treatment. One female (number 5) showed gaseous distension of
the gastro-intestinal tract and sloughing of the non-glandular gastric
epithelium. The remaining two females treated at this dose level did not
reveal any macroscopic abnormalities.
administration of the test material to rats for up to five days at dose
levels between 50 and 500 mg/kg/day resulted in significant toxicity at
500 and 350 mg/kg/day. The Maximum Tolerated Dose was therefore
considered to be between 200 and 300 mg/kg/day.
Part 2: Fourteen
day Repeated Dose Oral (Gavage) Range-Finding Toxicity StudyResults:
of either sex treated with 250 mg/kg/day were killedin extremison
Day 10 following substantial bodyweight losses and a decline in physical
health. There were no further unscheduled deaths.
male treated with 250 mg/kg/day displayed increased salivation and noisy
respiration soon after dosing from Day 1 and one female treated at this
dose level displayed post-dose increased salivation from Day 2. Another
female displayed diarrhoea on Days 3 and 4. Diarrhoea was also evident
for one male on Day 3 and this male was observed as hunched on Day 4 and
from Day 7 onwards. Incidents of increased salivation were also evident
for remaining males from this dose group, from Day 2 and staining around
the ano-genital region, suggestive of diarrhoea was observed in a number
of animals of either sex from Day 4. On the morning of Day 10, clinical
signs of lethargy, hunched posture, dehydration and diarrhoea were
observed for all animals.
clinical signs, together with bodyweight losses was considered excessive
and the animals treated at this dose level were terminated on Day 10. Increased
salivation was detected soon after dosing for animals of either sex
treated with 150 mg/kg/day between Days 5 to 14. One male also displayed
noisy respiration, although this was confined to Day 12 only.
macroscopic abnormalities were detected for animals of either sex
losses in bodyweight were evident for animals of either sex treated with
250 mg/kg/day, with the effect more prominent in males, which resulted
in statistically significantly differences in this dose group when
compared to control values (P<0.01).
substantial bodyweight losses and the clinical signs observed, resulted
of this dose group on Day 10. Slight
bodyweight losses were also evident for females treated with 150
mg/kg/day between Days 1 and 4 resulting in statistically significant
reductions when compared to controls (P<0.05), although improvement was
evident thereafter. The overall gain during the treatment period at 150
mg/kg/day was only slightly lower than controls (males -3.8%, females
-2.9%), therefore, this was not considered to represent an adverse
effect of treatment.
adverse effect on bodyweight change was evident for animals of either
sex treated with 75 mg/kg/day. Females treated with 75 mg/kg/day showed
a statistically significant reduction in bodyweight gains (P<0.05),
although this was only observed during the final four days of treatment.
reduction in dietary intake was evident for animals of either sex
treated with 250 mg/kg/day prior to their early sacrifice on Day 10.
reductions in dietary intake (approximately 11%) were also evident for
animals of either sex treated with 150 mg/kg/day when compared to
control values over the fourteen day treatment period. These reductions
were considered not to represent an adverse effect of treatment.
adverse effects on dietary intake were evident for animals of either sex
treated with 75 mg/kg/day.
in water consumption were evident for animals of either sex treated with
250 mg/kg/day when compared to controls during the nine days of dosing,
prior to their early sacrifice.
adverse effects on water intake were evident for animals of either sex
treated with 150 or 75 mg/kg/day.
of either sex treated with 150 mg/kg/day showed a statistically
significant increase in absolute and relative liver weights when
compared to controls (P<0.01).
effect extended into the 75 mg/kg/day dose group, although statistical
significance was only achieved for males (P<0.01).
following macroscopic findings were observed for the high dose group
terminated on Day 10: one male displayed pale lungs, a thickened urinary
bladder with pale coloured contents, raised limiting ridge of the
stomach, and a thickened and sloughing nonglandular region of the
stomach. Another male showed reddened lungs and stomach changes
consisting of gaseous distension, sloughing of the non-glandular region
and a reddened appearance. The third male displayed a thickened
non-glandular region which also showed sloughing. Sloughing
of the non-glandular region was also evident for two females, one of
which also showed a raised limiting ridge. One interim death female did
not show any macroscopic abnormalities.
males and one female treated with 150 mg/kg/day displayed a thickened
nonglandular region of the stomach, which was also evident for one
female treated with 75 mg/kg/day.
macroscopic abnormalities were detected for males treated with 75
oral administration of Bis (2-hydroxyethyl) coco alkylamine (CAS Number
61791-31-9) to rats by gavage for a period of up to fourteen consecutive
days at dose levels of 250, 150 and 75 mg/kg/day resulted in
treatment-related effects at all dose levels.
signs were observed at the highest dose level. These included increased
salivation, noisy respiration, staining around the ano-genital region,
diarrhoea and hunched posture. By Day 10, all animals showed lethargy,
hunched posture, dehydration and diarrhoea. Significant bodyweight
losses were also evident in this dose group, together with an increase
in water intake and reduced dietary intake. Due to the severity of these
effects, this dose level was considered excessive and the dose group was
terminated on Day 10.Post-mortemexaminations revealed a number of
effects, the most noticeable were stomach changes including raised
limiting ridge, and thickened and sloughing of the gastric epithelia.
signs at 150 mg/kg/day were confined to isolated instances of increased
salivation soon after dosing and noisy respiration. Slight bodyweight
losses were evident for females during the first four days of treatment,
although overall bodyweight change in this dose group was not adversely
different from control values. There
were no adverse effects on dietary intake detected at this dose level,
althoughpost-mortemfindings revealed an increase in absolute and
bodyweight-relative liver weights when compared to controls. Macroscopic
examinations also revealed thickened non-glandular gastric epithelia for
three animals from this treatment group.
effects at 75 mg/kg/day were confined to increases in absolute and
bodyweight-relative liver weights, which were observed for animals of
either sex, and a thickened non-glandular region of the stomach, which
was observed for one female during thepost-mortemexaminations.
oral administration of Bis (2-hydroxyethyl) coco alkylamine (CAS Number
61791-31- 9) to rats by gavage for a period of up to fourteen
consecutive days at dose levels of 250, 150 and 75 mg/kg/day resulted in
significant toxicity at 250 mg/kg/day.
effects including increased liver weights and macroscopic gastric
changes were also evident at 150 and 75 mg/kg/day; therefore a ‘No
Observed Effect Level’ (NOEL) was not established at the dose levels
employed in the fourteen day range-finding phase.
(GAVAGE) COMBINED REPEAT DOSE TOXICITY STUDY WITH
REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN THE RAT (OECD 422
was performed according to the protocol presented in Appendix 25 and was
designed to screen for potential adverse effects of the test material on
reproduction, including offspring development, following repeated oral
administration to the Wistar Han™:HsdRccHan™:WIST strain rat for up to
forty-five days(including a two week maturation phase, pairing,
gestation and early lactation),at dose levels of 10, 30 and
125 mg/kg/day. A control group was dosed with vehicle alone (Arachis oil
recovery groups, each of five males, were treated with the high dose
(125 mg/kg/day) or the vehicle alone for forty-two days and then
maintained without treatment for a further fourteen days.
was designed to comply with the OECD Guidelines for Testing of Chemicals
No. 422“Combined Repeated Dose Toxicity Study with the
Reproduction/Developmental Toxicity Screening Test” (adopted 22 March
material was administered by gavage to three groups each of ten male and
ten female Wistar Han™:HsdRccHan™:WIST strain rats, for up to forty-five
consecutive days (including a two week maturation phase, pairing,
gestation and early lactation for females), at dose levels of 10, 30 and
125 mg/kg/day. A control group of ten males and ten females was dosed
with vehicle alone (Arachis oil BP). Two recovery groups, each of five
males, were treated with the high dose (125 mg/kg/day) or the vehicle
alone for forty-two days and then maintained without treatment for a
further fourteen days.
signs, behavioural assessments, bodyweight development, food and water
consumption were monitored during the study. Haematology and blood
chemistry were evaluated prior to mating and at termination on five
selected males and females from each dose group.
animals within each dose group was undertaken on a one male: one female
basis within each treatment group on Day 15 of the study, with females
subsequently being allowed to litter and rear their offspring to Day 5
lactation phase, daily clinical observations were performed on all
surviving offspring, together with litter size and offspring weights and
assessment of surface righting reflex.
functional observations were performed on five selected males from each
dose group after the completion of the mating phase, and for five
selected parental females from each dose group on Day 4post partum.
males were terminated on Day 43, followed by the termination of all
surviving females and offspring on Day 5post partum. All animals
were subjected to a gross necropsy examination and histopathological
evaluation of selected tissues was performed.
administration of Bis (2-hydroxyethyl) coco alkylamine (CAS Number
61791-31-9) to rats by gavage, at dose levels of 125, 30 and 10
mg/kg/day, resulted in treatment-related effects at 125 and 30
mg/kg/day. These effects consisted of a localised irritant effect, and
almost complete regression was evident following the treatment-free
period. This change may be considered to be an adverse event and of
importance when considering the impact on reproductive
performance. Based upon the histopathological changes observed in the
stomach, a “No Observed Adverse Effect Level” (NOAEL) for systemic
toxicity, was considered to be 30 mg/kg/day.
litter sizes due to lower numbers of corpora lutea and implantation
sites, and higher post implantation losses were evident at 125
mg/kg/day. A NOEL was therefore considered to be 30 mg/kg/day for
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