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EC number: 445-790-1
CAS number: 404362-22-7
- Table 1: Group Mean Weekly Bodyweights and Standard Deviations
Dose Level (mg/kg/day)
Number of Animals
Bodyweight (g) at Day
# = five animals per dose group during treatment-free period
- = not applicable
- Table 2: Group Mean Weekly Bodyweight Gains and Standard
Increase in Bodyweight (g) during Week
*** = significantly different from corresponding control group p
Results in support of a LOAEL of 15 mg/kg bw/d:
- Table 3: Summary Incidence of Histopathological Findings
0 (Control) Recovery group
50 Recovery group
Number of animals examined at terminal kill
Vacuolation oflamina propria cells
Proliferation sarcolemmal nuclei
Pericardial inflammation and abscess
The study was designed to investigate the systemic toxicity of the
test material and complies with the following regulatory guidelines:
OECD Guideline for Testing of Chemicals No. 407 "Repeated Dose 28
Day Oral Toxicity Study in the Rodent".
The test material was administered by gavage to three groups, each
of five male and five rats, for twenty-eight consecutive days, at dose
levels of 5, 15 and 50 mg/kg/day. A control group of five males and five
females was dosed with vehicle alone (Arachis oil BP). Two recovery
groups, each of five males and five females, were treated with the high
dose (50 mg/kg/day) or vehicle alone for twenty-eight consecutive days
and then maintained without treatment for a further fourteen days.
Clinical signs, functional observations, bodyweight development,
food and water consumption were monitored during the study. Haematology,
blood chemistry and urinalysis were evaluated for all non-recovery group
animals at the end of the treatment period and for all recovery group
animals at the end of the treatment-free period. All animals were
subjected to gross necropsy examination and histopathological evaluation
of selected tissues was performed.
There were no deaths during the study. No effects observed at all
dose levels in endpoints water consumption and gross pathology.
For endpoints body weight / weight gain, food comsumtion, food
efficiency, haematology, clinical chemistry, urinalysis, neurobehaviour,
andorgan weights, effects were reported at the high dose level 50 mg/kg
bw/d, however all effects fully reversible.
Concerning clinical signs, increased salivation prior to and/or up
to ten minutes after dosing was detected at the 50 mg/kg/day dose level
from Day 6 onwards. The physical condition of the animals began to
deteriorate during the third week of treatment with the development of
clinical signs including hunched posture, pilo-erection, tiptoe gait,
waddling gait, increased inhumation, respiratory pattern changes and
staining of the external body fur. Observations began to regress
following cessation of treatment with only hunched posture reported in
recovery 50 mg/kg/day animals by the end of the fourteen day
treatment-free period. No such effects were detected at 15 or 5
In histopathologic analysis several-related changes were observed
at 50 mg/kg bw/d which all were fully reversible (foamy vacuolation of
hepatocytes, generalised hepatocyte enlargement, and vacuolar distension
of scattered cells, lymphoid hyperplasia and vacuolar distension of
scattered cells with associated apoptosis, highher grades of severity of
vacuolation of cortical cells,
hyperplasia of the transitional epithelium, foamy histiocytes in
the mesenteric lymph nodes).
A greater incidence of myocarditis was seen in relation to
treatment for females dosed at 50 mg/kg/day and possibly at 15
mg/kg/day. There was no toxicologically significant difference in the
incidence or severity of myocarditis between recovery control and 50
mg/kg/day animals following completion of the recovery period.
Vacuolation of lamina propria cells in the duodenum, jejunum, and
ileum was related to treatment for rats of either sex dosed at 50
mg/kg/day and for the ileum only in a few animals of either sex dosed at
15 mg/kg/day. Appreciable regression of the condition was observed for
animals from the recovery 50 mg/kg/day treatment group, with just a few
animals showing residual changes in the ileum.
Foamy alveolar macrophages were prevalent throughout the lung
parenchyma in animals of either sex dosed at 50 mg/kg/day. There was no
evidence of regression of the condition among recovery 50 mg/kg/day
group animals following an additional fourteen days without treatment.
Foamy vacuolation of corpora luteal cells was seen in relation to
treatment for females dosed at 50 mg/kg/day. Partial regression of the
condition was observed for recovery 50 mg/kg/day females.
Muscle fibre degeneration and necrosis, and proliferation of
sarcolernrnal nuclei were observed in relation to treatment for animals
of either sex dosed at 50 mg/kg/day and to a much lesser extent for
animals dosed at 15 mg/kg/day. Significant regression of both conditions
was apparent for recovery 50 mg/kg/day animals following an additional
fourteen days without treatment.
Finally it is concluded that oral administration of the test
material MXDA/SM Adduct, to rats for a period of twenty-eight
consecutive days at dose levels of up to 50 mg/kg/day resulted in
toxicologically significant effects at 50 and 15 mg/kg/day. However, the
majority of effects in 50 mg/kg/day recovery group were reversible,
whereas the effects occured in 15 mg/kg/day dose group were marginal and
offten equivalent to findings in the control group. No such effects were
detected for animals of either sex at 5 mg/kg/day. Therefore resulting
LOAEL is proposed at 50 mg/kg bw/d, and the NOAEL at 15 mg/kg bw/d.
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