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CAS number: -
The oral administration of H-MI ammonium
salt to rats by gavage for a period of twenty-eight
consecutive days at dose levels of 30, 300 and 1000 mg/kg/day resulted
in treatment related effects at 300 and 1000 mg/kg/day.
An episode of increased salivation
pre-dosing was observed in one male whilst increased salivation to
thirty minutes post dosing was observed in one female treated with 1000
mg/kg/day. Increased salivation is often recorded following the oral
administration of an unpleasant tasting and or irritant test material
formulation. Although such isolated episodes would not be indicative of
toxicity, laboratory investigations revealed an increase in water intake
for non-recovery animals of either sex treated with 1000 mg/kg/day from
Week 3 onwards. This also extended into Week 5 for the recovery 1000
mg/kg/day males. Histopathological evaluation of the tissue showed
associated gastric changes comprising of agglomeration of secretion,
mucous cell hypertrophy/ hyperplasia, mucosal basophilia and
acanthosis/hyperkeratosis of the limiting ridge were seen in animals of
either sex treated with 1000 mg/kg/day. These changes also extended to
animals of either sex treated with 300 mg/kg/day. Following cessation of
treatment the histopathological findings identified in the non-recovery
animals were considered to have regressed in the recovery 1000 mg/kg/day
Introduction. The study was designed
to investigate the systemic toxicity of the test material and complies
with the following regulatory guidelines:
i) Commission Directive 96/54/EC (Method
ii) The Japanese Ministry of Economy Trade
and Industry (METI), Ministry of Health, Labour and Welfare (MHLW) and
Ministry of the Environment (MOE) Guidelines of 21 November 2003 for a
twenty-eight day repeat dose oral toxicity study as required by the Law
Concerning the Evaluation of Chemical Substances and Regulation of their
Manufacture, etc (Chemical Substance Control Law) 1973 of Ministry of
International Trade and Industry (MITI) amended 2004.
iii) The OECD Guidelines for Testing of
Chemicals No. 407 "Repeated Dose 28 Day Oral Toxicity Study in Rodents"
(adopted 03 October 2008).
iv) USA Environmental Protection Agency
(EPA) Health Effects Test Guidelines, OPPTS 870.3050 Repeated Dose
28-Day Oral Toxicity Study in Rodents, July 2000.
Methods. The test material was
administered by gavage to three groups, each of five male and five
female Wistar Han™:HsdRccHan™:WIST strain rats, for twenty-eight
consecutive days, at dose levels of 30, 300 and 1000 mg/kg/day
(incorporating a correction factor for 90.3% purity). A control group of
five males and five females was dosed with vehicle alone (Distilled
water). Two recovery groups, each of five males and five females, were
treated with the high dose (1000 mg/kg/day) or the 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
Mortality. There were no deaths
during the study.
Clinical Observations. An isolated
episode of increased salivation was observed in one animal of either sex
treated with 1000 mg/kg/day.
No such effect was detected in animals of
either sex treated with 300 or 30 mg/kg/day.
Behavioural Assessment. There were no
treatment-related changes in the behavioural parameters measured.
Functional Performance Tests. There
were no adverse changes in the functional performance parameters
Sensory Reactivity Assessments. There
were no treatment-related changes in sensory reactivity.
Bodyweight. No treatment-related
effect on bodyweight change was detected for treated animals, in
comparison to controls.
Food Consumption. No treatment-related
effect on dietry intake of food efficiency was detected for treated animals,
in comparison to controls.
Water Consumption. An increase in
water consumption was seen in non-recovery 1000 mg/kg/day males from
Week 3 onwards and recovery 1000 mg/kg/day males up to and including
Week 5. Females from this treatment group showed an increase in water
consumption during Weeks 3 and 4.
No such effect was detected in animals of
either sex treated with 300 and 30 mg/kg/day or recovery 1000 mg/kg/day
Haematology. There were no
toxicologically significant changes in the haematological parameters
Blood Chemistry. There were no
toxicologically significant changes in the blood chemical parameters
Urinalysis: No adverse effect on
uranalytical parameters was detected for treatment animals, in
comparison to controls.
Organ Weights. There were no
toxicologically significant changes in organ weight measurement.
Necropsy. Macroscopic examination of
the tissues did not reveal any toxicologically significant findings.
Histopathology. The following
treatment-related changes were observed.
STOMACH: Agglomeration of secretion,
mucous cell hypertrophy/hyperplasia, mucosal basophilia, and
acanthosis/hyperkeratosis of the limiting ridge were seen in relation to
treatment for animals of either sex treated with 1000 mg/kg/day or 300
mg/kg/day. One female treated with 30 mg/kg/day also demonstrated
changes but these conditions are seen occasionally and spontaneously
among control animals such that effects in one animal, even in the
absence of such effects among concurrent controls, cannot be reliably
regarded as an effect of treatment.
Conditions were considered to have generally
regressed among recovery animals of either sex treated with 1000
mg/kg/day following an additional fourteen days without treatment,
although two 1000 mg/kg/day males had residual changes. One recovery
control animal demonstrated all conditions.
Conclusion. The oral administration
of H-MI ammonium salt to rats for a period of twenty-eight consecutive
days at dose levels of 30, 300 and 1000 mg/kg/day resulted in
treatment-related effects at 300 and 1000 mg/kg/day.
The changes seen at treatment levels up to
1000 mg/kg/day were considered to be adaptive and not represent an
adverse health effect. The ‘No Observed Adverse Effect Level’ (NOAEL)
should, therefore, be regarded as 1000 mg/kg/day.
No treatment-related effects were identified
at 30 mg/kg/day the “No Observable Effect Level” (NOEL) for animals of
either sex was therefore considered to be 30 mg/kg/day.
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