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EC number: 695-097-5
CAS number: 15789-90-9
Repeated dose toxicity, oral (Analogy CAS 127-51-5; OECD 408):- NOAEL male = 30 mg/kg bw/day, NOAEL female = 500 mg/kg bw/day- NOEL male = 5 mg/kg bw/day, NOEL female = 30 mg/kg bw/day- LOAEL male/female = 500 mg/kg bw/day
The oral administration of the test material to rats for a period of
ninety consecutive days at dose levels of 5, 30 and 500 mg/kg/day
resulted in treatment related effects in males at 500 and 30 mg/kg/day
and in females at 500 mg/kg/day. The No Observed Effect Level (NOEL) was
considered to be 30 mg/kg/day for females and 5 mg/kg/day for males.
A study was conducted to investigate the systemic toxicity of the test
material. The test material was administered by gavage to three groups,
each of ten male and ten female Sprague-Dawley Crl:CD(SD)IGS BR strain
rats for 90 consecutive days. A control group of ten males and ten
females was dosed with the vehicle alone (corn oil). The animals were
acclimatised for 6 days. At the start of treatement the males weighed
131 to 172 grams and the females weighed 122 to 155 grams. The animals
were approximately 6-8 weeks old. Animals were housed in groups of three
or four by sex in polypropylene grid-floor cages suspended over trays
lined with absorbent paper. The animals were allowed free access to food
and water. A pelleted diet (Rodent 5LF2 (Certified) Diet) was used.
Mains drinking water was supplied from polycarbonate bottles attached to
the cage. The animals were housed in a single air-conditioned room with
an air exchange rate of at least 15 air changes per hour and the low
intensity lighting was controlled to give twelve hours continuous light
and twelve hours darkness. The temperature and relative humidity were
set to achieve target values of 21 +/- 2 C and 55 +/- 15%, respectively.
Dose levels were 5, 30 and 500 mg/kg/day at a volume of 4 ml/kg. All
animals were examined for overt signs of toxicity, ill-health or
behavioural changes immediately before dosing and one and five hours
after dosing during the working week. Animals were observed immedately
before dosing and one hour after dosing at weekends. Prior to the start
of treatment and at weekly intervals thereafter, all animals were
observed for signs of functional/behavioural toxicity. Functional
performance tests were also performed on all animals during Week 12, together
with an assessment of sensory reactivity to different stimuli. Clinical
signs, functional observations, bodyweight development and food and
water consumption were monitored during the study. Haematology and blood
chemistry were evaluated for all animals at the end of the study.
Ophthalmosscopic examination was also performed on control and high dose
animals (500 mg/kg). All animals were subjected to gross necropsy
examination and histopathological evaluation of selected tissues was
performed Statistical analyses were performed.
There were no unscheduled death and no clinical sings of toxicity
observed. No adverse effects on bodyweight, dietary intake or food
efficiency and treatment-related haematology changes were detected. A
statistically significant increase in liver and kidney weights both
absolute and relative was observed in animals treated with 500 mg/kg/day
and a significant increase in plasma creatinine, total protein and
cholesterol were also observed in high-dose animals. Histopathology
revealed an enlargement of hepatocytes in the liver (generally regarded
as adaptive in nature) of animals treated with 500 mg/kg/day. Males
treated with 500 mg/kg/day also showed a significant increase in spleen
weight and in plasma albumin. No abnormalities were observed at
necropsy. A greater incidence of globular accumulations of eosinophilic
material in the kidney’s tubular epithelium was noted in males treated
with 30 and 500 mg/kg/day and a higher incidence of follicular cell
hypertrophy in thyroid and adipose infiltration of the bone marrow
(indicative of morrow hyperplasia) in males treated with 500 mg/kg/day.
The NOEL was considered to be 30 mg/kg/day for females and 5 mg/kg/day
for males. Because the kidney changes noted in male rats were consistent
with well documented changes that are peculiar to the male rat in
response to treatment with some hydrocarbons, the NOAEL for males may be
considered to be 30 mg/kg/day.
In the second supporting study (Oser,
1965), another 90 day study used 15 FDRL rats (per sex per dose),
weighing 82.1 +/- 2.3 grams for males and 77.1 +/- 2.3 grams for
females. There was one control group for every 3 test groups, as several
test substances were examined in this campaign. Each test substance was
diluted in cotton-seed oil in a concentration sufficient to provide the
predetermined dosage in 2% of the diet. Dosages were administered on a
uniform body weight basis by biweekly adjustments of the concentration
of the test material in the cotton-seed oil. Observations included body
weight and food consumption. In addition, haematological and blood
chemical determinations were made on 8 rats of each sex at a 6 week
period and in all rats at 12 weeks. The tests were terminated at 90
days. All animals were sacrificed and a gross necropsy was carried out.
At necropsy, liver and kidney weights were recorded and the following
organs from half the animals in each group were taken for histological
examination: liver, kidneys, stomach, small and large intestines,
spleen, pancreas, heart, lungs, bone marrow, muscle, brain, spin cord,
bladder, adrenals, thyroid, pituitary, gonads, salivary glands, and
lymph nodes. Haemoglobin and blood urea nitrogen were slightly decreased
in the males, but those findings were within control ranges or only
slightly out of range, and were not considered adverse.
In order to assess the endpoint of repeated dose toxicity, data
from the four principal components α-iso-methylionone, methyl-α-ionone,
methyl-β-ionone, and isomethyl-β-ionone of methyl ionone were used as
well as data from related ionones. For more information, please refer to
the attached read-across justification.
Due to the lack of sufficient data regarding oral repeated dose
toxicity, data for the analogue substance alpha-iso-methylionone (CAS
No.127-51-5) were taken into account. For this substance two 90-day oral
subchronic studies under GLP were performed according to OECD Guideline
408 (Dunster, 2006 and Politano 2012). Ten male and ten female
Sprague-Dawley rats (Crl:CD(SD)IGS BR) were daily administered by gavage
with 5, 30, 500 mg/kg bw/d at a volume of 4 ml/kg bw in olive oil. While
no toxic effects were noted at 5 mg/kg bw/d, a greater incidence of
higher severity grades of globular accumulations of eosinophilic
material were observed in the tubular epithelium of nine out of ten
males at 30 mg/kg bw/day. Administration of 500 mg/kg bw/d led to
centrilobular or generalised hepatocyte enlargement in four out of ten
males and nine out of ten females. Also, greater incidences of higher
severity grades of globular accumulations of eosinophilic material were
observed in the tubular epithelium in nine out of ten males. Two male
rats treated at this dose level exhibited associated higher grades of
tubular basophilia, whereas a higher incidence of follicular cell
hypertrophy in the thyroid was seen in relation to treatment for seven
out of ten males. In addition, a higher incidence of lower grades of
severity of adipose infiltration of the bone marrow, indicative of
marrow hyperplasia, was observed in relation to treatment for all males
treated at this dose level.
The authors stated that the kidney changes identified
histopathologically were consistent with well documented changes that
are peculiar to the male rat in response to treatment with some
hydrocarbons. This effect may not be indicative of a hazard to human
health and for the purposes of hazard evaluation the no observed adverse
effect level for males should be regarded as 30 mg/kg/day. Besides this,
hepatocyte enlargement is commonly observed in the rodent liver
following the administration of xenobiotics and in the absence of
associated degenerative changes may be interpreted as adaptive in
nature. Therefore, the no effect level (NOEL) was estimated as 5 and 30
mg/kg bw/d for males and females, respectively. NOAELs were observed to
be 30 mg/kg bw/d for males and females. Due to the structural
similarities, the same result could also be expected for methylionone.
Justification for selection of repeated dose toxicity via oral
route - systemic effects endpoint:
OECD guideline study according to GLP, detailed report published.
The present data on repeated dose toxicity do not fulfill the criteria
laid down in 67/548/EEC and 1272/2008/EEC, and therefore, a
non-classification is warranted.
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