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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Remarks:
Combined Chronic Toxicity / Carcinogenicity Study
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1968
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Not all the raw study results have been published in the publication, limited information available on methods (no guideline followed, no info regarding dosing preparation). The study was reviewed by the JECFA (2006) as part of their safety evaluation (JECFA (2006). Safety evaluation of certain food additives. Who Food Additives Series:56. Prepared by the sixty fifth meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA). World Health Organization, Geneva).The study was also considered valid by the EFSA expert panel (EFSA Journal 2015;13(9):4244).

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1969

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Version / remarks:
1981, EFSA assignment
GLP compliance:
no
Remarks:
pre-GLP
Limit test:
no

Test material

1
Chemical structure
Reference substance name:
2-ethyl-3-hydroxy-4-pyrone
EC Number:
225-582-5
EC Name:
2-ethyl-3-hydroxy-4-pyrone
Cas Number:
4940-11-8
Molecular formula:
C7H8O3
IUPAC Name:
2-ethyl-3-hydroxy-4H-pyran-4-one
Test material form:
solid

Test animals

Species:
rat
Strain:
other: Charles River weanling albino
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River
- Age at study initiation: weanling
- Housing: Individual
- Diet: Ground rat food mixed with the test substance
- Water (e.g. ad libitum): ad libitum

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Mixing appropriate amounts with (Type of food): Rockland Ground Rat Food
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
None
Duration of treatment / exposure:
2 years
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
200 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
50 mg/kg bw/day (nominal)
No. of animals per sex per dose:
25
Control animals:
yes, concurrent no treatment
Details on study design:
10 males and 10 females were mated to produce two separate litters, in order to test reproductive toxicity (described in the endpoint on reproductive toxicity)
Positive control:
not applicable

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 0, 3, 6, 9, 12, 18 and 24 months
- Anaesthetic used for blood collection: Not specified
- Animals fasted: No
- How many animals: 5 males and 5 females per group
- Parameters checked: Hemoglobin, hematocrit, red blood cells, white blood cells, differential count

URINALYSIS: Yes
- Time schedule for collection of urine: 0, 3, 6, 9, 12, 18 and 24 months
- Metabolism cages used for collection of urine: Yes
- Animals fasted: overnight water deprivation, not fasted.
- Parameters checked: color, volume, specific gravity, pH, blood, albumin, glucose, and microscopic examination of the sediment after centrifugation

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
The following organs were evaluated: heart, lung, liver, kidney, pancreas, spleen, thymus, mesenteric lymph node, adrenals, thyroid, brain, hypophysis, uterus and ovary;

HISTOPATHOLOGY: Yes
The following tissues were evaluated: brain (sectioned at the optic chiasm, mammillary body, cerebellum, pons, and medulla oblongata), cervical spinal cord, hypophysis, eye, parotid gland, thyroid and parathyroid, thymus, heart, lung, sternum, rib, aorta, liver, spleen, pancreas, kidneys, adrenals, stomach (fore and hind), small and large intestine (four levels), mesenteric lymph node, reproductive tract (all levels), urinary bladder, skeletal muscle, femoral nerve, femoral bone marrow, skin and mammary gland
Statistics:
No data

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
All parameters were considered normal.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The body weight of test and control animals evolved in a comparable manner over the 2 year exposure period
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
All parameters were considered normal.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
One control rat developed anemia (RBC, 1.8 x 10^3 /mm3; hemoglobin, 8.0 % and hematocrit,18.5 %) of unknown etiology.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
All parameters were considered normal.
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
All rats showed a tendency toward albuminuria; All other parameters were considered normal.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
All parameters were considered normal.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Pathologic changes consistent with aged rats were observed primarily in the pulmonary, endocrine, urinary, and cardiovascular systems.
Neuropathological findings:
not examined
Description (incidence and severity):
No specific neurotoxicity examination was performed.
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Pathologic changes consistent with aged rats were observed primarily in the pulmonary, endocrine, urinary, and cardiovascular systems.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Neoplasia occurred in a random manner with no apparent relationship between number, location, or type of tumors and treatment. This was due presumably to the advanced age of the animals.
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
Ethyl maltol had no effect on fertility, gestation, parturition, lactation, or fetal development. A fall in fertility was noted in test and control groups at the second mating. This was due presumably to the advanced age of the animals.

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
>= 200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: highest dose tested

Target system / organ toxicity

Key result
Critical effects observed:
no

Any other information on results incl. tables

Refer to Tables 4 -6 in publication attached.

Applicant's summary and conclusion

Conclusions:
This chronic oral toxicity study (feeding) in rats (similar to OECDTG 453) did not report any treatment-related effects. Based on these findings, a NOAEL of >=200 mg/kg bw/day was established.
Executive summary:

In a combined chronic toxicity/carcinogenicity study (Gralla et al., 1969), Ethyl Maltol was administered to 4 groups of Charles River weanling albino male and female rats (25/sex/group) in the diet at dose levels of 0, 50, 100 and 200 mg/kg bw/day daily for 2 years.

There were no effects observed on clinical signs, mortality, body weights, food consumption, clinical biochemistry and organ weight. There was a non-treatment-related effect observed on urinalysis; all rats showed a tendency toward albuminuria, with other parameters normal. There were non-treatment-related effects observed on gross pathology and (non)-neoplastic histopathology, due to the advanced age of the animals; changes were consistent with aged rats or there was no apparent relationship between effect and treatment.

The NOAEL (male/female) was >=200 mg/kg bw/day.