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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Remarks:
JECFA/EFSA peer reviewed study

Data source

Reference
Reference Type:
publication
Title:
Toxicity Studies with Ethyl Maltol
Author:
Gralla, Stebbins, Coleman, And Delahunt
Year:
1969
Bibliographic source:
Toxicology and Applied Pharmacology 15, 604-613 (1969)

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
GLP compliance:
no
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 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: Individually caged
- Diet: Rockland Ground Rat Food ad libitum
- Water: ad libitum

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
Rockland Ground Rat Food was mixed with ethyl maltol


Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
90 days
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
250 mg/kg bw/day (nominal)
Dose / conc.:
500 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10 males and females
Control animals:
yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights consumption were measured weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
Food consumption were measured weekly and test item concentrations in food were adjusted accordingly.

HAEMATOLOGY: Yes; after 45 and 90 days on test, 5 rats from each male and female group were bled from a tail incision for hemoglobin, hematocrit, RBC, total WBC, and differential count.

CLINICAL CHEMISTRY: Yes; At the completion of this study, all rats were anesthetized and bled from the abdominal aorta using heparinized syringes. Samples were centrifuged and plasma glucose values determined.

URINALYSIS: Yes; After 45 and 90 days on test, 5 rats from each male and female group were deprived water overnight and urine samples were obtained for urinalyses, which included color, volume, specific gravity, pH, blood, albumin, glucose, and microscopic examination of the sediment after centrifugation.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes ; all rats were autopsied and examined grossly. The following organs were removed, trimmed, and weighed: heart, lung, liver, kidney, pancreas, spleen, thymus, mesenteric lymph node, adrenals, thyroid, brain, hypophysis, uterus and ovary; these, plus additional tissues, were placed in Bouins’ solution, except the eyes and nervous system tissue which were fixed in 15 % formalin.

HISTOPATHOLOGY: Yes; All specimens were embedded in paraffin, sectioned, and stained with hematoxylin and eosin. The following tissues of each rat were examined microscopically: 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

Results and discussion

Results of examinations

Clinical signs:
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Body weight gains for female rats fed 500-1000 mg/kg bw/day, were slightly, but not significantly, less than those of comparable controls or the female group receiving 250 mg/kg bw/day (Fig. 1B). The same dose levels had no effect on male rat development (Fig. 1A).
Food consumption and compound intake (if feeding study):
no effects observed
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):
Two females and three males at the lowest dose had decreased haemoglobin concentration and slightly amber-coloured serum, but these changes were not seen at higher doses.
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
At autopsy, all organ weights of treated rats compared favorably with those of controls.
Gross pathological findings:
no effects observed
Description (incidence and severity):
At autopsy, no gross pathologic changes were observed.
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Microscopically, kidney lesions were noted in the rats receiving 1000 mg/kg bw/day. The basic change was distinguished by an extremely dilated, acellular glomerular tuft with protein loss into Bowman’s space and cast formation within the lumina of dilated corticomedullary tubules.
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Effect levels

Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
In a 90 day repeated dose toxicity in Charles River rats, the NOAEL (male/female) for Ethyl Maltol was 500 mg/kg bw/day.
Executive summary:

In a subchronic repeated dose toxicity study (Gralla et al., 1969), Ethyl Maltol was administered to 4 groups of Charles River male and female rats (10/sex/group) in the diet at dose levels of 0, 250, 500, 1000 mg/kg bw/day daily for 90 days.

Food consumption were measured weekly and test item concentrations in food were adjusted accordingly. Body weight gains for female rats fed 500-1000 mg/kg bw/day, were slightly, but not significantly, less than those of comparable controls or the female group receiving 250 mg/kg bw/day. The same dose levels had no effect on male rat development. Two females and three males at the lowest dose had decreased haemoglobin concentration and slightly amber-coloured serum, but these changes were not seen at higher doses. There were no effecs observed on clinical chemistry and urinalysis parameters. At autopsy, all organ weights of treated rats compared favorably with those of controls and no gross pathologic changes were observed. Microscopically, kidney lesions were noted in the rats receiving 1000 mg/kg bw/day. The basic change was distinguished by an extremely dilated, acellular glomerular tuft with protein loss into Bowman’s space and cast formation within the lumina of dilated corticomedullary tubules.

The NOAEL (male/female) was 500 mg/kg bw/day.