3-hydroxy-2-methyl-4-pyrone

Repeated dose toxicity: oral

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

Test material information

1

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 / concentrations

Doses / concentrations 1

Dose / conc.:

250 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

500 mg/kg bw/day (nominal)

Doses / concentrations 3

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.