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Administrative data

Description of key information

Combined Chronic Toxicity/Carcinogenicity NOAEL (rat): >= 200 mg/kg bw/day, highest dose tested (Equivalent or similar to OECD 453).

Combined Chronic Toxicity/Carcinogenicity NOAEL (dog): >= 200 mg/kg bw/day, highest dose tested (Equivalent or similar to OECD 453).

Subchronic NOAEL (rat): 500 mg/kg bw/day (Equivalent or similar to OECD 408)

Subchronic NOAEL (dog): 250 mg/kg bw/day (Equivalent or similar to OECD 409)

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

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).
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
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

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
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
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
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.
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
Key result
Critical effects observed:
no

Refer to Tables 4 -6 in publication attached.

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.

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting 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).
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
no
GLP compliance:
no
Remarks:
pre-GLP
Limit test:
no
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
- Weight at study initiation: approximately 70-85 grams
- Housing: Individual
- Diet: Rockland ground rat food mixed with the test substance
- Water (e.g. ad libitum): ad libitum

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:
90 days
Frequency of treatment:
Daily
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Dose / conc.:
500 mg/kg bw/day (nominal)
Dose / conc.:
250 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Positive control:
none
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: Day 45 and Day 90
- 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

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of study
- Animals fasted: Not specified
- How many animals: all
- Parameters checked: plasma glucose

URINALYSIS: Yes
- Time schedule for collection of urine: Day 45 and Day 90
- 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
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weight gains for female rats fed ethyl maltol, 500-1000 mg/kg, were slightly, but not significantly, less than those of comparable controls or the female group receiving 250 mg/kg. The same dose levels had no effect on male rat development
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, treatment-related
Description (incidence and severity):
2 females and 3 males receiving the lowest level of ethyl maltol (250 mg/kg) showed a slight fall in hemoglobin and slightly amber-colored serum.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
All parameters were considered normal.
Urinalysis findings:
no effects observed
Description (incidence and severity):
All 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:
no effects observed
Description (incidence and severity):
All parameters were considered normal.
Neuropathological findings:
no effects observed
Description (incidence and severity):
No specific neurotoxicity examination was performed, however there were no neuropathological indications from cage side observations or histological examination of the brain (sectioned at the optic chiasm, mammillary body, cerebellum, pons, and medulla oblongata), cervical spinal cord or hypophysis.
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 ethyl maltol (incidence not given). The 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:
no effects observed
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
1 000 mg/kg bw/day (nominal)
System:
urinary
Organ:
kidney
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified

The incidence for the observed kidney lesions is not provided in the study publication.

Refer to Figure 1A and 1B in publication attached.

Conclusions:
This 90-day oral toxicity study (feeding) in rats (similar to OECDTG 408) found treatment-related renal effects (histopathological) in the 1000 mg/kg/day dosing group (limit concentration). Based on these findings, a NOAEL of 500 mg/kg bw/day was established.
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.


Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting 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.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents)
Deviations:
no
GLP compliance:
no
Remarks:
pre-GLP
Limit test:
no
Species:
dog
Strain:
Beagle
Sex:
male/female
Details on test animals or test system and environmental conditions:
Not Specified



Route of administration:
oral: capsule
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
None
Duration of treatment / exposure:
90 days
Frequency of treatment:
Daily
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Remarks:
250 mg/kg twice a day
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
125 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
4 animals per dose level (not distributed according to sex)
Control animals:
yes, concurrent no treatment
Positive control:
not applicable
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes, complete physical examination
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: at 0, 14, 30, 60 and 90 days
- Dose groups that were examined: All

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at 0, 14, 30, 60 and 90 days
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: 4 per dose group
- Parameters checked: hemoglobin, hematocrit, RBC, total WBC, and differential count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at 14, 30, 60 and 90 days
- Animals fasted: Not specified
- How many animals:4 per dose group
- Parameters checked: plasma glucose (Hoffman,1937), blood urea nitrogen (BUN) (March et al., 1965), alkaline phosphatase (Marsh et al., 1959), and total bilirubin (Jendrassik and Grof, 1938), SGOT, SGPT by Karmen's (1955) method, and BSP excretion 30 min after 5 mg/kg, intravenously.

URINALYSIS: Yes
- Time schedule for collection of urine: at 0, 14, 30, 60 and 90 days
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Not specified
- 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, kidneys, pancreas, spleen, thymus, adrenals, thyroid, brain, pituitary, testes, epididymes, seminal vesicles, prostate, uterus, and ovary.

HISTOPATHOLOGY: Yes
The following tissues were evaluated: brain (sections at levels of the optic nerve, chiasm, mammillary body, cerebellum, pons, and medulla oblongata) cervical spinal cord, hypophysis, eye, optic nerve, thyroid and parathyroid, thymus, heart (left auricle and ventricle), lung, carinal node, sternum, rib, brachia! plexus, aorta, liver (three lobes), spleen, pancreas (head, body, and tail), kidneys, adrenal, stomach (frontal, antral), small and large intestine (four levels), mesenteric node, male and female reproductive tracts (all levels), urinary bladder, femoral bone marrow, sciatic nerve, skeletal muscle, submaxillary gland, mammary gland, and tongue.
Clinical signs:
no effects observed
Description (incidence and severity):
All parameters examined were considered normal.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
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:
no effects observed
Description (incidence and severity):
All parameters were considered normal.
Haematological findings:
no effects observed
Description (incidence and severity):
All parameters were considered normal.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
All dogs receiving the highest dose of ethyl maltol showed elevated serum bilirubin levels at 30 days until termination.
Two of the dogs receiving the lowest dose showed elevated serum bilirubin levels at 30 days which returned to normal at later timepoints.
Urinalysis findings:
no effects observed
Description (incidence and severity):
All parameters were considered normal.
Behaviour (functional findings):
not examined
Description (incidence and severity):
Not specifically examined according to the report, however no abnormalities were reported during the duration of the study.
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:
no effects observed
Description (incidence and severity):
All parameters were considered normal.
Neuropathological findings:
no effects observed
Description (incidence and severity):
No specific neurotoxicity examination was performed, however there were no neuropathological indications from cage side observations or histological examination of the brain, cervical spinal cord or hypophysis.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Microscopically, changes were noted in the livers of dogs receiving 250 mg/kg bw/day ethyl maltol. The change was distinguished by a few to moderate number of Kupffer cells containing hemosiderin with small amounts of intracellular bilirubin. At the 125 mg/kg bw/day level, a few to moderate number of hemosiderin-laden Kupffer cells, but no hepatocellular bilirubin, was observed. As the observed abnormal cells were few to moderate, the change is considered adaptive.
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical biochemistry
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
500 mg/kg bw/day (actual dose received)
System:
hepatobiliary
Organ:
blood
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified

Refer to Table 2 in publication attached.

Conclusions:
This 90-day oral toxicity study in dogs (similar to OECDTG 409) found treatment-related adverse effects in the 500 mg/kg/day dosing group. Based on these findings, a NOAEL of 250 mg/kg bw/day was established.
Executive summary:

In a subchronic repeated dose toxicity study (Gralla et al.,1969), Ethyl Maltol was adminitered to 4 groups of male and female Beagle dogs (4/group, not distributed according to sex) by capsule at dose levels of 0, 125, 250, 500 mg/kg daily for 90 days.

No effects were observed on clinical signs, mortality, body weight, food consumption, ophthalmological, haematological, urinalysis and organ weight. No abnormalities observed in behaviour. No neuropathological indications from cage side observations or histological examination of the brain, cervical spinal cord or hypophysis.At clinical biochemistry, all dogs receiving the highest dose of ethyl maltol showed elevated serum bilirubin levels at 30 days until termination. Two of the dogs receiving the lowest dose showed elevated serum bilirubin levels at 30 days  which returned to normal at later timepoints. Microscopically, changes were noted in the livers of dogs receiving 250 mg/kg bw/day ethyl maltol. The change was distinguished by a few to moderate number of Kupffer cells containing hemosiderin with small amounts of intracellular bilirubin. At the 125 mg/kg bw/day level, a few to moderate number of hemosiderin-laden Kupffer cells, but no hepatocellular bilirubin, was observed.  As the observed abnormal cells were few to moderate, the change is considered adaptive.


The NOAEL (male/female) was 250 mg/kg bw/day.

Endpoint:
chronic toxicity: oral
Remarks:
Combined Chronic Toxicity / Carcinogenicity Study
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1968
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Study results were sufficiently described, but did not contain detailed descriptions of the individual animal data. Dosing was performed 5 days/week but was not jusitified, 8 dogs were used per dose group however the male/female distribution was not provided and the use of a non-rodent species not justified.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Version / remarks:
1981, EFSA assignment
Deviations:
yes
Remarks:
8 animals were used per dose level (dogs), no justification was provided for the use of dogs, dosing was not performed daily but 5 days/week
GLP compliance:
no
Remarks:
pre-GLP
Limit test:
no
Species:
dog
Strain:
Beagle
Sex:
male/female
Details on test animals or test system and environmental conditions:
Not Specified



Route of administration:
oral: capsule
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
None
Duration of treatment / exposure:
2 years
Frequency of treatment:
5 days/week
Dose / conc.:
200 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
50 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
8 animals per dose level (not distributed according to sex)
Control animals:
yes, concurrent no treatment
Positive control:
not applicable
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes, complete physical examination
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: at 0, 3, 6, 9, 12, 18 and 24 months
- Dose groups that were examined: All

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at 0, 3, 6, 9, 12, 18 and 24 months
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: 8 per dose group
- Parameters checked: hemoglobin, hematocrit, RBC, total WBC, and differential count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at 0, 3, 6, 9, 12, 18 and 24 months
- Animals fasted: Not specified
- How many animals: 8 per dose group
- Parameters checked: plasma glucose (Hoffman,1937), blood urea nitrogen (BUN) (March et al., 1965), alkaline phosphatase (Marsh et al., 1959), SGOT, SGPT by Karmen's (1955) method, and BSP excretion 30 min after 5 mg/kg, intravenously.

URINALYSIS: Yes
- Time schedule for collection of urine: at 0, 3, 6, 9, 12, 18 and 24 months
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Not specified
- 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:
Two dogs per dose were killed after 1 year on test, and the remaining animals after a total of 2 years; both groups were autopsied.

GROSS PATHOLOGY: Yes
The following organs were evaluated: heart, lung, liver, kidneys, pancreas, spleen, thymus, adrenals, thyroid, brain, pituitary, testes, epididymes, seminal vesicles, prostate, uterus, and ovary.

HISTOPATHOLOGY: Yes
The following tissues were evaluated: brain (sections at levels of the optic nerve, chiasm, mammillary body, cerebellum, pons, and medulla oblongata) cervical spinal cord, hypophysis, eye, optic nerve, thyroid and parathyroid, thymus, heart (left auricle and ventricle), lung, carinal node, sternum, rib, brachial plexus, aorta, liver (three lobes), spleen, pancreas (head, body, and tail), kidneys, adrenal, stomach (frontal, antral), small and large intestine (four levels), mesenteric node, male and female reproductive tracts (all levels), urinary bladder, femoral bone marrow, sciatic nerve, skeletal muscle, submaxillary gland, mammary gland, and tongue.
Statistics:
No data
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
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:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Single, slightly elevated SGPT values occurred in 4 dogs receiving 200 mg/kg/day; ; all other parameters of liver function and liver morphology were normal.
Urinalysis findings:
no effects observed
Description (incidence and severity):
All parameters were considered normal.
Behaviour (functional findings):
not examined
Description (incidence and severity):
Not specifically examined according to the report, however no abnormalities were observed during the duration of the study.
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:
no effects observed
Neuropathological findings:
no effects observed
Description (incidence and severity):
No specific neurotoxicity examination was performed, however there were no neuropathological indications from cage side observations or histological examination of the brain, cervical spinal cord or hypophysis.
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
>= 200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: highest dose tested
Key result
Critical effects observed:
no
Conclusions:
This chronic oral toxicity study (feeding) in dogs (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 male and female Beagle dogs (8/group, not distributed according to sex) by capsule at dose levels of 0, 50, 100, 200 mg/kg bw/day, 5 days per week, for 2 years.

There were no effects observed on clinical signs, mortality, body weights, food consumption, organ weights, urinalysis, ophthalmological or haematological parameters, gross pathology and (non)-neoplastic histopathology. There were no neuropathological indications from cage side observations or histological examination of the brain, cervical spinal cord or hypophysis. No abnormalities were observed on behaviour. Single, slightly elevated SGPT values occurred in 4 dogs receiving 200 mg/kg/day; all other parameters of liver function and liver morphology were normal.

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

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Results were sufficiently described, but did not contain detailed descriptions of the data. Most conservative dose descriptor was selected as NOAEL to cover also the effects seen at higher doses in the sub-chronic toxicity study. All studies were reviewed by the JECFA (2006) as part of their safety evaluation. The quality of the database is medium.
System:
urinary
Organ:
kidney

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Four studies are presented in which the repeated dose toxicity of Ethyl Maltol is examined. Two subchronic repeated dose toxicity studies, performed in rat and in dog are available. Furthermore two chronic repeated dose toxicity studies in rat and dog are also available. Adverse effects were observed in the highest dosed of the subchronic toxicity studies, leading to NOAEL derivation of 500 mg/kg bw for the rats and 250 mg/kg bw/day for the dogs. In the two chronic toxicity studies at >= 200 mg/kg bw/day no effects were seen. The highest dose tested in the chronic study with rat (most common species) is used to derive the NOAEL of 200 mg/kg bw/day, which covers also the effect dose of the sub-chronic studies with rat and dogs. All studies were 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.

Combined Chronic Toxicity/Carcinogenicity Studies

In the combined chronic toxicity/carcinogenicity key study (Equivalent or similar to OECD 453), 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. The study was also considered valid by the EFSA expert panel (EFSA Journal 2015;13(9):4244).

In a combined chronic toxicity/carcinogenicity supporting study (Equivalent or similar to OECD 453), Ethyl Maltol was administered to 4 groups of male and female Beagle dogs (8/group, not distributed according to sex) by capsule at dose levels of 0, 50, 100, 200 mg/kg bw/day, 5 days per week, for 2 years. There were no effects observed on clinical signs, mortality, body weights, food consumption, organ weights, urinalysis, ophthalmological or haematological parameters, gross pathology and (non)-neoplastic histopathology. There were no neuropathological indications from cage side observations or histological examination of the brain, cervical spinal cord or hypophysis. No abnormalities were observed on behaviour. Single, slightly elevated SGPT values occurred in 4 dogs receiving 200 mg/kg/day; all other parameters of liver function and liver morphology were normal. The NOAEL (male/female) was >=200 mg/kg bw/day.

Subchronic repeated dose toxicity studies

In a subchronic repeated dose toxicity supporting study (Equivalent or similar to OECD 408), 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.  

In a subchronic repeated dose toxicity supporting study (Equivalent or similar to OECD 409), Ethyl Maltol was adminitered to 4 groups of male and female Beagle dogs (4/group, not distributed according to sex) by capsule at dose levels of 0, 125, 250, 500 mg/kg daily for 90 days.  No effects were observed on clinical signs, mortality, body weight, food consumption, ophthalmological, haematological, urinalysis and organ weight. No abnormalities observed in behaviour. No neuropathological indications from cage side observations or histological examination of the brain, cervical spinal cord or hypophysis. At clinical biochemistry, all dogs receiving the highest dose of ethyl maltol showed elevated serum bilirubin levels at 30 days until termination. Two of the dogs receiving the lowest dose showed elevated serum bilirubin levels at 30 days  which returned to normal at later timepoints. Microscopically, changes were noted in the livers of dogs receiving 250 mg/kg bw/day ethyl maltol. The change was distinguished by a few to moderate number of Kupffer cells containing hemosiderin wit h small amounts of intracellular bilirubin. At the 125 mg/kg bw/day level, a few to moderate number of hemosiderin-laden Kupffer cells, but no hepatocellular bilirubin, was observed.  As the observed abnormal cells were few to moderate, the change is considered adaptive. The NOAEL (male/female) was 250 mg/kg bw/day.

The data was acceptable to use in the human health risk assessment.

Justification for classification or non-classification

Based on the available information in the dossier, the substance Ethyl Maltol (CAS No. 4940-11-8) does not need to be classified as specific target organ toxicity (repeated) when considering the criteria outlined in Annex I of 1272/2008/EC.