3-hydroxy-2-methyl-4-pyrone

Endpoint summary

Description of key information

Read-across to Ethyl Maltol (CAS No. 4940-11-8) - Subchronic NOAEL (rat): 500 mg/kg bw/day (Equivalent or similar to OECD 408)

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

Report is attached below.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Critical effects observed:

no

Conclusions:

In a 90 day repeated dose toxicity in Charles River rats, the predicted NOAEL (male/female) for Maltol was 500 mg/kg bw/day, based on the read-across study of Ethyl Maltol.

Reference 2

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

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

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

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

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

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

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

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Critical effects observed:

no

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.

Reference 3

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Remarks:

No NOAEL identified

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents)

GLP compliance:

no

Limit test:

no

Species:

dog

Strain:

Beagle

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

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

Dose / conc.:

125 mg/kg bw/day (nominal)

Dose / conc.:

250 mg/kg bw/day (nominal)

Dose / conc.:

500 mg/kg bw/day (nominal)

No. of animals per sex per dose:

Groups of male and female dogs, 4 per level (not necessarily distributed according to sex)

Control animals:

yes, concurrent no treatment

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes; the aninmals received a complete physical examination weekly.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights consumption were measured weekly

HAEMATOLOGY: Yes; At 0, 14, 30, 60, and 90 days, complete hematologic evaluations were made, plus prothrombin time

CLINICAL CHEMISTRY: Yes; At 0, 14, 30, 60, and 90 days, the following blood chemical determinations: plasma glucose, blood urea nitrogen (BUN), alkaline phosphatase, and total bilirubin , SGOT, SGPT and BSP excretion 30min after 5 mg/kg, intravenously.

URINALYSIS: Yes; At 0, 14, 30, 60, and 90 days, complete urine evaluations were made.

OPHTHALMOSCOPIC EXAMINATION: Yes; Yes; At 0, 14, 30, 60, and 90 days, complete ophthalmoscopic evaluations were made.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes ; all rats were autopsied and examined grossly. The following organs were removed and weighed: heart, lung, liver, kidneys, pancreas, spleen, thymus, adrenals, thyroid, brain, pituitary, testes, epididymes, seminal vesicles, prostate, uterus, and ovary. Tissues were placed in Bouin’s solution, except the eyes and nervous tissues, which were fixed in 15 % formalin, trimmed, embedded in paraffin, sectioned, and stained with hematoxylin and eosin. In addition, formalin-fixed, frozen sections from all livers and kidneys were stained with Oil Red 0; periodic acid-Schiff-Perls preparations were made on Bouin-fixed, paraffin sections of all livers and kidneys and on Genere-fixed, paraffin sections of all livers.

HISTOPATHOLOGY: Yes; The following tissues of each dog were examined microscopically : 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.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Episcleritis, icteric mucous membranes, emesis, ataxia and prostration was noted before death.

Mortality:

mortality observed, treatment-related

Description (incidence):

Three of four animals (sex not specified) at 500 mg/kg bw/day died within 21-41 days, and the fourth was killed when it became moribund.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Severe weight loss (3.0-4.8 kg) was noted in animals that died before the end of the study

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Two dogs (sex not specified} had decreased haemoglobin concentrations, erythrocyte volume fractions and red blood cell counts and increased blood urea nitrogen (Table 2).

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Three dogs (sex not specified} had elevated aspartate and alanine aminotransferase activities, and all four (sex not specified) had increased bilirubin levels.

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

Gross pathological findings:

no effects observed

Description (incidence and severity):

At autopsy, no gross pathologic changes were observed.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Pathological examination of the tissues revealed pulmonary oedema, hepatic and adrenal cortical and medullary necrosis, fatty degeneration of the myocardium and testicular degeneration.

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Dose descriptor:

NOEL

Effect level:

250 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

body weight and weight gain

histopathology: non-neoplastic

mortality

Conclusions:

In a 90 day repeated dose toxicity in Beagle dogs, the NOEL (male/female) for Maltol was 250 mg/kg bw/day.

Executive summary:

In a subchronic repeated dose toxicity study (Gralla et al., 1969), Maltol was administered to 4 groups of Beagle male and female rats (4 per level, not necessarily distributed according to sex) in the diet at dose levels of 0, 125, 250 and 500 mg/kg bw/day daily for 90 days.

Three of four animals (sex not specified) at 500 mg/kg bw/day died within 21-41 days, and the fourth was killed when it became moribund. Episcleritis, icteric mucous membranes, emesis, ataxia and prostration was noted before death. Severe weight loss (3.0-4.8 kg) was noted in animals that died before the end of the study. Two dogs (sex not specified) had decreased haemoglobin concentrations, erythrocyte volume fractions and red blood cell counts and increased blood urea nitrogen. Three dogs (sex not specified) had elevated aspartate and alanine aminotransferase activities, and all four (sex not specified) had increased bilirubin levels. There were no effects observed on ophthalmology, urinalysis or organ weight parameters. At autopsy, no gross pathologic changes were observed. Pathological examination of the tissues revealed pulmonary oedema, hepatic and adrenal cortical and medullary necrosis, fatty degeneration of the myocardium and testicular degeneration.

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

Reference 4

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Remarks:

No NOAEL identified

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

no

Limit test:

yes

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

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

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Remarks:

Test group was part of the ethyl maltol rat 90 day study

No. of animals per sex per dose:

10 males and females

Control animals:

yes, concurrent no treatment

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

Clinical signs:

not examined

Mortality:

mortality observed, treatment-related

Description (incidence):

There were 2 deaths (sex not specified).

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Decreased body-weight gain was reportedin males and females after weeks 3 and 9, respectively, the male rats being more severely affected (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):

A decrease in haemoglobin and slightly amber-coloured serum were observed in one male and one female at study termination.

Clinical biochemistry findings:

not specified

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

A high incidence of albuminuria was observed in all treated rats.

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

Dose descriptor:

NOEL

Effect level:

1 000 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

clinical biochemistry

histopathology: non-neoplastic

Conclusions:

In a 90 day repeated dose toxicity in Charles River rats, the NOEL (male/female) for Maltol was <1000 mg/kg bw/day.

Executive summary:

In a subchronic repeated dose toxicity study (Gralla et al., 1969), Maltol was administered to 1 group of Charles River male and female rats (10/sex/group) in the diet at dose levels of 0 and 1000 mg/kg bw/day daily for 90 days.

Food consumption were measured weekly and test item concentrations in food were adjusted accordingly. There were 2 deaths (sex not specified). Decreased body-weight gain was reported in males and females after weeks 3 and 9, respectively, the male rats being more severely affected. A decrease in haemoglobin and slightly amber-coloured serum were observed in one male and one female at study termination.  A high incidence of albuminuria was observed in all treated rats.  There were no effecs observed on clinical chemistry parameters. At autopsy, all organ weights of treated rats compared favorably with those of controls. At autopsy, 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 NOEL (male/female) was <1000 mg/kg bw/day.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The is one read-across Ethyl Maltol subchronic study in the rat and two Maltol subchronic studies (rat/dog); all are JECFA peer reviewed. The quality of the database is medium.

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

The repeated dose toxicity of Maltol has been evaluated in one read-across to Ethyl Maltol (CAS No. 4940-11-8) subchronic repeated dose toxicity study in the rat and two Maltol subchronic repeated dose toxicity studies in the rat and dog. All studies were reviewed by the JECFA (2006) as part of their safety evaluation. The read-across study was chosen as the key study as a NOAEL could be derived from it.

In a subchronic repeated dose toxicity read-across key 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. A NOAEL (male/female) of 500 mg/kg bw/day was also predicted for Maltol.

In a subchronic repeated dose toxicity supporting study (Equivalent or similar to OECD 408), Maltol was administered to 1 group of Charles River male and female rats (10/sex/group) in the diet at dose levels of 0 and 1000 mg/kg bw/day daily for 90 days. Food consumption were measured weekly and test item concentrations in food were adjusted accordingly. There were 2 deaths (sex not specified). Decreased body-weight gain was reported in males and females after weeks 3 and 9, respectively, the male rats being more severely affected. A decrease in haemoglobin and slightly amber-coloured serum were observed in one male and one female at study termination.  A high incidence of albuminuria was observed in all treated rats.  There were no effecs observed on clinical chemistry parameters. At autopsy, all organ weights of treated rats compared favorably with those of controls. At autopsy, 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 NOEL (male/female) was <1000 mg/kg bw/day.

In a subchronic repeated dose toxicity supporting study (Equivalent or similar to OECD 409), Maltol was administered to 4 groups of Beagle male and female rats (4 per level, not necessarily distributed according to sex) in the diet at dose levels of 0, 125, 250 and 500 mg/kg bw/day daily for 90 days. Three of four animals (sex not specified) at 500 mg/kg bw/day died within 21-41 days, and the fourth was killed when it became moribund. Episcleritis, icteric mucous membranes, emesis, ataxia and prostration was noted before death. Severe weight loss (3.0-4.8 kg) was noted in animals that died before the end of the study. Two dogs (sex not specified) had decreased haemoglobin concentrations, erythrocyte volume fractions and red blood cell counts and increased blood urea nitrogen. Three dogs (sex not specified) had elevated aspartate and alanine aminotransferase activities, and all four (sex not specified) had increased bilirubin levels. There were no effects observed on ophthalmology, urinalysis or organ weight parameters. At autopsy, no gross pathologic changes were observed. Pathological examination of the tissues revealed pulmonary oedema, hepatic and adrenal cortical and medullary necrosis, fatty degeneration of the myocardium and testicular degeneration. The NOEL (male/female) was 250 mg/kg bw/day.

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.

Justification for classification or non-classification

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