2-ethyl-3-hydroxy-4-pyrone

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

Screening for reproductive / developmental toxicity: This study is waived as a combined chronic toxicity/carcinogenicity and one generation study, in which the animals were mated to produce an F1 litter to assess the reproductive/developmental toxicity (similar to OECD TG 415/453 but less animals) were used is available.

Extented one-generated reproductive toxicity :This study is waived as there are no results from available repeated dose toxicity studies that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with reproductive toxicity

Link to relevant study records

Reference

Reference 1

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the extended one-generation reproductive toxicity study does not need to be conducted because there are no results from available repeated dose toxicity studies that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with reproductive toxicity

Reference 2

Endpoint:

screening for reproductive / developmental toxicity

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because a pre-natal developmental toxicity study is available

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Screening for reproductive / developmental toxicity: This study is waived as acombined chronic toxicity/carcinogenicity and one generation study, in which the animals were mated to produce an F1 litter to assess the reproductive/developmental toxicity(similar to OECD TG 415/453 but less animals) were used is available.

Extented one-generated reproductive toxicity :This study is waived as there are no results from available repeated dose toxicity studies that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with reproductive toxicity

Effects on developmental toxicity

Description of key information

Pre-natal developmental toxicity study (rat, oral):

NOAEL (parental/offspring): ≥200 mg/kg bw/day (Combined Chronic Toxicity/Carcinogenicity and One Generation study, in which the animals were mated to produce an F1 litter to assess the reproductive/developmental toxicity. Less animals were used compared to the current OECD Guidelines; equivalent or similar to OECD TG 415)

Pre-natal developmental toxicity study (dog, oral):

NOAEL (parental/offspring): ≥200 mg/kg bw/day (Combined Chronic Toxicity/Carcinogenicity and One Generation study, in which the animals were mated to produce an F1 litter to assess the reproductive/developmental toxicity. Less animals were used compared to the current OECD Guidelines; equivalent or similar to OECD TG 415)

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Remarks:

A ombined chronic toxicity/carcinogenicity and one generation study, in which the animals were mated to produce an F1 litter to assess the reproductive/developmental toxicity. Less animals were used compared to the current OECD Guidelines

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Comparable to guideline study. Not all the raw study results have been published in the publication, limited information available on methods, 1st generation included, but number of animals is lower than currently required. 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

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

other: OECD 415 (A Combined /Chronic Toxicity/Carcinogenicity /study and one generation study; animals were mated to produce an F1 litter to assess the reproductive/developmental toxicity. Less animals were used compared to the current OECD Guidelines)

Deviations:

yes

Remarks:

A Combined /Chronic Toxicity study/Carcinogenicity /study and one generation study, in which the animals were mated to produce an F1 litter to assess the reproductive/developmental toxicity. Less animals were used compared to the current OECD Guidelines

GLP compliance:

no

Remarks:

pre-GLP

Limit test:

no

Species:

rat

Strain:

other: Charles River Weanling Albino

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

Details on 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 mating procedure:

Between 15 and 21 and 30 and 36 weeks, 10 males and 10 females per level were mated to produce two separate litters.
Age at mating of the mated animals in the study: 15-21 and 30-36 weeks

Duration of treatment / exposure:

2 years

Frequency of treatment:

daily

Duration of test:

2 years

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

Maternal examinations:

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

FOOD EFFICIENCY: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 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: 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

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No
- Number of implantations: No
- Number of early resorptions: No
- Number of late resorptions: No
- Other: Uterus and ovaries weiged and microscopically examined

Fetal examinations:

Fetuses were not examined
- External examinations: No
- Soft tissue examinations: No
- Skeletal examinations: No
- Head examinations: No

Examinations were performed in pups.

Statistics:

No data

Indices:

Methods are not specified

Historical control data:

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:

not examined

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

One control rat developed anemia (RBC, 1.8 x 103 /mm3; hemoglobin, 8.0g % and hematocrit,18.5 %) of unknown etiology.

Clinical biochemistry findings:

no effects observed

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

Gross pathological findings:

effects observed, non-treatment-related

Neuropathological findings:

not examined

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.

Number of abortions:

not examined

Pre- and post-implantation loss:

not examined

Total litter losses by resorption:

not examined

Early or late resorptions:

not examined

Dead fetuses:

not specified

Changes in pregnancy duration:

no effects observed

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed

Changes in number of pregnant:

effects observed, non-treatment-related

Description (incidence and severity):

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.

Other effects:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

>= 200 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: Highest dose tested

Fetal body weight changes:

not examined

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

no effects observed

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

not specified

Key result

Dose descriptor:

NOAEL

Effect level:

>= 200 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

No direct exposure (only via parents)

Sex:

male/female

Basis for effect level:

other: highest dose tested

Key result

Developmental effects observed:

no

Refer to Tables 3 - 6 in attached publication.

Conclusions:

In a ombined chronic toxicity/carcinogenicity and one generation study in Charles River rats with Ethyl Maltol, the NOAEL (parental, offspring) was ≥200 mg/kg bw/day.

Executive summary:

In a combined chronic toxicity/carcinogenicity and one generation study (Gralla et al., 1969), Ethyl Maltol was administered to 4 groups of Charles River 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. Between 15 and 21 and 30 and 36 weeks, 10 males and 10 females per level were mated to produce two separate litters. The offspring were killed at weaning. In the parental group, five of each sex were killed after 1 year and the remaining five of each sex at the end of the study.

All dose levels of ethyl maltol were well tolerated throughout the 2-year feeding period. The test and control animals grew and maintained the body weight in a comparable manner. After two years on test, one control rat had a massive anemia of unknown etiology. Otherwise, all hematologic values for test and control animals were within normal ranges. All rats showed a tendency toward albuminuria; otherwise, urinalysis values were essentially normal. Pathologic changes consistent with aged rats were observed primarily in the pulmonary, endocrine, urinary, and cardiovascular systems. Neoplasia occurred in a random manner with no apparent relationship between number, location, or type of tumors and treatment.

A fall in fertility was noted in test and control groups at the second mating but controls were affected also (60% conception at 200 mg/kg bw/day, 50% conception for controls). This was due presumably to the advanced age of the animals. Ethyl maltol had no effect on gestation, parturition or lactation.

Ethyl maltol had no effect on fetal development and no gross internal abnormalities were noted. In the 1st F1 litter, at 0 mg/kg bw/day, the 21 day survival rate was 93%; at 200 mg/kg bw/day it was 92%. In the 2nd F1 litter, at 0 mg/kg bw/day, the 21 day survival rate was 49%; at 200 mg/kg bw/day it was 66%. There was no difference in the average weight of pups at 21 days lactation between controls and treated groups.

The NOAEL (parental/offspring) was ≥200 mg/kg bw/day.

Reference 2

Endpoint:

developmental toxicity

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 p ublished in the publication, limited information available on methods, 1st generation included, 8 dogs/ dose level, dosing 5 days/week.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

other: OECD TG 415

Deviations:

yes

Remarks:

1st generation included, dosing 5 days/week

GLP compliance:

no

Remarks:

pre-GLP

Limit test:

no

Species:

other: Dog

Strain:

other: Beagle

Details on test animals or test system and environmental conditions:

Not specified

Route of administration:

oral: capsule

Details on exposure:

None

Details on mating procedure:

Whenever females displayed signs of estrus, they were mated with a male from the same drug level group. Dosing was continuous and covered gestation, parturition, and lactation. The offspring were examined closely for signs of abnormal development.

Duration of treatment / exposure:

2 years

Frequency of treatment:

5 days/week

Duration of test:

2 years

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

Control animals:

yes, concurrent no treatment

Maternal examinations:

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

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.

OTHER: Between 15 and 21 and 30 and 36 weeks, 10 males and 10 females per level were mated to pro-duce two separate litters. The resulting offspring were counted, weighed, and examined for abnormal development at birth and during lactation. At weaning they were sacri-ficed and examined for internal malformations.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Not specified
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No
- Number of implantations: No
- Number of early resorptions: No
- Number of late resorptions: No
- Other: Uterus and ovaries weiged and microscopically examined

Fetal examinations:

Fetuses were not examined
- External examinations: No
- Soft tissue examinations: No
- Skeletal examinations: No
- Head examinations: No

Examinations were performed in pups.
- Number and sex of pups
- Presence of gross anomalies
- Weight gain

Statistics:

No data

Indices:

Methods for calculation not specified

Historical control data:

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:

not examined

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.

Urinalysis findings:

no effects observed

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

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

Number of abortions:

not examined

Pre- and post-implantation loss:

not examined

Total litter losses by resorption:

not examined

Early or late resorptions:

not examined

Dead fetuses:

not specified

Changes in pregnancy duration:

no effects observed

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed

Changes in number of pregnant:

effects observed, non-treatment-related

Description (incidence and severity):

Breeding efforts were not remarkably successful, a total of 15 normal pups were delivered by two bit ches which had received ethyl maltol at the high and intermediate dose levels from 6 to 20 months before parturition.

Other effects:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

>= 200 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: highest dose tested

Fetal body weight changes:

not examined

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

no effects observed

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

not examined

Key result

Dose descriptor:

NOAEL

Effect level:

>= 200 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

No direct exposure (only via parents)

Sex:

male/female

Basis for effect level:

other: highest dose tested

Key result

Developmental effects observed:

no

Conclusions:

In a combined chronic toxicity/carcinogenicity and one generation study in Beagle dog with Ethyl Maltol, the NOAEL (parental, offspring) was ≥200 mg/kg bw/day.

Executive summary:

In a combined chronic toxicity/carcinogenicity and one generation study (Gralla et al., 1969), Ethyl Maltol was administered to 4 group Beagle male and female dogs (8/group) by capsule at dose levels of 0, 50, 100, 200 mg/kg bw/day 5 day/week for 2 years. Whenever females displayed signs of estrus, they were mated with a male from the same drug level group. Dosing was continuous and covered gestation, parturition, and lactation. The offspring were examined closely for signs abnormal development. 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.

No effects observed on parental clinical signs, mortality, body weight, food consumption, haematological, urinalysis, organ weight, gross pathological, histopathological ( non-neoplastic) and histopathological ( neoplastic). 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.

While breeding efforts were not remarkably successful, a total number of 15 normal pups were delivered by two bitches which had received ethyl maltol at the high and intermediate dose levels from 6 to 20 months before parturition. No adverse toxic, reproductive or embryogenic effects at doses up to and including 200 mg/kg bw/day were observed.

The NOAEL (parental/offspring) was ≥200 mg/kg bw/day.  

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Both studies are Combined Chronic Toxicity/Carcinogenicity and One Generation studies, in which the animals were mated to produce an F1 litter to assess the reproductive/developmental toxicity. Less animals were used compared to the current OECD Guidelines; equivalent or similar to OECD TG 415. 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

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Two studies are presented in which the reproductive toxicity (fertility and developmental toxicity) of Ethyl Maltol is examined. Neither of the studies reported adverse reproductive effects (fertility and developmental toxicity). The rat study was chosen as key study as this was performed with the most common species. The rat 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.

Pre-natal developmental toxicity study (rat)

In a combined chronic toxicity/carcinogenicity and one generation key study (Gralla et al., 1969), Ethyl Maltol was administered to 4 groups of Charles River 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. Between 15 and 21 and 30 and 36 weeks, 10 males and 10 females per level were mated to produce two separate litters. The offspring were killed at weaning. In the parental group, five of each sex were killed after 1 year and the remaining five of each sex at the end of the study.

All dose levels of ethyl maltol were well tolerated throughout the 2-year feeding period. The test and control animals grew and maintained the body weight in a comparable manner. After two years on test, one control rat had a massive anemia of unknown etiology. Otherwise, all hematologic values for test and control animals were within normal ranges. All rats showed a tendency toward albuminuria; otherwise, urinalysis values were essentially normal. Pathologic changes consistent with aged rats were observed primarily in the pulmonary, endocrine, urinary, and cardiovascular systems. Neoplasia occurred in a random manner with no apparent relationship between number, location, or type of tumors and treatment.

A fall in fertility was noted in test and control groups at the second mating but controls were affected also (60% conception at 200 mg/kg bw/day, 50% conception for controls). This was due presumably to the advanced age of the animals. Ethyl maltol had no effect on gestation, parturition or lactation.

Ethyl maltol had no effect on fetal development and no gross internal abnormalities were noted. In the 1st F1 litter, at 0 mg/kg bw/day, the 21 day survival rate was 93%; at 200 mg/kg bw/day it was 92%. In the 2nd F1 litter, at 0 mg/kg bw/day, the 21 day survival rate was 49%; at 200 mg/kg bw/day it was 66%. There was no difference in the average weight of pups at 21 days lactation between controls and treated groups.

The NOAEL (parental/offspring) was ≥200 mg/kg bw/day.

Pre-natal developmental toxicity study (dog)

In a combined chronic toxicity/carcinogenicity and one generation study (Gralla et al., 1969), Ethyl Maltol was administered to 4 group Beagle male and female dogs (8/group) by capsule at dose levels of 0, 50, 100, 200 mg/kg bw/day 5 day/week for 2 years. Whenever females displayed signs of estrus, they were mated with a male from the same drug level group. Dosing was continuous and covered gestation, parturition, and lactation. The offspring were examined closely for signs abnormal development. 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.

No effects observed on parental clinical signs, mortality, body weight, food consumption, haematological, urinalysis, organ weight, gross pathological, histopathological ( non-neoplastic) and histopathological ( neoplastic). 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.

While breeding efforts were not remarkably successful, a total number of 15 normal pups were delivered by two bitches which had received ethyl maltol at the high and intermediate dose levels from 6 to 20 months before parturition. No adverse toxic, reproductive or embryogenic effects at doses up to and including 200 mg/kg bw/day were observed.

The NOAEL (parental/offspring) was ≥200 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 for reproductive toxicity when the criteria outlined in Annex I of 1227/2008/EC are applied.