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EC number: 225-582-5 | CAS number: 4940-11-8
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
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
- 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
- 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
Referenceopen allclose all
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
- 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
- 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.
- 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.
Referenceopen allclose all
Refer to Tables 3 - 6 in attached publication.
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.
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