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EC number: 204-271-8 | CAS number: 118-71-8
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- fertility, other
- Remarks:
- One Generation Reproductive Toxicity/Combined Chronic Toxicity & Carcinogenicity Study
- 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:
- The study was performed before the introduction of OECD guidelines but is, however, considered valid by the EFSA.
Data source
Reference
- Reference Type:
- publication
- Title:
- Toxicity studies with Ethyl Maltol
- Author:
- Gralla, E.J., Stebbins, R.B., Coleman, L., Delahunt, C.S.,
- Year:
- 1 969
- Bibliographic source:
- Toxicology and applied pharmacology, 15, 604-613
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- The study was performed before the introduction of OECD guidelines but is, however, considered valid by the EFSA. It was similar to a One Generation Reproductive Toxicity (OECD 415) and Combined Chronic Toxicity & Carcinogenicity Study (OECD 453). Groups of 25 male and 25 female Charles River rats received ethyl maltol in the diet at dose levels of 50, 100 or 50 mg/k bw/day for 2 years. Blood and urine examinations were made after 3, 6, 9, 12, 18 and 24 months. Between 15 and 21 and 30 and 36 weeks, 10 males and 10 females per level were mated to produce two separate litters. The resulting offspring were counted, weighed, and examined for abnormal development at birth and during lactation. At weaning they were sacrificed and examined for internal malformations. In the parent groups, 5 of each sex at each level were autopsied after 1 year on test, the remainder after 2 years. Gross and microscopic evaluations were carried out.
EFSA Journal 2015;13(9):4244 - GLP compliance:
- no
- Limit test:
- no
- Justification for study design:
- The study (One Generation Reproductive Toxicity/Combined Chronic Toxicity & Carcinogenicity Study) was performed before the introduction of OECD guidelines but is, however, considered valid by the EFSA.
Test material
- Reference substance name:
- 2-ethyl-3-hydroxy-4-pyrone
- EC Number:
- 225-582-5
- EC Name:
- 2-ethyl-3-hydroxy-4-pyrone
- Cas Number:
- 4940-11-8
- Molecular formula:
- C7H8O3
- IUPAC Name:
- 2-ethyl-3-hydroxy-4H-pyran-4-one
- Test material form:
- solid
1
Test animals
- Species:
- rat
- Strain:
- other: Charles River albino
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River
- Age at study initiation: Weanling
- Housing: Individually caged
- Diet: Rockland Ground Rat Food ad libitum
- Water: ad libitum
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- DIET PREPARATION
Rockland Ground Rat Food was mixed with ethyl maltol - 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.
- Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 2 years
- Frequency of treatment:
- Daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 200 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 25 males and 25 females
- Control animals:
- yes, plain diet
Examinations
- Parental animals: Observations and examinations:
- 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; Blood examinations were made after 3, 6, 9, 12, 18 and 24 months (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; Urine examinations were made after 3, 6, 9, 12, 18 and 24 months (color, volume, specific gravity, pH, blood, albumin, glucose, and microscopic examination of the sediment after centrifugation).. - Litter observations:
- Offspring were counted, weighed, and examined for abnormal development at birth and during lactation.
- Postmortem examinations (parental animals):
- GROSS PATHOLOGY: Yes ; In the parent groups, 5 of each sex at each level were autopsied after 1 year on test, the remainder after 2 years. 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 5 rats of each sex at each level 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 - Postmortem examinations (offspring):
- At weaning, offspring were sacrificed and examined for internal malformations.
- Reproductive indices:
- Percent conception, Average litter size at birth,
- Offspring viability indices:
- Pup survival at Day 21, average litter size 21 days and average weight, pups at 21 days lactation were recorded.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- All dose levels of ethyl maltol were well tolerated throughout the 2-year feeding period.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- The test and control animals grew and maintained the body weight in a comparable manner.
- Food consumption and compound intake (if feeding study):
- not specified
- 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):
- After two years on test, one control rat had a massive anemia (RBC, 1.8 x 10*3/mm3; hemoglobin, 8.0g% and hematocrit, 18.5 %) of unknown etiology. Otherwise, all hematologic values for test and control animals were within normal ranges.
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- All rats showed a tendency toward albuminuria; otherwise, urinalysis values were essentially normal.
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- 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 (Table 5).
- 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 (Table 6).
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- effects observed, non-treatment-related
- Description (incidence and severity):
- 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 Ethyl maltol, 50% controls; Table 3). This was due presumably to the advanced age of the animals.
Ethyl maltol had no effect on gestation, parturition or lactation.
Effect levels (P0)
- Dose descriptor:
- NOAEL
- Effect level:
- >= 200 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: Highest dose tested
Target system / organ toxicity (P0)
- Critical effects observed:
- no
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- not examined
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- mortality observed, non-treatment-related
- Description (incidence and severity):
- 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%. - Body weight and weight changes:
- no effects observed
- 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:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Anogenital distance (AGD):
- not examined
- Nipple retention in male pups:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Ethyl maltol had no effect on fetal development
- Histopathological findings:
- not examined
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not examined
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not examined
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- >= 2 000 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: highest dose tested
Target system / organ toxicity (F1)
- Critical effects observed:
- no
Overall reproductive toxicity
- Reproductive effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- In a One Generation Reproductive Toxicity/Combined Chronic Toxicity & Carcinogenicity Study in Charles River rats with Ethyl Maltol, the NOAEL (parental, offspring) was ≥200 mg/kg bw/day.
- Executive summary:
In a one generation reproductive toxicity/combined chronic toxicity & carcinogenicity 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.
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 EFSA peer-reviewed NOAEL (parental/offspring) was ≥200 mg/kg bw/day.
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