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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

Toxicity to Reproduction (Screening):

Read-across to Ethyl Maltol (CAS No. 4940-11-8) - NOAEL (parental): ≥200 mg/kg bw/day (Similar to OECD 415/453)

Read-across to Ethyl Maltol (CAS No. 4940-11-8) - NOAEL (offspring): ≥200 mg/kg bw/day (Similar to OECD 415/453)

Link to relevant study records

Referenceopen allclose all

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.
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.
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 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
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
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.
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: 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.
Dose descriptor:
NOAEL
Effect level:
>= 200 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: Highest dose tested
Critical effects observed:
no
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
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
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
Critical effects observed:
no
Reproductive effects observed:
no
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.

Endpoint:
fertility, other
Remarks:
One Generation Reproductive Toxicity/Combined Chronic Toxicity & Carcinogenicity Study
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:
>= 2 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: highest dose tested
Critical effects observed:
no
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 200 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: highest dose tested
Critical effects observed:
no
Reproductive effects observed:
no
Conclusions:
The predicted NOAEL (male/female) for Maltol was ≥200 mg/kg bw/day, based on the read-across study of Ethyl Maltol.
Effect on fertility: 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:
There is one EFSA peer reviewed read-across Ethyl Maltol one generation reproductive toxicity/combined chronic toxicity & carcinogenicity study available; the quality of the database is medium.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Toxicity to Reproduction (Screening):

There is no toxicity to reproduction (screening) study available for Maltol available. Read-across was performed to an EFSA peer-reviewed

one generation reproductive toxicity/combined chronic toxicity & carcinogenicity study in rats with Ethyl Maltol.

In a one generation reproductive toxicity/combined chronic toxicity & carcinogenicity read-across study (Similar to OECD415/453), 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. A NOAEL (parental/offspring) of ≥200 mg/kg bw/day was also predicted for Maltol.

EFSA Journal 2015;13(9):4244

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the available information in the dossier, the substance Maltol (CAS No. 118-71-8) does not need to be classified for reproductive toxicity when the criteria outlined in Annex I of 1227/2008/EC are applied, based on the results of the read-across study from Ethyl Maltol (CAS No.4940-11-8).

Additional information