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Administrative data

Endpoint:
one-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Remarks:
This study was selected as the key study because the information provided for the hazard endpoint is sufficient for the purpose of classification and labelling and/or risk assessment. Data taken from accepted publication with limited details on methods and results

Data source

Reference
Reference Type:
publication
Title:
Studies of mannose metabolism and effects of long-term mannose ingestion in the mouse
Author:
Davis JA, Freeze HH
Year:
2001
Bibliographic source:
Biochimica et Biophysica Acta 1528 (2001) 116-126

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
Deviations:
yes
Remarks:
The study was conducted for 5 months, 3 M/F for each group
GLP compliance:
no
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
D-mannose
EC Number:
222-392-4
EC Name:
D-mannose
Cas Number:
3458-28-4
Molecular formula:
C6H12O6
IUPAC Name:
D-mannose
Details on test material:
Purity: not reported

Test animals

Species:
mouse
Strain:
other: C57 Bl/6
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: not reported
- Weight at study initiation: not reported
- Fasting period before study: no
- Housing: individual cages
- Diet: standard rat chow ad libitum
- Water: dosed with test item ad libitum



ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1 ºC
- Humidity (%): 55 ± 5%
- Photoperiod (hrs dark / hrs light): 12/12 hours

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SUBSTANCE PREPARATION
- Preparation frequency: drinking water was changed thrice a week

Details on mating procedure:
During the 5 month dosing, females were impregnated twice.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Parental rats (P1 generation) were dosed daily in the drinking water until weaning (Day 21) of the F1 offspring. The F1 generation was dosed during weaning and for 9 days after weaning.
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
1 other: %
Remarks:
nominal in water
Dose / conc.:
3 other: %
Remarks:
nominal in water
Dose / conc.:
10 other: %
Remarks:
nominal in water
Dose / conc.:
20 other: %
Remarks:
nominal in water
No. of animals per sex per dose:
3 male and female rats from each dose group
Control animals:
yes, concurrent vehicle
Details on study design:
For repeated dose parameters evaluated, see Sec. 7.5.1: DL.K2.5Mon.DW.M.Pub.KD

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Both mother and pups were monitored for ill health such as bloating, diarrhoea and abnormal weight gain or loss. Behaviour of these animals was also monitored.

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes

OTHER: Haematology, Clinical Chemistry and Neurobehavioural examinations
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities

Postmortem examinations (parental animals):
Organs were examined for size and weight . histological appearance of major organs or tissues were examined.



Postmortem examinations (offspring):
Organs were examined for size and weight

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Haematological findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Effect levels (P0)

Key result
Dose descriptor:
dose level:
Effect level:
20 other: % in drinking water
Based on:
test mat.
Sex:
male/female
Basis for effect level:
water consumption and compound intake
Remarks on result:
other: % in drinking water

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
20 other: % in drinking water
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects at the highest dose tested
Remarks on result:
other: % in drinking water

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Any other information on results incl. tables

Litter sizes (7-9 pups) and all pups were normal at birth. Pups grew at a normal rate, were healthy, and all survived until weaning at 21 days.

Test item level in the blood gradually elevated with increasing test item in the water, reaching 900 µM with 20% test item supplements compared to 100 µM in control. A similar test item concentration profile was also observed in males and non-pregnant females. Blood test item levels in 30-day-old pups also increased steadily and reached 900 µM with 20% test item water. In the milk samples, the test item rose from 60 µM in normal mice up to > 500 µM in mice given 20% test item water.

The test item did not cause bloating, diarrhoea, abnormal behaviour, weight gain or loss, or increase in haemoglobin glycation.

Applicant's summary and conclusion

Conclusions:
This study and the conclusions which are drawn from it fulfil the quality criteria (validity, reliability, repeatability).
Organ weights, histology, litter size, and growth of pups were normal after 5 months of dosing test item in drinking water.
Executive summary:

Test item-supplemented water given to mice for 5 months did not show any adverse or pathological effects on parents or offspring. Organ weights, histology, litter size, and growth of pups were normal. Water intake of mice given 20% test item in their water was reduced to half compared to other groups. Test item level in the blood gradually elevated with increasing test item in the water, reaching 900 µM with 20% test item supplements compared to 100 µM in control. A similar test item concentration profile was also observed in males and non-pregnant females. Blood test item levels in 30-day-old pups also increased steadily and reached 900 µM with 20% test item water. In the milk samples, the test item rose from 60 µM in normal mice up to > 500 µM in mice given 20% test item water.

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