D-mannose

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Drinking water study; Mouse; One generation reproduction study; NOAEL = 20%.One generation reproduction study; No effects were observed in reproductive parameters examined at the highest concentration tested. Reliability = 2

Link to relevant study records

Reference

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

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

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

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

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

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

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: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

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

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

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

Key result

Reproductive effects observed:

no

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.

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.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

Study duration:

subchronic

Species:

mouse

Quality of whole database:

study well documented, meets general accepted scientific principles, acceptable for assessment

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

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.

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

No test substance-related adverse effects on reproductive outcomes were observed after exposure to the test substance in a 5-month mouse drinking water study. No adequate developmental data are available for the test substance.  Therefore, the substance cannot be classified at this time for reproductive toxicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.