Sodium ascorbate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

The available information does not show adverse effects on fertility. Information on this endpoint is waived because a valid prenatal developmental toxicity study in the rat is available (cf. regulation (EC) No. 1907/2006, Appendix VIII, No. 8.7.1, column 2).

Link to relevant study records

Reference

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

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

Effects on developmental toxicity

Description of key information

The substance has no potential for reproductive toxicity. The NOAEL was determined to be 1125 mg/kg bw/day.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

pre-guideline study; no differentiation of early or late resorptions

GLP compliance:

no

Remarks:

pre-GLP study

Species:

rat

Strain:

Wistar

Route of administration:

oral: gavage

Vehicle:

water

Details on analytical verification of doses or concentrations:

not specified

Details on mating procedure:

- Impregnation procedure: cohoused
- M/F ratio per cage: 1/4
- Length of cohabitation: overnight
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

first trial: GD 6-15
second trial: GD 0 to day 21 p.p.

Frequency of treatment:

7/week

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Remarks:

Control group

Dose / conc.:

150 mg/kg bw/day (actual dose received)

Remarks:

Lowest dose group

Dose / conc.:

250 mg/kg bw/day (actual dose received)

Remarks:

low dose group

Dose / conc.:

500 mg/kg bw/day (actual dose received)

Remarks:

mid dose group

Dose / conc.:

1 000 mg/kg bw/day

Remarks:

high dose group

No. of animals per sex per dose:

Historical controls: 760 dams
Concurrend control: 21 dams
Lowest dose group: 22 dams
Low dose group: 19 dams
Mid dose group: 21 dams
High dose group: 17 dams

Control animals:

yes, concurrent vehicle

yes, historical

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations: at start and termination; body weight gain reported


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: uterus

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: Yes
- Number of early resorptions: No; sum of earla and late resorptions

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: two third per litter
- Head examinations: Yes: No data

Statistics:

means ± SD; statistical significance; method not specified

Indices:

no

Historical control data:

yes; from 760 dams

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

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

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Number of abortions:

no effects observed

Description (incidence and severity):

Abortions as percentage of implantations
Historical controls: 760 dams 2.2 %
Concurrend control: 21 dams 2.4 %
Lowest dose group: 22 dams 3.7 %
Low dose group: 19 dams 1.1 %
Mid dose group: 21 dams 0.9 %
High dose group: 17 dams 0.0 %

Pre- and post-implantation loss:

not specified

Total litter losses by resorption:

not specified

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

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:

not specified

Other effects:

not examined

Details on maternal toxic effects:

no toxic effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: absence of adverse effects

Key result

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

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:

not examined

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:

no effects observed

Other effects:

not examined

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: absence of adverse effects

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Conclusions:

Ascorbic acid was not maternal toxic or reprotoxic in female Wistar rats up to 1000 mg/kg bw and day

Executive summary:

The developmental toxicity of ascorbic acid was investigated in female Wistar rats and NMRI mice in a series of pre-guideline studies.

In the first trial, the test substance dissolved in water was administered by oral gavage at dose levels of 0, 150, 250, 500 and 1000 mg/kg bw and day during GD 6-15. Caesarian section was performed at termination on GD 20. Uteri and fetuses were examined. Findings were subjected to statistical analysis. No maternal toxicity or developmental toxicity (including teratogenicity) was noted at any dose level including the top dose. Hence, the NOAEL was 1000 mg/kg bw and day in this study.

It should be noted that the same result was obtained with mice treated during GD 6-15 (data not reported in this endpoint study record).

Further, a second trial was conducted which is not reported here in full detail. Briefly, dams (24-27 per group at termination) received ascorbic acid (0, 250, 500, 1000 mg/kg bw and day) by oral gavage from GD 0 until day 21 post parturition. This treatment had no adverse effect on pregnancy, parturition, breeding instinct and lactation capacity of the mother animals, nor on the embryonic, foetal, and postpartum development of the progeny.

Overall, ascorbic acid at 1000 mg/bw and day was not maternal or developmental toxic in the rat. The studies were performed before the existence of a suitable test guideline, but generally meet the accepted methodology and are therefore considered to be valid and suitable for assessment.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 125 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

sufficient fior assessment

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

No maternal or developmental toxicity was seen in rats and mice receiving ascorbic acid by oral gavage during GD 6-15 pregnancy at doses up to and including 1000 mg/kg bw and day, or when rats received the test substance form GD 0 until day 21 post parturition (Frohberg et al., 1973). This pre-guideline study is scientifically acceptable and valid, and suitable for assessment. The results can be adopted for sodium ascorbate. Taking the molecular weights into consideration, this corresponds to 1125 mg sodium ascorbate/kg bw and day.

This result is supported by a rat study using an insufficient number of test animals which, therefore, is rated to be invalid (reliability 3) but does support the results outlined above (Siman and Eriksson, 1997).

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

Based on available data on reproductive toxicity, the substance is not considered to be classified for toxicity to reproduction according to Regulation (EC) No 1272/2008 (CLP), as amended for the tenth time in Regulation (EU) No 2017/776.