Sodium ascorbate

Endpoint summary

Description of key information

The NOAEL of the substance was determined to be 4500 mg sodium ascorbate /kg bw and day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

For justification please refer to read across statement in IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

6 524 mg/kg bw/day (actual dose received)

Based on:

test mat.

Remarks:

target substance

Sex:

male

Basis for effect level:

other: no adverse effects seen

Remarks on result:

other: results of the source substance (5800 mg/kg bw/day) are converted to the target substance taking into account the molecular weights (factor 1.125)

Key result

Dose descriptor:

NOAEL

Effect level:

4 500 mg/kg bw/day (actual dose received)

Based on:

test mat.

Remarks:

target substance

Sex:

female

Basis for effect level:

other: minimal reticulum-cell hyperplasia

Remarks on result:

other: results of the source substance (4000 mg/kg bw/day) are converted to the target substance taking into account the molecular weights (factor 1.125)

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

9 560 mg/kg bw/day (actual dose received)

System:

haematopoietic

Organ:

bone marrow

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

no

Reference 2

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

ophthalmology, clinical biochemistry, FOB not specified in the final report, TR 247

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

CAS number 50-81-7
Purity: 97.6 to 101.1%

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Industries, Greenfield, IN
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 6 weeks
- Weight at study initiation: approx. 115 g (males) and 95 g (females)
- Housing: housed in groups of 5 per cage
- Diet; ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks

Route of administration:

oral: feed

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

7/week

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

controls

Dose / conc.:

25 000 mg/kg diet

Remarks:

dose approx. 1350 (m) and 1900 (f) mg/kg bw and day

Dose / conc.:

50 000 mg/kg diet

Remarks:

dose approx. 2800 (m) and 3950 (f) mg/kg bw and day

Dose / conc.:

100 000 mg/kg diet

Remarks:

dose approx. 5800 (m) and 8500 (f) mg/kg bw and day

No. of animals per sex per dose:

10

Control animals:

yes, concurrent no treatment

Positive control:

not needed

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Compound intake calculated as time-weighted averages from the consumption data: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

OPHTHALMOSCOPIC EXAMINATION: Not specified

HAEMATOLOGY: Yes
- Time schedule for collection of blood: days 0, 7, 30, and 90
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: all
- Parameters examined: at least: mean corpuscular volume; mean corpuscular haemoglobin; platelets; reticulocytes; haemoglobin; packed cell volume; red blood cell counts

CLINICAL CHEMISTRY: Not specified

URINALYSIS: Not specified


NEUROBEHAVIOURAL EXAMINATION: Not specified

IMMUNOLOGY: Not specified

OTHER:
data only shown for the second 90-day study that was conducted to gather additional data on the myelofibrosis observed in female rats in the first 13-week study. Groups of 20 female F344/N rats were fed diets containing 0, 25,000, or 50,000 ppm L-ascorbic acid for 91 days.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
Necropsies were performed on animals that survived to the end of the study and on all animals found dead, unless precluded in whole or in part by autolysis or cannibalization. The following specimens were examined from control and the 100,000 ppm groups: gross lesions, tissue masses, abnormal lymph nodes, skin, mandibular lymph nodes, mammary gland, salivary gland, bone marrow, thymus, larynx, trachea, lungs and bronchi, heart, thyroid, parathyroid, esophagus, stomach, duodenum, jejunum, ileum, colon, mesenteric lymph nodes, liver, gallbladder (mice), pancreas, spleen, kidneys, adrenals, urinary bladder, seminal vesicles/ prostate/ testes or ovaries/ uterus, brain, pituitary, and spinal cord. Tissues were preserved in 10% neutral buffered formalin, embedded in paraffin, sectioned, and stained with haematoxylin and eosin. Femoral bone marrow sections were examined from female rats in the controls, 25,000-, 50,000-, and 100,000-ppm groups.

HISTOPATHOLOGY: Not specified

Statistics:

yes, but not specified

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

In the first study, alterations of teh femur bone marrow (reticulum-cell hyperplasia) was observed in 2/ 10 female rats receiving 25,000 ppm, 1/ 10 female rats receiving 50,000 ppm, and 4/10 receiving 100,000 ppm.
This was not seen in the 2-year study.

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Key result

Dose descriptor:

NOAEL

Effect level:

5 800 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: no adverse effects seen

Key result

Dose descriptor:

NOAEL

Effect level:

4 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: minimal reticulum-cell hyperplasia

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

8 500 mg/kg bw/day (actual dose received)

System:

haematopoietic

Organ:

bone marrow

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

no

Changes in the femur bone marrow were seen in the first 90 -day study, but not in the 2 -year study. The reason is not known.

Conclusions:

Ascorbic acid was well tolerated in oral feed studies even at extreme dose levels. Classification criteria are not met.

Executive summary:

In a pre-test to the 2-year carcinogenicity study, the repeated dose toxicity of ascorbic acid was investigated in 14-day studies (rats and mice, 5 animals per dose and sex; data not reported in this dossier) and in 90-day studies using rats and mice. The first of two 90-day rat studies is reported in this dossier. Ascorbic acid was administered to young Wistar rats (10 per sex and dose) in the feed at concentrations of 0, 25,000, 50,000, and 100,000 ppm. No adverse effects were seen apart from alterations of the femur bone marrow (reticulum cell hyperplasia) in females in a non-dose related manner (2/10 at the low dose; 1/10 at the mid dose; 4/10 at the high dose). These findings were not confirmed in a second 90-day rat study (only females) or in the two-year carcinogenicity study, both with 25,000 and 50,000 ppm ascorbic acid in the diet. This effect appears to be of minor importance.

In summary, ascorbic acid was not toxic to rats in a 90-day study (oral gavage) at doses up to 5800 mg/kg bw and day (male rats) and 4000 mg/kg bw and day (female rats). Based on these results, the maximum dose level for the carcinogenicity studies was defined to be 50,000 ppm in the feed (NTP, 1983).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

4 500 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

excellent and sufficient for assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

In a pre-test to the 2-year carcinogenicity study, the repeated dose toxicity of ascorbic acid was investigated in 14-day studies (rats and mice, 5 animals per dose and sex; data not reported in this dossier) and in 90-day studies using rats and mice. The first of two 90-day rat studies is reported in this dossier.

Ascorbic acid was administered to young Wistar rats (10 per sex and dose) in the feed at concentrations of 0, 25,000, 50,000, and 100,000 ppm. No adverse effects were seen apart from alterations of the femur bone marrow (reticulum cell hyperplasia) in females in a non-dose related manner (2/10 at the low dose; 1/10 at the mid dose; 4/10 at the high dose). These findings were not confirmed in a second 90-day rat study (only females) or in the two-year carcinogenicity study, both with 25,000 and 50,000 ppm ascorbic acid in the diet. This effect appears to be of minor importance.

In summary, ascorbic acid was not toxic to rats in a 90-day study (oral gavage) at doses up to 5800 mg/kg bw and day (male rats) and 4000 mg/kg bw and day (female rats). Based on these results, the maximum dose level for the carcinogenicity studies was defined to be 50,000 ppm in the feed (NTP, 1983).

This result can be adopted for sodium ascorbate. Considering the molecular weights of ascorbic acid (176.13) and sodium ascorbate (198.11) results in a conversion factor of 1.125, Therefore, the NOAEL is 4500 mg sodium ascorbate /kg bw and day.

Justification for classification or non-classification

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

The available experimental test data is reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on available data on repeated dose toxicity, the test item is not classified specific organ toxicity (repeated dose) according to Regulation (EC) No 1272/2008 (CLP), as amended for the tenth time in Regulation (EU) No 2017/776.