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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
repeated dose toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic information provided

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Final Report on the Safety Assessment of Ascorbyl Palmitate, Ascorbyl Dipalmitate, Ascorbyl Stearate, Erythorbic Acid, and sodium Erythorbate
Author:
F. Alan Andersen, Cosmetic Ingredient Expert Review Panel
Year:
1999
Bibliographic source:
International Journal of Toxicology 1999 18 (suppl. 3): 1-26
Reference Type:
publication
Title:
Tumorigenicity study of sodium erythorbate administered orally to mice.
Author:
Inai K, Akamizu H, Eto R, Nishida T, Ohe K, Kobuke T, Nambu S, Matsuki K, Tokuoka S.
Year:
1989
Bibliographic source:
Hiroshima J Med Sci. Sep;38(3):135-9.

Materials and methods

Principles of method if other than guideline:
Preliminary test: Male and female B6C3F1 mice (10 per sex per group) were given drinking water containing 0.625%, 1.25%, 2.5%, 5.0%, or 10% Sodium Erythrobate for 10 weeks. Water and feed were available ad libitum. The untreated control group consisted of 20 male and 20 female mice. Mortality, bodyweight gain, gross pathology and histopathology were noted.

Main test: Sodium Erythorbate was administered in drinking water to male B6C3Fi mice at concentrations of 1.25% and 2.5%.
Female mice received 2.5% and 5% (MTD). Each group contained 50 mice. Treatment continued for 96 weeks; the study was terminated at week 110. Feed and water were available ad libitum. Mortality, body weight, organ weights and neoplastic histopathology were noted.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: in drinking water
Details on test material:
- Name of test material (as cited in study report):Sodium erythorbate

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Diet: ad libitum
- Water: ad libitum

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Duration of treatment / exposure:
Preliminary study: 10 weeks
Main study: 96 weeks
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0.625%, 1.25%, 2.5%, 5.0%, or 10%
Basis:
other: Preliminary test
Remarks:
Doses / Concentrations:
1.25%, 2.5%
Basis:
other: Main test (Males)
Remarks:
Doses / Concentrations:
2.5%, 5.0%
Basis:
other: Main test (Females)
No. of animals per sex per dose:
Preliminary study: 10 males and 10 females for test substance; 20 males and 20 females for untreated controls
Main study: 50 males (1.25%, 2.5%) and 50 females (2.5%, 5.0%)
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
BODY WEIGHT: Yes (Preliminary and main study)

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes (Main study)
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (Preliminary and main study)
HISTOPATHOLOGY: Yes (Preliminary and main study)

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
Preliminary study: By the end of the 1st week of treatment, six male mice and one female mouse of the 10% dosing group had died.

BODY WEIGHT AND WEIGHT GAIN
Preliminary study: In male mice given 5.0% Sodium Erythrobate, the average weekly body weight gain was slightly less than 90% that of the control female mice. Body weight gain was increased in female mice given Sodium Erythrobate at a concentration of 5.0%, compared to that of control mice.
Main study: The average body weights of the treated mice were similar to controls.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
Main study: No significant difference was observed between groups in the amount of water intake. As a consequence, the males in the high dose group received a dose of Sodium Erythorbate that was approximately 1.5 times greater than that of the low-dose group. For the female groups, Sodium Erythorbate intake by the high-dose group was approximately 1.8 times greater than that of the low-dose group.

ORGAN WEIGHTS
Main study: Of the male mice (without tumors) that survived beyond week 43, dose-dependent reductions in the heart and brain weights were observed. The weights of the heart, lungs, kidneys, and brain of female mice (without tumors) were significantly different between the high dose group and the control group.

GROSS PATHOLOGY
Preliminary study: No significant changes were observed in the visceral organs of untreated mice or mice given the dose less than or equal to the MTD of Sodium Erythrobate

HISTOPATHOLOGY: NON-NEOPLASTIC
Preliminary study: Mice given doses greater than the MTD had marked atrophy of both hepatocytes and splenic lymphoid follicles, as well as hydropic degeneration of the renal tubular epithelium.

HISTOPATHOLOGY: NEOPLASTIC
Main study: The tumors observed in the male mice were hepatocellular tumors, subcutaneous sarcoma, adenoma and carcinoma of the lungs, and lymphoma/leukemia. The time-adjusted analysis of tumor incidence was performed on the hepatocellular tumors and subcutaneous sarcomas, the incidence of which was significant. The lymphoma/leukemia had the highest incidence in female mice treated with Sodium Erythorbate, but this was not significant. Overall, tumor incidence, time to death with tumors, and the distribution of tumors in treated mice did not differ significantly from mice of the control group.


Effect levels

open allclose all
Dose descriptor:
dose level: Maximum Tolerated Dose (MTD)
Effect level:
2.5 other: %
Sex:
male
Basis for effect level:
other: Preliminary study
Dose descriptor:
dose level: Maximum Tolerated Dose (MTD)
Effect level:
5 other: %
Sex:
female
Basis for effect level:
other: Preliminary study

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Executive summary:

In a repeated dose and carcinogenicity study, 2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone was administered to 10 B6C3F1 mice/sex/dose in drinking water at dose levels of 0, 0.625, 1.25, 2.5, 5 and 10% for 10 weeks (preliminary study) and then to 50 B6C3F1 mice in water at dose levels of 1.25 and 2.5% (males) and 2.5 and 5% (females) for 96 weeks (main study).

In the preliminary study, six male mice and one female mouse of the 10% dosing group had died by the end of week 1. In male mice given 5.0% Sodium Erythrobate, the average weekly body weight gain was slightly less than 90% that of the control female mice. Body weight gain was increased in female mice given Sodium Erythrobate at a concentration of 5.0%, compared to that of control mice. No significant changes were observed in the visceral organs of untreated mice or mice given the dose less than or equal to the maximum tolerated dose (MTD) of Sodium Erythrobate. Mice given doses greater than the MTD had marked atrophy of both hepatocytes and splenic lymphoid follicles, as well as hydropic degeneration of the renal tubular epithelium. The MTD of Sodium Erythrobate in drinking water was 2.5% for male mice and 5.0% for female mice.

In the main study, the average body weights of the treated mice were similar to controls. Of the male mice (without tumors) that survived beyond week 43, dose-dependent reductions in the heart and brain weights were observed. The weights of the heart, lungs, kidneys, and brain of female mice (without tumors) were significantly different between the high dose group and the control group.At the doses tested, there was not a treatment related increase in tumor incidence when compared to controls. Overall, tumor incidence, time to death with tumors, and the distribution of tumors in treated mice did not differ significantly from mice of the control group.