2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Adequate documentation of protocol and results.

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Unnamed

Year:

1974

Reference 2

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

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone

EC Number:

228-973-9

EC Name:

2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone

Cas Number:

6381-77-7

Molecular formula:

C6H8O6.Na

IUPAC Name:

sodium (2R)-2-[(1R)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Name of test material (as cited in study report): FDA 71-68 (Sodium erythorbate)
- Physical state: Fine white powdered material

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS

- Age at study initiation: Adult
- Housing:Individually in mesh-bottom cages
- Diet: ad libitum
- Water: Tap water ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): Temperature controlled
- Humidity (%): Humidity controlled

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on mating procedure:

Females were mated with young adult males and observation of the vaginal sperm plug was considered Day 0 of gestation. (One male was not permitted to impregnate more than one female per group).

Duration of treatment / exposure:

Days 6-15 days of gestation

Duration of test:

All dams were subjected to caesarean section on day 20.

Doses / concentrations

Remarks:

Doses / Concentrations:
9.0, 41.8, 194.0, or 900.0 mg/kg bw/day
Basis:

No. of animals per sex per dose:

Positive control: 22 animals
0, 900 mg/kg bw/day: 24 animals
9, 41.8 mg/kg bw/day: 20 animals
194 mg/kg bw/day: 21 animals

Control animals:

yes, sham-exposed

other: Positive control (Aspirin 250 mg/kg bw/day)

Examinations

Maternal examinations:

CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily for appearance and behaviour

BODY WEIGHT: Yes
- Time schedule for examinations: Day 0, 6, 11, 15 and 20

FOOD CONSUMPTION: Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: Urogenital tract was examined for anatomical abnormality.

Ovaries and uterine content:

Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
-Other: live and dead fetuses

See Table 1:Reproductive and developmental toxicity of Sodium Erythorbate in Wistar rats

Fetal examinations:

- External examinations: Yes: [all per litter]. All fetuses were examined grossly for presence of external congenital abnormalities.
- Soft tissue examinations: Yes:. One third of the fetuses of each litter underwent detailed visceral examinations employing the Wilson technique.
- Skeletal examinations: Yes: The remaining two third of fetuses were cleared in potassium hydroxide, stained with Alizarin Red S dye and examined for skeletal defects.
- Head examinations: Yes
-Other: Body weight of live pups

Indices:

See Table 1:Reproductive and developmental toxicity of Sodium Erythorbate in Wistar rats

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no data

Details on maternal toxic effects:
No statistically significant differences were observed in number of pregnancies, corpus lutea, implantation rates, live births, resorptions, dams with >1 site resorbed, dams with all sites resorbed, % partial resorptions, complete resorptions, number live fetuses (average/dam) betwen treated and control groups. Abnormalities were observed in rats given aspirin.

See Table 1:Reproductive and developmental toxicity of Sodium Erythorbate in Wistar rats and Appendix II - Individual Reproduction Data

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

900 mg/kg bw/day

Basis for effect level:

maternal abnormalities

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No statistically significant differences in average fetus weight or number of live fetuses examined at term in rats of the negative control group or in rats given Sodium Erythorbate. No gross, skeletal or soft tissue morphological abnormalities were observed in rats of the negative control group or in rats given Sodium Erythorbate. Abnormalities were observed in rats given aspirin.

See Table 1:Reproductive and developmental toxicity of Sodium Erythorbate in Wistar rats and Appendix II - Individual Reproduction Data

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

900 mg/kg bw/day

Basis for effect level:

reduction in number of live offspring

changes in litter size and weights

skeletal malformations

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Table 1:Reproductive and developmental toxicity of Sodium Erythorbate in Wistar rats

Endpoint			Treatment group
	Negative control	Positive control	9.0 mg/kg bw/day	41.8 mg/kg bw/day	194.0 mg/kg bw/day	900.0 mg/kg bw/day
Pregnancies (total no./no. to term)	20/20	20/20	20/20	20/20	20/20	20/20
No. corpora lutea (average/dam)	268 (11.2)	252 (11.5)	266 (13.3)	257 (12.9)	270 (12.9)	254 (10.6)
No. live litters	19	20	20	20	20	20
No. implant sites (average/dam)	244 (12.2)	227 (11.4)	237 (11.9)	233 (11.7)	238 (11.9)	234 (11.7)
No. resorptions	13	46	2	2	3	4
Dams with >1 site resorbed	5	11	2	2	3	4
Dams with all sites resorbed	1
% Partial resorptions	25.0	55.0	10.0	10.0	15.0	20.0
% Complete resorptions	0.96	1.10	0.82	0.94	0.84	1.09
No. live fetuses (average/dam)	231 (11.6)	181 (9.05)	235 (11.8)	231 (11.6)	230 (11.5)	230 (11.5)
M/F ratio	0.96	1.10	0.82	0.94	0.84	1.09
No. dead fetuses					5
Dams with >1 dead					1
Dams with all dead
% Partial dead					5.00
% All dead
Average fetus weight (g)	3.95	2.62	3.96	3.95	3.87	3.92
Live fetuses examined at term*	161/19	129/20	166/20	161/20	160/20	161/20
Stemebrae-incomplete ossification	28/10	52/16	55/15	21/11	56/16	27/14
Stemebrae-bipartite		11/6
Stemebrae-fused		1/1
Stemebrae-extra		2/2
Stemebrae-missing	8/2	106/20	13/5	8/5	21/10  -	4/4
Ribs-incomplete ossification		19/8				1/1
Ribs-fused/split		5/3
Ribs-wavy	18/8	52/14	8/5	14/7	8/5	12/4
Ribs->13	4/3	39/14	2/1		2/2	2/1
Vertebrae-incomplete ossification	7/2	60/16			7/4	1/1
Vertebrae-extra centers of ossification		2/1
Skull-incomplete closure	30/12	54/15	17/10	16/8	15/5	26/13
Skull-missing		1/1
Extremities-incomplete ossification		7/2
Miscellaneous-hyoid missing	22/9	52/16	16/8	19/9	16/8	23/11
Miscellaneous-hyoid reduced	21/11	5/2	15/10	15/7	14/7	14/10

*Numerator = number of fetuses affected; denominator = number of litters affected.

Study report attachments:

Appendix II - Individual Reproduction Data

Applicant's summary and conclusion

Conclusions:

The administration of up to 900 mg/kg bw/day of 2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone to pregnant Wistar rats had no clearly discernible effect on nidation or on maternal or fetal survival.

Executive summary:

In a developmental toxicity study (FDABF-GRAS-350) 2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone was administered to groups of Wistar rats by gavage at dose levels of 0.0, 9.0, 41.8, 194.0, or 900.0 mg/kg bw/day from days 6 through 15 of gestation.

No statistically significant differences were observed in number of pregnancies, corpus lutea, implantation rates, live births, resorptions, dams with >1 site resorbed, dams with all sites resorbed, % partial resorptions, complete resorptions, number live fetuses (average/dam) betwen treated and control groups. The maternal NOAEL is 900 mg/kg bw/day.

There were no treatment-related effects in developmental parameters (average fetus weight, number of live fetuses, gross, skeletal or soft tissue morphological abnormalities) The developmental NOAEL is 900 mg/kg bw/day.