Sodium hydrogen di(acetate)

Toxicity to reproduction

Administrative data

Endpoint:

toxicity to reproduction

Remarks:

other: read-across from a fertility study with an analogue

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The analogue Citric Acid, sodium salt which shares the same functional group with Sodium diacetate, also has comparable values for the relevant molecular properties for the toxicity to reproduction endpoint.

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

other: read-across

Title:

Unnamed

Year:

2010

Materials and methods

Principles of method if other than guideline:

Read-across approach from published experimental data on fertility on the analogue Citric acid, sodium salt.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Details on test material:

- Name of test material (as cited in study report): citric acid, sodium salt
- Molecular formula (if other than submission substance): H7NaC6O7
- Molecular weight (if other than submission substance): 214.105
- Smiles notation (if other than submission substance): [Na+].OC(=O)CC([O-])(CC(=O)O)C(=O)O
- InChl (if other than submission substance): InChI=1/C6H7O7.Na/c7-3(8)1-6(13,5(11)12)2-4(9)10;/h1-2H2,(H,7,8)(H,9,10)(H,11,12);/q-1;+1
- Structural formula attached as image file (if other than submission substance): see Fig. in attached report

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Details on results (P0)

Based on the experimental results obtained with the analogue Citric acid, sodium salt, on rats daily treated by feed for several months (NOAEL for reproductive effects = 50 mg/kg bw/day; LOAEL > 50 mg/kg bw/day for the same effects), and the molecular weights, the read-across approach was applied and the NOAEL with the substance Sodium diacetate is calculated to be 100 mg/kg bw/day, and LOAEL greater than 100 mg/kg bw/day for reproductive effects.

Effect levels (P0)

1

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: (reproductive effects)

2

Dose descriptor:

LOAEL

Effect level:

> 50 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: (reproductive effects)

Results: F1 generation

General toxicity (F1)

Clinical signs:

not examined

Mortality / viability:

not examined

Body weight and weight changes:

not examined

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

The analogue Citric acid sodium salt which shares the same functional group with Sodium dicetate, also has comparable values for the relevant molecular properties. These properties are:

- a low log Pow value, which is -0.28 for Citric acid sodium salt and -3.72 for Sodium diacetate,

- a high water solubility, which is 166 g/L for Citric acid sodium salt and 1000 g/L for Sodium dicetate at 25 ºC, and

- similar molecular weights, which are 214.11for Citric acid sodium salt and 142.086 for Sodium dicetate.

As indicated in the European Chemical Agency Practical Guide 6 “How to report read –across and categories”, the structural grouping was realized using “OECD QSAR APPLICATION TOOL BOX” version 1.1.0.Presented results show that both substances have common (eco)toxicological behavior (attachment).

Table 1: Data matrix, Analogue approach.

 

 

CAS Number		Source chemical 994-36-5	Target chemical 126-96-5
CHEMICAL NAME		Citric acid, sodium salt	Sodium diacetate
PHYSICO-CHEMICAL DATA
Melting Point		No data	Measured data: Decomposes above 150 ºC
Boiling Point		No data	Measured data: Decomposes above 150°C
Density		No data	Experimental results: 4.405
Vapour Pressure		Negligible	Estimated data: 0.000000716 mm Hg at 25 ºC
Partition Coefficient (log Kow)		Estimated data: -0.28	Estimated data: -3.72
Water solubility		Estimated data: 1000 g/L	Estimated data : 1000 g/L at 25 ºC
ENVIRONMENTAL FATE and PATHWAY
Aerobic Biodegradation		No data	Read across: Readily biodegradable
ENVIRONMENTAL TOXICITY
Acute Toxicity to Fish		No data	LC50=184.7 mg/L (calculated)
Acute Toxicity to Aquatic Invertebrates		No data	EC50=141 mg/L (calculated)
Toxicity to Aquatic Plants		No data	EC50=164 mg/L (calculated)
MAMMALIAN TOXICITY
Acute Toxicity: Oral		Experimental data: LD 50 = 7100 mg/kg bw (mice)	The oral LD50 of Sodium diacetate for rats is 5600 mg/kg bw. .
Acute Toxicity: Inhalation		No data	No data
Acute Toxicity: Dermal		No data	The dermal LD50 of Sodium diacetate for rats is greater than 2000 mg/kg bw
Skin Sensitization		No data	Weight of evidence:   Read-across from the analogue substances Citric acid, Glycolic acid, Sodium Glycolate, Lactic acid, Ammonium lactate, and Triacetin, based on functional group:   All this substances were not sensitising for human and guinea pigs. Based on these results, Sodium diacetate is also considered to be not sensitising.
Repeated Dose Toxicity		Repeated dose toxicity: oral: Experimental results:   In a 1 year study with rats daily treated by feed, theNOAEL was ca. 50 mg/kg bw/day(based on no effects observed at the only dose tested).	NOAEL=132 mg/kg/bw (calculated)
Genetic Toxicity in vitro	Gene mutation in bacteria Mammalian gene mutation Chromosomal aberration	Experimental data:   Citric acid, sodium salt was tested in an assay usingSaccharomyces cerevisiaecells in the presence and absence of metabolic activation; however, insufficient information was provided in the robust summary of this study to adequately evaluate the results.	Read-across from experimental results with Sodium acetate: In the first study, reported by Ishidate et al., 1984, a reverse mutation assay using S. typhimurium strains TA92, TA1535, TA100, TA1537, TA94 and TA98 was carried out with Sodium Acetate according to the method of Ames et al. (1975), but only with metabolic activation. No significant increases in the numbers of revertant colonies were detected in any S. typhimurium strains at the maximum dose tested. Based on these results, the read-across approach is applied and Sodium Diacetate is also considered as not mutagenic under test conditions. In the same report, Ishidate et al. reported chromosomal aberrations tests with Sodium Acetate using a Chinese hamster fibroblast cell line, CHL. The cells were exposed to each sample at three different doses for 24 and 48 hours. No metabolic activation systems were applied. The maximum dose of each sample was selected by a preliminary test in which the dose needed for 50% cell-growth inhibition was estimated using a cell densiometer. The incidence of cells with aberrations (including gaps) was 0%. Based on these results, the read-across approach is applied and Sodium Diacetate is also considered as not mutagenic under test conditions. Read-across from experimental results obtained with Acetic Acid: A test within the National Toxicology Program’s mutagenicity testing program and according to GLP was reported by Zeiger et al., 1992. This test was carried out with Acetic acid using Salmonella typhimurium strains TA 98, TA 100, TA 1535, and TA 97, with and without matabolic activation. Acetic acid did not show any mutagenic effect under test conditions. Based on these results, the read-across approach is applied and Sodium Diacetate is also considered as not mutagenic under test conditions. In the next report (by Morita et al., 1990) a cytogenetic assay was carried out with Acetic acid using Chinese hamster ovary K1 cells, with and without metabolic activation. In the absence of S9 mix, cells were exposed for 24 h to test substance at doses of 8, 10, 12, 14, and 16 mM. In the presence of S9 mix, cells were exposed for 6 h to test substance at doses of 4, 8, 10, and 12 mM, and recultured in fresh medium for 18 h. The medium used was Ham’s F12 supplemented with 17 mM NaHCO3 and 10% fetal calf serum. Cytotoxicity was evaluated by counting surviving cells. The relationship between the pH of the medium and the clastogenic activity was examined. In order to study the effects of neutralization of the treatment medium, two kinds of treatment media were examined. One was adjusted to pH 5.8 or pH 6.0 and the other was so adjusted and then immediately neutralized to pH 6.4 and pH 7.2 with 1 M NaOH. Acetic acid was not clastogenic at concentrations close to those showing cytotoxicity. Low pH did induce some artificial chromosome aberrations, but these were eliminated by neutralization of the test medium. The read-across approach is applied and Sodium Diacetate is also considered to be not clastogenic under test conditions. Read-across from experimental results obtained with Acetic Anhydride: In the paper reported by Seifreid et al. (2006), a L5178Y Mouse Lymphoma Cell Mutation Assay was performed with Acetic anhidride to test its mutagenic potencial. The chemical was tested with and without metabolic activation. The range of concentartions was 0.04 - 0.3 g/mL. The toxicity of test substance was also determined both with and without liver S9. The mutagenicity assay was performed according to the procedure described by Clive and Spector. Resistance to trifluorothymidine (TFT) was determined by adding TFT (final concentration, 3 µg/mL) to the cloning medium for mutant selection. Results have been evaluated under the traditional criteria (old evaluation) as well as the current international “harmonization” recommendations (new evaluation). With old evaluation: Test substance was not mutagenic with metabolic activation, and was positive without metabolic activation (this positive result is not reliable, because full requeriments for a valid test were not met). With new evaluation: Test substance was ambiguous with and without metabolic activation. Based on these results, the read-across approach is applied and Sodium Diacetate is considered to be ambiguous on mouse lymphoma cells, with and without metabolic activation. Read-across from experimental results obtained with Phenoxyacetic acid: A L5178Y Mouse Lymphoma Cell Mutation Assay was performed with Phenoxyacetic acid (National Toxicology Program Database). The chemical was tested with and without metabolic activation and, in general, tested concentrations were: 62.5, 125, 250, 500, 750, 1000, 1500, and 2000 µg/mL. Phenoxyacetic acid resulted to be not mutagenic with and without metabolic activation. It was toxic to cells, but at higher concentrations than precipitating concentrations. The read-across approach is applied and Sodium diacetate is considered to be not mutagenic on mouse lymphoma cells. Estimated results with Sodium Diacetate from Danish (Q)SAR Database: A Danish (Q)SAR prediction with the Multicase model was realized to estimate the mutagenic potencial of sodium diacetate on mammalian cells (mouse lymphoma and HGRT (CHO): Chinese hamster ovary cell HGPRT forward mutation assay). The substance sodium diacetate was predicted to be not mutagenic in mammalian cells. This prediction should be used for classification and risk assessment.
Genetic Toxicity in vivo		No data	Read-across from experimental results with Sodium Acetate: The Testicular DNA-synthesis inhibition test (DSI test) was performed on male mice with Sodium Acetate. This is not a standard genotoxicity test system, but it provides evidence that acetic acid, sodium salt is not genotoxic in animals. The basis of the method is to measure 3H-thymidine incorporation. Animals receive a single oral dose by gavage at concentrations of 200, 500, and 1000 mg/kg bw of test substance. No inhibitory effect on DNA-replication was detectable in animals treated with Sodium Acetate. Based on these results, the read-across approach is applied and Sodium Diacetate is also considered as not mutagenic under test conditions.
Carcinogenicity		No data	No data
Reproductive Toxicity		TOXICITY TO REPRODUCTION: Experimental data: In a 1 year study with rats daily treated by feed, theNOAEL was ca. 50 mg/kg bw/day(based on no effects observed at the only dose tested).   DEVELPMENTAL TOXICITY / TERATOGENICITY: No data	TOXICITY TO REPRODUCTION: Read across: Based on the experimental results obtained with the analogue Citric acid on rats daily treated by feed for several months (NOAEL for reproductive effects = 600 mg/kg bw/day; LOAEL > 600 mg/kg bw/day for the same effects), and the molecular weights, the read-across approach was applied and the NOAEL with the substance Sodium diacetate is calculated to be 665.5 mg/kg bw/day, and LOAEL higher than 665.5 mg/kg bw/day for reproductive effects. Based on the experimental results obtained with the analogue Citric acid (NOAEL >= 2500 mg/kg bw/day in rats (basis for effect: number of pregnancies, number of young born, or survival of young animals)), and the molecular weights, the read-across approach was applied and the NOAEL with the substance Sodium diacetate is calculated to be equal or greater than 2274 mg/kg bw/day for studied effects. Based on the experimental results obtained with the analogue Citric acid, sodium salt, on rats daily treated by feed for several months (NOAEL for reproductive effects = 50 mg/kg bw/day; LOAEL > 50 mg/kg bw/day for the same effects), and the molecular weights, the read-across approach was applied and the NOAEL with the substance Sodium diacetate is calculated to be 50 mg/kg bw/day, and LOAEL greater than 50 mg/kg bw/day for reproductive effects.   DEVELOPMENTAL TOXICITY / TERATOGENICITY: Based on the experimental results with Acetic acid (NOAEL >= 1600 mg/kg bw/day for maternal toxicity), and Sodium acetate (no maternal toxicity was observed at a 1000 mg/kg bw/day) ), the read-across approach is applied and the NOAEL for maternal toxicity of Sodium diacetate is calculated to be equal or greater than 1185 mg/kg bw/day. Based on the experimental results obtained with the analogue Citric acid (NOAEL >= 2500 mg/kg bw/day in mice and in rats (basis for effect: number of pregnancies, number of young born, or survival of young animals)), and the molecular weights, the read-across approach was applied and the NOAEL with the substance Sodium diacetate is calculated to be equal or higher than 2774 mg/kg bw/day for studied effects. Based on the experimental results obtained with the analogue Calcium formate (NOAEL >= 200 mg/kg bw/day in Wistar rats for maternal and developmental toxicity), and the molecular weights, the read-across approach was applied and the NOAEL with the substance Sodium diacetate is calculated to be equal or higher than 218.5 mg/kg bw/day for maternal and developmental toxicity.:

Applicant's summary and conclusion

Conclusions:

The NOAEL with the substance Sodium diacetate is calculated to be 50 mg/kg bw/day, and LOAEL greater than 50 mg/kg bw/day for reproductive effects.

Executive summary:

Based on the experimental results (reported under endpoint record 07.08.01_03) obtained with the analogue Citric acid, sodium salt, on rats daily treated by feed for several months (NOAEL for reproductive effects = 50 mg/kg bw/day; LOAEL > 50 mg/kg bw/day for the same effects), and the molecular weights, the read-across approach was applied and the NOAEL with the substance Sodium diacetate is calculated to be 50 mg/kg bw/day, and LOAEL greater than 50 mg/kg bw/day for reproductive effects.