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Toxicological information

Genetic toxicity: in vivo

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Administrative data

Endpoint:
in vivo mammalian cell study: DNA damage and/or repair
Remarks:
Type of genotoxicity: DNA damage and/or repair
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The analogue Sodium Acetate which is part of the molecule of Sodium Diacetate, also has comparable values for the relevant molecular properties for the genetic toxicity endpoint.
Cross-reference
Reason / purpose:
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 (Testicular DNA-synthesis inhibition test (DSI test)) on the analogue Sodium acetate.
GLP compliance:
no
Type of assay:
other: read-across from a Testicular DNA-synthesis inhibition test (DSI test) with an analogue

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): sodium acetate
- Molecular formula (if other than submission substance):NaC2H3O2
- Molecular weight (if other than submission substance): 82.03
- Smiles notation (if other than submission substance):[Na+].[O-]C(C)=O
- InChl (if other than submission substance):InChI=1/C2H4O2.Na/c1-2(3)4;/h1H3,(H,3,4);/q;+1/p-1
- Structural formula attached as image file (if other than submission substance): see Fig.

Results and discussion

Test results
Sex:
male
Genotoxicity:
negative
Toxicity:
no effects
Vehicle controls valid:
yes
Positive controls valid:
not specified
Additional information on results:
Based on published experimental data on the analogue Sodium Acetate which produced no inhibitory effect on DNA-replication in male mice treated with Sodium Acetate, and applying the read-across approach, the substance Sodium Diacetate is also considered as not mutagenic under test conditions.

The analogue Sodium acetate which is part of the molecule of Sodium Diacetate, also has comparable values for the relevant molecular properties. These properties are:
- a low log Pow value, which is -3.72 for Sodium Acetate and -3.72 for Sodium Diacetate,
- a high water solubility, which is 1.25 g/mL at 25 ºC for Sodium acetate and 1000 g/L for Sodium Diacetate, and
- similar molecular weights, which are 82.0 for Sodium acetate and 142.086 for Sodium Diacetate.

Any other information on results incl. tables

Sodium diacetate is also considered as not mutagenic in male mice.

The analogue Sodium acetate 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 -3.72 for both substances

- a high water solubility, which is 1250 g/L for Sodium acetate and 1000 g/L for Sodium dicetate at 25 ºC, and

- similar molecular weights, which are 82.03 for Sodium acetate 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

127-09-3

Target chemical

126-96-5

 

CHEMICAL NAME

 

Sodium acetate

Sodium diacetate

PHYSICO-CHEMICAL DATA

 

Melting Point

Measured data:

324 ºC

Measured data:

Decomposes above 150 ºC

Boiling Point

Estimated data:

Decomposes above 400°C

Measured data:

Decomposes above 150°

Density

Experimental results:

1.53

Experimental results:

1.405

Vapour Pressure

Estimated data:

0.00000000537 mm Hg at 25 ºC

Estimated data:

0.000000716 mm Hg at 25 ºC

Partition Coefficient (log Kow)

Estimated data:

-3.72

Estimated data:

-3.72

Water solubility

 

Experimental results:

1250 g/L at 25 ºC

Estimated data :

1000 g/L at 25 ºC

ENVIRONMENTAL FATE and PATHWAY

 

Aerobic Biodegradation

 

Experimental results:

Readily biodegradable

 

Read across:

Readily biodegradable

 

ENVIRONMENTAL TOXICITY

 

Acute Toxicity to Fish

Experimental data:

(96 h) LC 50 > 100 mg/L(Brachydanio rerio)

 

Supporting study:

Read-across from Potassium acetate (category analogue) based on molecular weights:

 

(96 h) LC 50 > 414.87 mg/L (Brachydanio rerio)

 

LC50=184.7 mg/L (calculated)

Acute Toxicity to Aquatic Invertebrates

Experimental data:

(24-48 h) EC 50 > 1000 mg/L(Daphnia magna)

 

EC50=141mg/L (calculated)

Toxicity to Aquatic Plants

 

Key studies:

Read-across from Potassium acetate (category analogue) based on molecular weights:

 

(72 h) EC 50 > 417.92 mg/L (Skeletonema costatum)

(72 h) NOEC = 417.92 mg/L (Skeletonema costatum)

Supporting studies:

Read-across from analogue substance Acetic Acid, based on molecular weights:

 

(8 d) Toxicity threshold (TT) = 5468.67 mg/L (Scenedesmus quadricauda)

 

EC50=164 mg/L (calculated)

MAMMALIAN TOXICITY

 

Acute Toxicity: Oral

Read-across from Potassium acetate (category

analogue) based on molecular weights:

LD 50 = 2.72 (2.07-3.56) g/kg bw

Read-across from Calcium acetate (category

analogue) based on molecular weights:

LD 50 = 2800 mg/kg bw

The oral LD50 of Sodium diacetate for rats is 5600 mg/kg bw.

.

 

Acute Toxicity: Inhalation

Read-across from Calcium acetate (category analogue) based on molecular weights:

Key study:

LC 50 (4 h) > 5.81 mg/L

No data

Acute Toxicity: Dermal

Read-across from the analogue Fumaric acid, based on molecular weights:

LD50 (4 h) > 28269.15 mg/kg bw (female New Zealand White rabbits)

 

The dermal LD50 of Sodium diacetate for rats is greater than 2000 mg/kg bw

Skin Sensitization

 

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 acetate is also considered to be not sensitising.

 

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:

Weight of evidence:

Experimental results:

 

Repeated dose toxicity: oral: 112-day study in male Wistar rats. The NOAEL was determined as 0.01 mg/kg bw/day.

 

Repeated dose toxicity: oral: 3-month study in male Long-Evans rats. The NOAEL was determined as 21 mg/kg bw/day.

 

Repeated dose toxicity: oral: 4-week study in male Wistar rats. The NOAEL was determined as 3600 mg/kg bw/day.

 

Repeated dose toxicity: oral: 8-month study in male Long-Evans rats. The NOAEL was determined as 0.05 mg/kg bw/day.

 

 

Read-across from the analogue Citric acid, sodium salt, based on molecular weights:

 

TheNOAEL >= 57.44 mg/kg bw/day, in rats daily treated by feed for ca. 1 year.

 

NOAEL=132 mg/kg/bw (calculated)

Genetic Toxicity in vitro

 

Gene mutation in bacteria

Mammalian gene mutation Chromosomal aberration

Weight of evidence:

 

Experimental results:

Reverse mutation assay using S. typhimurium strains TA92, TA1535, TA100, TA1537, TA94 and TA98 with metabolic activation. Resultslead to the conclusion that Sodium Acetate did not cause point mutations in the microbial systems.

 

Read-across from the analogue substance Acetic Acid, based on functional group:

Sodium Acetate is considered to be not mutagenic on S. typhimurium TA 98, TA 100, TA 1535, TA 97, and/or TA 1537, with and without metabolic activation.

Read-across from the analogue Acetic anhydride, based on functional group:

Sodium acetate is considered to be not mutagenic on mouse lymphoma L5178Y cells, with and without metabolic activation.

                  

Read-across from the source chemical Phenoxyacetic acid to the target chemical, based on functional group:

Sodium acetate is considered to be not mutagenic on Chinese hamster ovary cells, with and without metabolic activation.

Estimated data from Danish (Q)SAR Database:

Sodium acetate was not mutagenic in mammalian cell gene mutation assays on mouse lymphoma L5178Y cells nor on Chinese hamster ovary cells.

 

Experimental result:

In an in vitro chromosomal aberration assay with a Chinese hamster fibroblast cell line, CHL, without metabolic activation systems, Sodium acetate did not induce chromosomal aberrations(including gaps).

Read-across from the analogue substance Acetic Acid, based on functional group:

Sodium Acetate is considered as not clastogenic on Chinese hamster Ovary (CHO) cells, without metabolic activation.

 

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

 

Experimental results:

The Testicular DNA-synthesis inhibition test (DSI test) on male mice provides evidence that Sodium acetate is not genotoxic in animals (basis of the method: measuring 3H-thymidine incorporation). Acetic acid, sodium salt did not inhibit DNA replication in this assay.

 

.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

 

Data waiving (the substance is not classified as mutagen)

 

Data waiving (the substance is not classified as mutagen)

 

Reproductive Toxicity

TOXICITY TO REPRODUCTION:

Read-across from the analogue Citric Acid, based on molecular weights:

A study on rats and mice daily treated by feed before, during, and after mating. For Sodium Acetate, the NOAEL is calculated to be equal or greater than 3201.46 mg/kg bw/day (basis for effect: number of pregnancies, number of young born, or survival of young).

A fertility test on female rats daily treated by feed for several months. For Sodium Acetate, the NOAEL is calculated to be 768.35 mg/kg bw/day, and LOAEL greater than 768.35 mg/kg bw/day for reproductive effects.

Read-across from the analogue Citric Acid, sodium salt, based on molecular weights:

A fertility study on female rats daily treated by feed for several months. For Sodium Acetate, the NOAEL is calculated to be 57.44 mg/kg bw/day, and LOAEL greater than 57.44 mg/kg bw/day for reproductive effects.

 

DEVELPMENTAL TOXICITY / TERATOGENICITY:

Weight of evidence:

Experimental results:

Pregnant CD-1 mice were treated by oral gavage with Sodium Acetate on days 8-12 of gestation. TheNOAEL is equal or greater than 1000 mg/kg bw/day for maternal toxicity and neonatal effects (mortality and body weight).

 

Read-across from the analogue Citric Acid, based on molecular weights:

A study on rats and mice daily treated by feed before, during, and after mating. For Sodium Acetate, the NOAEL is calculated to be equal or greater than 3201.46 mg/kg bw/day (basis for effect: number of pregnancies, number of young born, or survival of young).

Read-across from the analogue substance Calcium Formate, based on molecular weights:

A three-generation drinking water study was performed. For Sodium Acetate, the NOAEL is calculated to be equal or higher than 252.18 mg/kg bw/day.

Read-across from the analogue substance Acetic Acid, based on molecular weights:

A one-generation study was performed on female mice, rats and rabbits with Acetic Acid. The read-across approach was applied and the NOAEL with the substance Sodium acetate is calculated to be equal or greater than 2187.47 mg/kg bw/day for maternal and developmental toxicity in mice, rats, and rabbits.

 

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:
Interpretation of results (migrated information): negative
Sodium diacetate is also considered as not mutagenic in male mice.
Executive summary:

Based on published experimental data on the analogue Sodium Acetate (reported under the endpoint record 07.06.02_01 NaAc Seiler) which produced no inhibitory effect on DNA-replication in male mice treated with Sodium Acetate, and applying the read-across approach, the substance Sodium Diacetate is also considered as not mutagenic under test conditions.