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Toxicological information

Acute Toxicity: inhalation

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Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The analogue Acetic acid which shares the same functional group with Sodium Diacetate, also has comparable values for the relevant molecular properties for the acute inhalation 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 on the analogue Acetic acid.
GLP compliance:
no
Test type:
other: read-across from a study with an analogue

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Acetic acid
- Molecular formula (if other than submission substance): C2H4O2
- Molecular weight (if other than submission substance): 60.05
- Smiles notation (if other than submission substance): CC(=O)O
- InChl (if other than submission substance): InChI=1/C2H4O2/c1-2(3)4/h1H3,(H,3,4)
- Structural formula attached as image file (if other than submission substance): see Fig. in attached report

Results and discussion

Effect levels
Dose descriptor:
LCLo
Effect level:
18 929 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Other findings:
Based on the experimental results obtained with the analogue Acetic Acid (LCLo for rats = 16000 mg/L air) and the molecular weights, the read-across approach is applied and the LC50 for substance Sodium Diacetate is calculated to be 18929 mg/L air under test conditions.

Any other information on results incl. tables

The analogue Acetic acid 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 -0.17 for Acetic acid and -3.72 for Sodium diacetate,

- a high water solubility, which is 50 g/L for Acetic acid and 1000 g/L for Sodium dicetate at 25 ºC, and

- similar molecular weights, which are 60.05 forAcetic acidand 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

64-19-7

Target chemical

126-96-5

 

CHEMICAL NAME

 

Acetic acid

Sodium diacetate

PHYSICO-CHEMICAL DATA

 

Melting Point

Measured data:

16.7 ºC

Measured data:

Decomposes above 150 ºC

 

Boiling Point

Measured data:

118.1 ºC

Estimated data:

Decomposes above 150°C

 

Density

Measured data:

1.0446 g/cm3 at 25 ºC

Experimental results:

4.405

Vapour Pressure

Measured data:

11.4 mm Hg at 20 °C

 

Estimated data:

0.000000716 mm Hg at 25 ºC

Partition Coefficient (log Kow)

Measured data:

-0.17

Estimated data:

-3.72

 

Water solubility

 

Measured data:

50 g/L

 

Estimated data :

1000 g/L at 25 ºC

ENVIRONMENTAL FATE and PATHWAY

 

Aerobic Biodegradation

 

Experimental results:

Biodegradable

 

Read across:

Readily biodegradable

 

ENVIRONMENTAL TOXICITY

 

Acute Toxicity to Fish

Experimental data:

(96 h) LC 50 = 251 mg/L(Gambusia affinis)

 

Read across:

Based on the experimental results obtained with the supporting substance Acetic acid (96-h LC 50 =251 mg/L for gambusia affinis) and the molecular weights, the read-across approach is applied and the LC 50 for the substance Sodium diacetate is calculated to be 297 mg/L under test conditions.

Based on the experimental results obtained with the supporting substance Acetic acid (48-h LC 50 =410 mg/L for Leuciscus idus melanotus) and the molecular weights, the read-across approach is applied and the LC 50 for the substance Sodium diacetate is calculated to be 485 mg/L under test conditions.

Based on the experimental results obtained with the supporting substance Acetic acid (96-h LC 50 =79 -88 mg/L for Fathead minnow) and the molecular weights, the read-across approach is applied and the LC 50 for the substance Sodium diacetate is calculated to be 93.5 -104 mg/L under test conditions.

Based on the experimental results obtained with the supporting substance Acetic acid (96-h LC 50 =272.87 mg/L for Mozambique tilapia) and the molecular weights, the read-across approach is applied and the LC 50 for the substance Sodium diacetate is calculated to be 322.5 mg/L under test conditions.

Based on experimental data on the analogue Sodium Acetate (a limit acute toxicity test was performed with Brachydanio rerio in a semi-static system, 96h-LC0 was greater than 100 mg/L) the LC0 calculated for Sodium diacetate is greater than 87 mg/L under test conditions.

Based on experimental data on the analogue Sodium Acetate (120h-LC50 was 13.33 g/L) and the molecular weight, the LC50 calculated for Sodium diacetate is 11.54 g/L under test conditions (120h).

Based on experimental data on the analogue Sodium Acetate (96h-LC0 was 10.0 g/L) and the molecular weight, the LC50 calculated for Sodium diacetate is 8.664 g/L under test conditions.

As it can be observed the LC50 values for fish are much lower when read across are done from data on Acetic Acid. When is done from data on Sodium acetate, the values are even more than 100 times higher. The elevate toxicity of acetic acid is caused bu the low pH of the substance in water. The pH for sodium diacetate is approx 4.5-5.0 and the water solution of the substance is a buffer which keeps the pH constant (the 0.1M acetic acid is 2.9, and 0.1M Sodium acetate is 8.9). To average the LC50 for Sodium diacetate the medium value between the read across of both substances is used: >93.5 and <11540 (average: 5816.8mg/L).

 

Acute Toxicity to Aquatic Invertebrates

Experimental data:

(48 h) EC 50 = 65 mg/L(Daphnia magna)

 

Read across:

Based on experimental data on the analogue Sodium Acetate (the 24 hour LC50 was determined by means of a standardised procedure using 24-h-old animals from a clone of Daphnia magna. The 24-h LC50 was 7170 mg/L) and the molecular weights, the read-across approach is applied and the LC 50 for the substance Sodium diacetate is calculated to be 6209.5 mg/L under test conditions.

Based on experimental data on the analogue Sodium Acetate (the 48 hour LC0 was 1000mg/L and the 48-h LC50 was greater than 1000 mg/L) and the molecular weights, the read-across approach is applied and the LC0 for the substance Sodium diacetate is calculated to be 866 mg/L under test conditions and LC50 (48h) is >866mg/L.

Based on experimental data on the analogue Acetic acid (the 48 hour EC50 determined for Daphnia magna was 65 mg/L) and the molecular weights, the read-across approach is applied and the EC 50 for the substance Sodium diacetate is calculated to be 77.5 mg/L under test conditions.

Based on experimental data on the analogue (EC 50 of acetic acid was 95 mg/L wittout adjustment of pH and EC50 was 6000 mg/L with adjustment of pH to 8 and the molecular weights, the read-across approach is applied and the EC 50 for the substance Sodium diacetate is calculated to be 112 and 7098.5 mg/L respectively under test conditions.

Based on experimental data on the analogue Acetate Acetic acid and the molecular weights, the read-across approach is applied and the EC 50 for the substance Sodium diacetate is calculated to be 55.5 mg/L respectively under test conditions.

Based on experimental data on the analogue Acetate Acetic acid and the molecular weights, the read-across approach is applied and the 96h LC50 for the substance Sodium diacetate is calculated to be 193.73 mg/L respectively under test conditions.

Based on experimental data on the analogue Acetate Acetic acid and the molecular weights, the read-across approach is applied and the 16 h NOEC for the substance Sodium diacetate is calculated to be 177.5 mg/L respectively under test conditions.

 

As it is observed the LC50 values for Daphnia are much lower when read accross are done from data on Acetic Acid. When is done from data on Sodium acetate, the values are even more than 100 times higher. The pH influence on the toxicity is observed clearly in the study when the EC 50 was measured with and without pH adjustment. The elevate toxicity of acetic acid is caused by the low pH of the substance in water. The pH for sodium diacetate is approx 4.5-5.0 and the water solution of the substance is a buffer which keeps the pH constant (the 0.1M acetic acid is 2.9, and 0.1M Sodium acetate is 8.9).To average the LC50 for Sodium diacetate the medium value between the read across of both substances is used: >55.5 and <866 (average: 460.75 mg/L).

 

Toxicity to Aquatic Plants

 

Experimental data:

 

(8 d) Toxicity threshold (TT) = 4000 mg/L (Scenedesmus quadricauda)

 

Read across:

Based on published experimental data on the analogue Acetic acid (8d-Toxicity threshold (TT) Microcystis aeruginosa was 90 mg/L) and the molecular weights, the read-across approach is applied and the Toxicity Threshold for Sodium dicetate is calculated to be 106 mg/L.

Based on published experimental on the analogue Acetic acid (24h-EC 50 was 156 mg/L) and the molecular weights, the read-across approach is applied and the 24h EC50 for Sodim dicetate is calculated to be 184 mg/L in Green algae.

Based on published experimental data on the analogue Acetic acid (8d-Toxicity threshold (TT) for Scenedesmus quadricauda was 4000 mg/L) and the molecular weights, the read-across approach is applied and the Toxicity Threshold for Sodium dicetate is calculated to be 4732.5 mg/L.

Based on published experimental data on the analogue Sodium acetate (60h-Growth inhibition for Anacystis nidulans was 2460 mg/L) and the molecular weights, the read-across approach is applied and the Toxicity Threshold for Sodim dicetate is calculated to be 2130.5 mg/L.

 

MAMMALIAN TOXICITY

 

Acute Toxicity: Oral

Experimental data:

LD 50 = 3250-8610 mg/kg bw (rats)

LD 50 = 4960 mg/kg bw (mice)

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

.

 

Acute Toxicity: Inhalation

Experimental results:

(4 h) LC50 = 11.4 mg/L

Read across:

Based on the experimental results obtained with the analogue Calcium Acetate (LC 50 for female rats > 5.6 mg/L air) and the molecular weights, the read-across approach is applied and the LC50 for substance Sodium Acetate is calculated to be higher than 5.03 mg/L air under test conditions.

Based on the experimental results (reported under the endpoint record 07.02.02_03) obtained with the analogue Acetic Acid (LCLo for rats = 16000 mg/L air) and the molecular weights, the read-across approach is applied and the LCLo for substance Sodium Diacetate is calculated to be than 18929 mg/L air under test conditions.

Acute Toxicity: Dermal

Experimental results:

LD 50 = 1060 mg/kg bw (rabbits)

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:

 

8-month study with male rats treated by gavage 3 times per week. TheLOAEL = 60 mg/kg bw/day(based on hyperplasia of the esophagus and forestomach, indicative of irritation at point of contact, only one dose tested). The NOAEL = Not established(only one dose tested).

 

Repeated dose toxicity: inhalation:

 

35-day study with rats and mice. The

NOAEL was ca. 0.09 mg/L/day(based on no evidence of adverse effects at any dose tested).

Read across:

Based on the experimental results obtained with the analogue Citric acid, sodium salt (NOAEL >= 50 mg/kg bw/day, nominal in diet in rats treated daily by feed for ca. 1 year), and the molecular weights, the read-across approach was applied and the NOAEL with the substance Sodium acetate is calculated to be equal or greater than 50 mg/kg bw/day.

Based on the experimental results obtained with the analogue Sodium acetate (NOAEL >= 0.05 mg/kg bw/day in male Long-Evans rats treated daily by drinking water for 8 months), 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 0.043 mg/kg bw/day.

Based on the experimental results obtained with the analogue Sodium acetate (NOAEL >= 3600 mg/kg bw/day in male Wistar rats treated daily by feed for 4 weeks), 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 3117mg/kg bw/day.

Based on the experimental results obtained with the analogue Sodium acetate (NOAEL >= 21 mg/kg bw/day in male Long-Evans rats treated daily by feed for 3 months), 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 18 mg/kg bw/day.

Based on the experimental results obtained with the analogue Sodium acetate (NOAEL >= 0.01 mg/kg bw/day in male Wistar rats treated daily by drinking water for 112 days), 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 0.0085 mg/kg bw/day

 

Genetic Toxicity in vitro

 

Gene mutation in bacteria

Mammalian gene mutation Chromosomal aberration

Experimental results:

 

In a bacterial reverse mutation assay using Salmonella typhimurium(TA98, TA100, TA1535, TA97 and TA1537) in the presence and absence of metabolic activation and up to 10000μg/plate, acetic acid was not mutagenic.

 

Acetic acid was not clastogenic in anin vitroassay using Chinese hamster ovary K1 cells at concentrations < 16 mM; 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:

No data

 

DEVELPMENTAL TOXICITY / TERATOGENICITY:

A series of developmental toxicity studies were conducted in CD-1 mice, Wistar rats, and Dutch-belted rabbits. Pregnant females were daily administered acetic acid by gavage on gestation day 6 – 16 for rats and mice, and 6 – 19 for rabbits. The NOAEL (maternal and developmental toxicity) (rats, mice, and rabbits) = 1600 mg/kg bw/day (based on no effects observed at the highest dose tested).

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:

 Read across:

Based on the experimental resultsobtained with the analogue Sodium Acetate (NOAEL >= 1000 mg/kg bw/day in Pregnant CD-1 mice treated by oral gavage on days 8-12 of gestation, based on maternal toxicity: mortality, pregnancy and resorption; and on neonatal effects: mortality and body weight), 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 866 mg/kg bw/day.

Based on the experimental results (reported under the endpoint record 07.08.02_02) obtained with the analogue Acetic acid (NOAEL >= 1600 mg/kg bw/day in female mices, rats and rabbits treated for 10 days for maternal toxicity, mortality and body weight gain, and for developmental toxicity, numbers of live and dead fetuses, external and internal examinations), and the molecular weights, the read-across approach was applied and the NOAEL with the substance Sodium acetate is calculated to be equal or greater than 1893 mg/kg bw/day for maternal and developmental toxicity.

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

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LCLo for substance Sodium Diacetate is calculated to be 18929 mg/L air under test conditions.
Executive summary:

Based on the experimental results (reported under the endpoint record 07.02.02_03) obtained with the analogue Acetic Acid (LCLo for rats = 16000 mg/L air) and the molecular weights, the read-across approach is applied and the LCLo for substance Sodium Diacetate is calculated to be than 18929 mg/L air under test conditions.