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Repeated dose toxicity: oral

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Administrative data

Endpoint:
repeated dose toxicity: oral
Remarks:
other: read-across from a chronic 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 Acetate, also has comparable values for the relevant molecular properties for the repeated dose 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 from a non-standard study on the analogue Citric acid, sodium salt.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
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 of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Details on results:
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 57.44 mg/kg bw/day.

The analogue Citric acid, sodium salt, which shares the same functional group with Sodium acetate, 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 acetate,
- a high water solubility which is 1 g/mL for Citric acid, sodium salt, and 1.25 g/mL at 25 ºC for Sodium acetate, and
- similar molecular weights which are 214.11 for Citric acid, sodium salt, and 82.03 for Sodium acetate.

Effect levels

Dose descriptor:
NOAEL
Effect level:
>= 57.44 other: mg/kg bw/day (estimated)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: overall effects

Target system / organ toxicity

Critical 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 acetate, 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 acetate,

 

- a high water solubility which is 1 g/mL for Citric acid, sodium salt, and 1.25 g/mL at 25 ºC for Sodium acetate, and

 

- similar molecular weights which are 214.11 for Citric acid, sodium salt, and 82.03 for Sodium acetate.

Both chemicals are grouped together by US EPA category groupCarboxylic Food Acids and Salts Category.

 

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

127-09-3

CHEMICAL NAME

 

Citric acid, sodium salt

Sodium acetate

PHYSICO-CHEMICAL DATA

 

Melting Point

No data

Measured data:

324 ºC

 

Boiling Point

No data

Estimated data:

Decomposes above 400°C

 

Density

No data

Experimental results:

1.53

 

Vapour Pressure

Negligible

Estimated data:

0.00000000537 mm Hg at 25 ºC

 

Partition Coefficient (log Kow)

Estimated data:

-0.28

Estimated data:

-3.72

 

Water solubility

 

Estimated data:

1000 g/L

 

Experimental results:

1.25 g/mL at 25 ºC

ENVIRONMENTAL FATE and PATHWAY

 

Aerobic Biodegradation

 

No data

Experimental results:

Readily biodegradable

 

ENVIRONMENTAL TOXICITY

 

Acute Toxicity to Fish

No data

Key study:

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)

 

Acute Toxicity to Aquatic Invertebrates

No data

Experimental data:

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

 

Toxicity to Aquatic Plants

 

No data

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 the analogue Acetic Acid, based on molecular weights:

 

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

 

MAMMALIAN TOXICITY

 

Acute Toxicity: Oral

Experimental data:

LD 50 = 7100 mg/kg bw (mice)

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

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

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

LD 50 = 2800 mg/kg bw

 

Acute Toxicity: Inhalation

No data

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

Key study:

LC 50 (4 h) > 5.81 mg/L

 

Acute Toxicity: Dermal

No data

 

Key study:

 

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

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

 

Skin sensitisation

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 acetate 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).

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 source chemical Citric acid, sodium salt to target chemical, based on molecular weights:

 

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

 

Genetic Toxicity in vitro

 

-         Gene mutation in bacteria

 

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.

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 substance analogue 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.

 

-         Mammalian gene mutation

No data

Weight of evidence:

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 analogue Phenoxyacetic acid, 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.

 

Chromosomal aberration

No data

Weight of evidence:

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 Acetic Acid, based on functional group:

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

 

Genetic Toxicity in vivo

 

No data

Key study:

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.

 

Carcinogenicity

 

No data

Data waiving (the substance is not classified as mutagen)

 

Reproductive Toxicity

TOXICITY TO REPRODUCTION:

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).

DEVELOPMENTAL TOXICITY / TERATOGENICITY:

 

No data

TOXICITY TO REPRODUCTION:

Weight of evidence:

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 source chemical Citric Acid, sodium salt, to the target chemical 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 kg bw/day for reproductive effects.

DEVELOPMENTAL 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 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.

 

 

Applicant's summary and conclusion

Conclusions:
The NOAEL with the substance Sodium acetate is calculated to be equal or greater than 57.44 mg/kg bw/day.
Executive summary:

Based on the experimental results (reported under the endpoint record 07.05.01_05 Citric acid sodium salt) 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 57.44 mg/kg bw/day.