Sodium acetate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: The analogue Citric Acid which shares the same functional group with Sodium Acetate, 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 from one-generation study on the analogue Citric acid.

GLP compliance:

no

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Citric acid

EC Number:

201-069-1

EC Name:

Citric acid

Cas Number:

77-92-9

IUPAC Name:

citric acid

Details on test material:

- Name of test material (as cited in study report): Citric acid
- Molecular formula (if other than submission substance): C6H8O7
- Molecular weight (if other than submission substance): 192.1
- Smiles notation (if other than submission substance): OC(=O)CC(O)(CC(O)=O)C(=O)O
- InChl (if other than submission substance): InChI=1/C6H8O7/c7-3(8)1-6(13,5(11)12)2-4(9)10/h13H,1-2H2,(H,7,8)(H,9,10)(H,11,12)
- Structural formula attached as image file (if other than submission substance): see Fig. in attached report

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
Based on the experimental results obtained with the analogue Citric acid (NOAEL >= 2500 mg/kg bw/day (basis for effect: number of pregnancies) in rats daily treated by feed before, during, and after mating), 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 3201.46 mg/kg bw/day.

The analogue Citric acid 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 -1.72 for Citric acid, and -3.72 for Sodium acetate,
- a high water solubility which is 1330 g/L for Citric acid, and 1.25 g/mL at 25 ºC for Sodium acetate, and
- similar molecular weights which are 192.1 for Citric acid, and 82.03 for Sodium acetate.

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

>= 3 201.46 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

>= 3 201.46 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic 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 young born, or survival of young animals)), 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 3201.46 mg/kg bw/day.

The analogue Citric acid 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 -1.72 for Citric acid, and -3.72 for Sodium acetate,
- a high water solubility which is 1330 g/L for Citric acid, and 1.25 g/mL at 25 ºC for Sodium acetate, and
- similar molecular weights which are 192.1 for Citric acid, and 82.03 for Sodium acetate.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

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

- a high water solubility, which is 50 g/L for Acetic acid and 1.25 g/mL for Sodium Acetate at 25 ºC,

- similar molecular weights, which are 60.0 for Acetic acid 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 77-92-9	Target chemical 127-09-3
CHEMICAL NAME		Citric acid	Sodium acetate
PHYSICO-CHEMICAL DATA
Melting Point		Measured data: 153 ºC	Measured data: 324 ºC
Boiling Point		Decomposes	Estimated data: Decomposes above 400°C
Density		Measured data: 1.665 g/cm3 at 20 ºC	Experimental results: 1.53
Vapour Pressure		Estimated data: 5.6E-09 mm Hg	Estimated data: 0.00000000537 mm Hg at 25 ºC
Partition Coefficient (log Kow)		Measured data: -1.72	Estimated data: -3.72
Water solubility		Measured data: 1330 g/L	Experimental results: 1.25 g/mL at 25 ºC
ENVIRONMENTAL FATE and PATHWAY
Aerobic Biodegradation		Experimental results: Readily biodegradable	Experimental results: Readily biodegradable
ENVIRONMENTAL TOXICITY
Acute Toxicity to Fish		Experimental data: (96 h) LC 50 = 1516 mg/L	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		Experimental data: (48 h) EC 50 = 1535 mg/L	Experimental data: (24-48 h) EC 50 > 1000 mg/L(Daphnia magna)
Toxicity to Aquatic Plants		Experimental data: (72 h) EC 50 = 640 mg/L	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 = 5790 – 7100 mg/kg bw (mice) LD 50 = 11700 mg/kg bw (rats)	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		Experimental data:   A 4-hour skin irritation study in rabbits exposed to a solution containing 60% citric acid caused erythema and edema. This study did not assess a lethal dose value. TheLD50 was not provided.	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		Experimental results:   Citric acid (2.5 % aqueous solution) is not sensitizing for the human skin.   No allergic reactions were seen when 60 patients with hand eczema, all of whom were involved in handling food, were patch tested (covered contact, probably 24 hr) with 2.5% citric acid in petrolatum.	Weight of evidence:   Read-across from the analogue substances Citric acid (source chemical), 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 150-day study with male New Zealand White rabbits daily treated by feed, theNOAEL was 1500 mg/kg bw/day(based on no effects observed at the only dose tested).   In a 6-week study with male Sprague-Dawley rats daily treated by feed, theNOAEL was 4800 mg/kg bw/day(based on no effects observed at the highest 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 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.
Genetic Toxicity in vitro	-         Gene mutation in bacteria	Experimental data:   In a bacterial reverse mutation assays usingS. typhimurium(TA97, TA98, TA100 and TA104) in the presence and absence of metabolic activation and up to 2000μg/plate, citric acid was not mutagenic.	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.
	-         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		Experimental data:   In a Dominant Lethal assay using male/female rats dosed at 3 g/kg for 5 days, citric acid did not induced germ cell genotoxicity.	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 data: In a one-generation oral reproductive toxicity study, female rats and mice were daily treated with citric acid before, during, and after mating. The NOAEL was equal or greater than 2500 mg/kg bw/day (basis for effect: number of pregnancies, number of young born, or survival of young). In a fertility study, female rats were exposed to citric acid in their daily diet for several months. TheNOAEL (reproductive toxicity) was 600 mg/kg bw/day(based on no effects observed at the only dose tested).   DEVELOPMENTAL TOXICITY / TERATOGENICITY:   Experimental data:   In a one-generation oral reproductive toxicity study, female rats and mice were daily treated with citric acid before, during, and after mating. The NOAEL was equal or greater than 2500 mg/kg bw/day (basis for effect: number of pregnancies, number of young born, or survival of young).	TOXICITY TO REPRODUCTION: Weight of evidence: Read-across from the source chemical Citric Acid to target chemical, 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. 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 source chemical Citric Acid to target chemical, 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 3201.46 mg/kg bw/day (basis for effect: number of pregnancies, number of young born, or survival of young animals).

Executive summary:

Based on the experimental results (reported under the endpoint record 07.08.02_02 Citric acid) 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 acetate is calculated to be equal or greater than 3201.46 mg/kg bw/day for studied effects.