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Toxicological information

Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation
Remarks:
in vivo
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 which shares the same functional group with Sodium diacetate, also has comparable values for the relevant molecular properties for the skin sensitisation 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 skin prick testing on the analogue Citric acid.
GLP compliance:
not specified
Type of study:
other: read-across from a skin prick testing with an analogue

Test material

Reference
Name:
Unnamed
Type:
Constituent
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

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
0.25
Group:
test group
Dose level:
2.5 %
No. with + reactions:
3
Total no. in group:
91
Clinical observations:
Weals
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 0.25. Group: test group. Dose level: 2.5 %. No with. + reactions: 3.0. Total no. in groups: 91.0. Clinical observations: Weals.
Reading:
rechallenge
Hours after challenge:
0.25
Group:
test group
Dose level:
2.5 %
No. with + reactions:
0
Total no. in group:
11
Clinical observations:
No effects
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 0.25. Group: test group. Dose level: 2.5 %. No with. + reactions: 0.0. Total no. in groups: 11.0. Clinical observations: No effects.
Reading:
1st reading
Hours after challenge:
0.25
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
247
Clinical observations:
No effects
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 0.25. Group: negative control. Dose level: 0. No with. + reactions: 0.0. Total no. in groups: 247.0. Clinical observations: No effects.

Any other information on results incl. tables

The analogue Citric 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 -1.72 for Citric acid and -3.72 for Sodium diacetate,

- a high water solubility, which is 1330 g/L for Citric acid and 1000 g/L for Sodium dicetate at 25 ºC, and

- similar molecular weights, which are 192.1 for Citric acid 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

77-92-9

 

Target chemical

126-96-5

 

CHEMICAL NAME

 

Citric acid

Sodium diacetate

PHYSICO-CHEMICAL DATA

 

Melting Point

Measured data:

153 ºC

Measured data:

Decomposes above 150 ºC

 

Boiling Point

Decomposes

 

Measured data:

Decomposes above 150°C

 

Density

Measured data:

1.665 g/cm3 at 20 ºC

Experimental results:

4.405

Vapour Pressure

Estimated data:

5.6E-09 mm Hg

 

Estimated data:

0.000000716 mm Hg at 25 ºC

Partition Coefficient (log Kow)

Measured data:

-1.72

Estimated data:

-3.72

 

Water solubility

 

Measured data:

1330 g/L

 

Estimated data :

1000 g/L at 25 ºC

ENVIRONMENTAL FATE and PATHWAY

 

Aerobic Biodegradation

 

Readily biodegradable

 

Read across:

Readily biodegradable

 

ENVIRONMENTAL TOXICITY

 

Acute Toxicity to Fish

Experimental data:

(96 h) LC 50 = 1516 mg/L

LC50=184.7 mg/L (calculated)

Acute Toxicity to Aquatic Invertebrates

Experimental data:

(48 h) EC 50 = 1535 mg/L

EC50=141 mg/L (calculated)

Toxicity to Aquatic Plants

 

Experimental data:

(72 h) EC 50 = 640 mg/L

EC50=164 mg/L (calculated)

MAMMALIAN TOXICITY

 

Acute Toxicity: Oral

Experimental data:

LD 50 = 5790 – 7100 mg/kg bw (mice)

LD 50 = 11700 mg/kg bw (rats)

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

.

 

Acute Toxicity: Inhalation

No data

No data

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.

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

Skin Sensitization

 

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, 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 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).

NOAEL=132 mg/kg/bw (calculated)

Genetic Toxicity in vitro

 

Gene mutation in bacteria

Mammalian gene mutation Chromosomal aberration

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.

 

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 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.

 

.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 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).

 

DEVELPMENTAL TOXICITY / TERATOGENICITY:

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:

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

Interpretation of results:
not sensitising
Remarks:
Migrated information
Conclusions:
Sodium diacetate is considered to be not sensitising for the human skin.
Executive summary:

Based on the experimental results (reported under the endpoint record 07.04.01_01 Citric acid) obtained with the analogue Citric acid (Citric acid, 2.5 % aqueous solution, is not sensitizing for the human skin), the read-across approach was applied and the substance Sodium diacetate is considered to be also not sensitising for the human skin.