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Acute Toxicity: dermal

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Administrative data

Endpoint:
acute toxicity: dermal
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 Fumaric acid which shares the same functional group with Calcium acetate, also has comparable values for the relevant molecular properties for acute dermal toxicity 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 (study with a test method similar to OECD 402) on the analogue Fumaric Acid.
GLP compliance:
no
Test type:
other: read-across from a standard acute method with an analogue

Test material

Constituent 1
Reference substance name:
Fumaric acid
EC Number:
203-743-0
EC Name:
Fumaric acid
Cas Number:
110-17-8
IUPAC Name:
but-2-enedioic acid
Details on test material:
- Name of test material (as cited in study report): Fumaric Acid
- Molecular formula (if other than submission substance): C4H4O4
- Molecular weight (if other than submission substance): 116.07
- Smiles notation (if other than submission substance): O=C(O)/C=C/C(=O)O
- InChl (if other than submission substance): InChI=1/C4H4O4/c5-3(6)1-2-4(7)8/h1-2H,(H,5,6)(H,7,8)/b2-1+
- Structural formula attached as image file (if other than submission substance): see Fig. in attached report

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 27 247.2 mg/kg bw
Based on:
test mat.
Other findings:
Based on the experimental results obtained with the analogue Fumaric Acid (4h-LD 50 for New Zealand rabbits > 20000 mg/kg bw) and the molecular weights, the read-across approach is applied and the LD 50 for substance Calcium Acetate is calculated to be greater than 27247.20 mg/kg bw under test conditions.

The analogue Fumaric Acid, which shares the same functional group with Calcium Acetate, also has comparable values for the relevant molecular properties. These properties are:
- a low log Pow value which is 0.25 for Fumaric Acid and - 1.38 for Calcium Acetate,
- water solubility which is 0.0063 g/mL at 25 ºC for Fumaric Acid and 1000 g/L at 25 ºC for Calcium acetate, and
- molecular weights which are 116.07 for Fumaric Acid and 158.17 for Calcium acetate.

Any other information on results incl. tables

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

110-17-8

 

Target chemical

62-54-4

 

CHEMICAL NAME

 

Fumaric acid

Calcium acetate

PHYSICO-CHEMICAL DATA

 

Melting Point

Experimental results:

290°C (sublimes)

Measured data:

160 ºC (decomposition)

 

Boiling Point

Experimental results:

290 °C (sublimes)

No data

 

Density

Experimental results:

1.64 at 20 ºC

Experimental results:

1.5 kg/m3

 

Vapour Pressure

Measured data:

1.5×10-4 mm Hg at 25°C

 

Estimated data:

0.73 Pa at 25 ºC

Partition Coefficient (log Kow)

Estimated data:

0.25

 

Estimated data:

-1.38

 

Water solubility

 

Measured data:

0.0063 g/mL at 25 ºC

 

Experimental results:

1000 g/L at 25 ºC

ENVIRONMENTAL FATE and PATHWAY

 

Aerobic Biodegradation

 

Experimental results:

Readily biodegradable

 

Read-across from Sodium Acetate (category analogue):

Readily biodegradable

 

ENVIRONMENTAL TOXICITY

 

Acute Toxicity to Fish

No data

Weight of evidence:

 

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

 

(96 h) LC 50 > 96.45 mg/L(Brachydanio rerio)

 

 

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

 

(96 h) LC 50 > 402.92 mg/L (Oncorhynchus mykiss)

 

(96 h) LC 50 > 402.92 mg/L (Cyprinodon variegatus)

 

(96 h) LC 50 > 399.98 mg/L(Brachydanio rerio)

 

Acute Toxicity to Aquatic Invertebrates

Experimental data:

48-h EC50 = 212 mg/L (Daphnia magna)

Weight of evidence:

 

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

 

(48 h) EC 50 > 370.28 mg/L(Daphnia magna)

(48 h) EC 0 = 227.5 mg/L (Daphnia magna)

 

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

 

(48 h) EC 50 > 964.09 mg/L(Daphnia magna)

 

Toxicity to Aquatic Plants

 

Experimental data:

 

72-h EC50 (growth) = 41 mg/L(Scenedesmus subcapitata)

Key studies:

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

 

(72 h) EC 50 > 402.92 mg/L (Skeletonema costatum)

(72 h) NOEC = 402.92 mg/L (Skeletonema costatum)

 

 

Supporting studies:

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

                       

(8 d) Toxicity threshold (TT) = 5272.33 mg/L (Scenedesmus quadricauda)

 

MAMMALIAN TOXICITY

 

Acute Toxicity: Oral

Experimental data:

LD 50 = 9300 - 10700 mg/kg bw (rats)

Key study:

Experimental results: 

LD50 = 2700 mg/kg bw

LD50 = 1943 mg/kg bw (female rats)

LD50 = 3160 - 4640 mg/kg bw (male rats)

 

Acute Toxicity: Inhalation

No data

Key study:

 

Experimental results:

 

(4 h) LC50 > 5.6 mg/L (rats)

 

Acute Toxicity: Dermal

Key study:

LD50 (4 h) > 20000 mg/kg bw (female New Zealand White rabbits)

Key study:

 

Read-across from the source chemical Fumaric acid to the target chemical, based on molecular weights:

LD50 (4 h) > 27247.2 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, Calcium acetate is also considered to be not sensitising.

 

Repeated Dose Toxicity

Repeated dose toxicity: oral:

Experimental data:

Repeated dose toxicity: oral: 2-year study in male and female rats which were treated by diet. The LOAEL = 750 mg/kg bw/day (based on slight increases in mortality and increased incidence of testes degeneration at the highest dose tested). The NOAEL = 600 mg/kg bw/day.

Repeated dose toxicity: oral:

Weight of evidence:

 

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

 

Repeated dose toxicity: oral: 112-day study in male Wistar rats. The NOAEL was determined as 0.0096 mg/kg bw/day.

 

Repeated dose toxicity: oral: 3-month study in male Long-Evans rats. The NOAEL was determined as 20.25 mg/kg bw/day.

 

Repeated dose toxicity: oral: 4-week study in male Wistar rats. The NOAEL was determined as 3472.02 mg/kg bw/day.

 

Repeated dose toxicity: oral: 8-month study in male Long-Evans rats. The NOAEL was determined as 0.048 mg/kg bw/day.

 

 

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

 

TheNOAEL >= 55.41 mg/kg bw/day, in rats daily treated by feed for ca. 1 year.

 

Genetic Toxicity in vitro

 

-         Gene mutation in bacteria

 

In a bacterial reverse mutation assay usingS. typhimurium(TA98, TA100, TA1535, TA97 and TA1537) in the absence of metabolic activation and concentrations up to 1000μg/plate, fumaric acid was not mutagenic.

Weight of evidence:

 

Read-across from Sodium Acetate (category analogue) based on functional group:

 

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

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

Calcium 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:

Calcium 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:

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

Estimated data from Danish (Q)SAR Database:

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

 

Chromosomal aberration

Fumaric acid was assayed in anin vitroassay using Chinese hamster fibroblast cells in the absence of metabolic activation at doses up to 1 mg/mL; however, insufficient information was provided in the robust summary to adequately evaluate this study.

Weight of evidence:

Read-across from Sodium Acetate (category analogue) based on functional group:

 

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

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

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

Genetic Toxicity in vivo

 

No data

 

Key studies:

Read-across from Sodium Acetate (category analogue) based on functional group:

 

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, calcium salt did not inhibit DNA replication in this assay.

 

Carcinogenicity

 

No data

 

Data waiving (the substance is not classified as mutagen)

 

Reproductive Toxicity

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 Calcium Acetate, the NOAEL is calculated to be equal or greater than 3087.65 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 Calcium Acetate, the NOAEL is calculated to be 741.04 mg/kg bw/day, and LOAEL greater than 741.04 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 Calcium Acetate, the NOAEL is calculated to be 55.41 mg/kg bw/day, and LOAEL greater than 55.41 mg/kg bw/day for reproductive effects.

 

DEVELOPMENTAL TOXICITY / TERATOGENICITY:

Weight of evidence:

Read-across from Sodium Acetate (category analogue) based on molecular weights:

 

Pregnant CD-1 mice were treated by oral gavage with Sodium Acetate on days 8-12 of gestation. For Calcium Acetate, theNOAEL is calculated to be equal or greater than 964.5 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 Calcium Acetate, the NOAEL is calculated to be equal or greater than 3087.65 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 Calcium Acetate, the NOAEL is calculated to be equal or higher than 243.13 mg/kg bw/day.

Read-across from theanalogue substanceAcetic 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 Calcium acetate is calculated to be equal or greater than 2108.93 mg/kg bw/day for maternal and developmental toxicity in mice, rats, and rabbits.

 

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The (4h) LD 50 for substance Calcium Acetate is calculated to be greater than 27247.20 mg/kg bw for rabbits.
Executive summary:

Based on the experimental results (reported under the endpoint record 07.02.03_02 Fumaric Acid) obtained with the analogue Fumaric Acid (4h-LD 50 for New Zealand rabbits > 20000 mg/kg bw) and the molecular weights, the read-across approach is applied and the LD 50 for substance Calcium Acetate is calculated to be greater than 27247.20 mg/kg bw under test conditions.