Calcium di(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:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The analogue Acetic Acid which shares the same functional group with Calcium 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 a one-generation study on the analogue Acetic Acid.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Acetic acid

EC Number:

200-580-7

EC Name:

Acetic acid

Cas Number:

64-19-7

IUPAC Name:

acetic acid

Details on test material:

- Molecular formula (if other than submission substance): C2H4O2
- Molecular weight (if other than submission substance): 60.0
- 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

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 Acetic acid (NOAEL >= 1600 mg/kg bw/day in female Dutch-belted rabbits treated for 13 days for maternal toxicity, mortality and body weight gain), and the molecular weights, 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.

The analogue Acetic 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 -0.17 for Acetic acid and -1.38 for Calcium Acetate,
- a high water solubility which is 50 g/L for Acetic acid and 1000 g/L for Calcium Acetate at 25 ºC, and
- similar molecular weights which are 60.0 for Acetic acid and 158.17 for Calcium Acetate.

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

>= 2 108.93 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

>= 2 108.93 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 Acetic acid (NOAEL >= 1600 mg/kg bw/day in female Dutch-belted rabbits treated for 13 days 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 Calcium acetate is calculated to be equal or greater than 2108.93 mg/kg bw/day.

The analogue Acetic 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 -0.17 for Acetic acid and -1.38 for Calcium Acetate,
- a high water solubility which is 50 g/L for Acetic acid and 1000 g/L for Calcium Acetate at 25 ºC, and
- similar molecular weights which are 60.0 for Acetic acid and 158.17 for Calcium Acetate.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Both chemicals are grouped together by US EPA category group Carboxylic 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 64-19-7	Target chemical 62-54-4
CHEMICAL NAME		Acetic acid	Calcium acetate
PHYSICO-CHEMICAL DATA
Melting Point		Measured data: 16.7 ºC	Measured data: 160 ºC (decomposition)
Boiling Point		Measured data: 118.1 ºC	No data
Density		Measured data: 1.0446 g/cm3 at 25 ºC	Experimental results: 1.5 kg/m3
Vapour Pressure		Measured data: 11.4 mm Hg at 20 °C	Estimated data: 0.73 Pa at 25 ºC
Partition Coefficient (log Kow)		Measured data: -0.17	Estimated data: -1.38
Water solubility		Measured data: 50 g/L	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		Experimental data: (96 h) LC 50 = 251 mg/L(Gambusia affinis)	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) EC 50 = 65 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:   (8 d) Toxicity threshold (TT) = 4000 mg/L (Scenedesmus quadricauda)	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 source chemical Acetic Acid to target chemical, based on molecular weights:   (8 d) Toxicity threshold (TT) = 5272.33 mg/L (Scenedesmus quadricauda)
MAMMALIAN TOXICITY
Acute Toxicity: Oral		Experimental data: LD 50 = 3250-8610 mg/kg bw (rats) LD 50 = 4960 mg/kg bw (mice)	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		Experimental results: (4 h) LC50 = 11.4 mg/L	Key study:   Experimental results:   (4 h) LC50 > 5.6 mg/L (rats)
Acute Toxicity: Dermal		Experimental results: LD 50 = 1060 mg/kg bw (rabbits)	Key study:   Read-across from the analogue Fumaric acid, based on molecular weights: LD50 (4 h) > 27247.2 mg/kg bw (female New Zealand White rabbits)
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, Calcium acetate 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).	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	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.	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 source chemical Acetic Acid to target chemical, 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	Experimental results:   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.	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 source chemical Acetic Acid to the target chemical, 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		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: 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 Sodium 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 the source chemical Acetic Acid to the target chemical, 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 2108.93 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 Calcium acetate is calculated to be equal or greater than 2108.93 mg/kg bw/day for maternal and developmental toxicity in rabbits.

Executive summary:

Based on the experimental results (reported under the endpoint record 07.08.02_13 Acetic acid) obtained with the analogue Acetic acid (NOAEL >= 1600 mg/kg bw/day in female Dutch-belted rabbits treated for 13 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 Calcium acetate is calculated to be equal or greater than 2108.93 mg/kg bw/day for maternal and developmental toxicity.