Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
741 mg/kg bw/day
Quality of whole database:
Read across
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Weight of evidence:

Experimental results obtained with analogues Citric Acid and Citric Acid, sodium salt on rats and mice.

In the study reported by Wright et al., 1976, a fertility and a one-generation study are described. This study examines the effect of a 5% dietary supplement of Citric acid (ca. 2.5 g/kg bw/day) on the reproductive capacity of rats and mice. Animals were treated before, during, and after mating. No effects were seen on number of pregnancies, number of young born, or survival of young in treated rats and mice with ca. 2.5 g/kg bw/day Citric Acid, compared to controls.

The read-across approach is applied and the NOAEL with Calcium Acetate is calculated to be 3087.65 mg/kg bw/day on rats and mice (basis for effects: number of pregnancies, number of young born, or survival of young).

In the paper reported by Bonting et al., 1956, a fertility test was carried out on rats with Citric Acid. Exposure began 29 weeks prior to mating and continued for a few months after mating. Animals were fed diets containing 1.2% citric acid (about 600 mg/kg bw/day). No effects were detected. The NOAEL for reproductive effects was 600 mg/kg bw/day. The LOAEL was greater than 600 mg/kg bw/day for the same effects.

Applying the read-across approach, the NOAEL with the substance Calcium acetate is calculated to be 741.04 mg/kg bw/day, and LOAEL greater than 741.04 mg/kg bw/day.

Bonting et al. also describes another fertility test on rats with Citric Acid, sodium salt. The method was exactly the same, the only difference is the given dose. In this case, treated animals received fed diets containing 0.1% citric acid, sodium salt (ca. 50 mg/kg bw/day). No effects were detected. The NOAEL for reproductive effects was 50 mg/kg bw/day. The LOAEL was greater than 50 mg/kg bw/day.

Applying the read-across approach, the NOAEL with the substance Calcium acetate is calculated to be 55.40 mg/kg bw/day, and LOAEL greater than 55.40 mg/kg bw/day for reproductive effects.


Short description of key information:
Effects on fertility: Weight of evidence: Read-across from experimental results on rats and mice treated with Citric Acid and Citric Acid, sodium salt. No toxicity to reproduction was observed in any case.

Effects on developmental toxicity

Description of key information
Developmental toxicity/Teratogenicity: Weight of evidence: Read-across from experimental results on rats, mice, and rabbits treated with Sodium Acetate, Citric Acid, Calcium Formate and Acetic Acid. No maternal or developmental toxicity was seen in treated animals exposed to high doses of these substances.
Link to relevant study records
Reference
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.
Reason / purpose:
reference to other study
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
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.
Dose descriptor:
NOAEL
Effect level:
>= 2 108.93 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
>= 2 108.93 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
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.
Abnormalities:
not specified
Developmental effects observed:
not specified

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.

 

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.

Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
2 109 mg/kg bw/day
Quality of whole database:
Read across
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Quality of whole database:
Read across study.
Additional information

Weight of evidence:

Read-across approach from experimental results obtained with analogues Sodium Acetate, Citric Acid, Calcium formate, and Acetic Acid on rats, mice, and rabbits.

In the first paper, reported by Kavlock et al., 1987, pregnant CD-1 mice were treated with Sodium Acetate by oral gavage on days 8-12 of gestation at a dose level predicted from a preliminary range finding study to induce a slight degree of maternal toxicity. Day 20 of gestation was considered postnatal day 1 (PD1). On PD1 and 3, the litters were counted and weighed as a unit.

No maternal toxicity and no neonatal effects (mortality and body weight) were observed at a dose level of 1000 mg/kg bw/day.

By read-across approach, for Calcium Acetate the NOAEL is calculated to be equal or greater than 964.5 mg/kg bw/day (based on maternal toxicity: mortality, pregnancy and resorption; and on neonatal effects: mortality and body weight).

In the study reported by Wright et al., 1976, a one-generation study is described. This study examines the effect of a 5% dietary supplement of Citric acid (ca. 2.5 g/kg bw/day) on the reproductive capacity of rats and mice. Animals were treated before, during, and after mating. No effects were seen on number of pregnancies, number of young born, or survival of young in treated rats and mice with ca. 2.5 g/kg bw/day Citric Acid, compared to controls.

The read-across approach is applied and the NOAEL with Calcium Acetate is calculated to be 3087.65 mg/kg bw/day on rats and mice (basis for effects: number of pregnancies, number of young born, or survival of young).

In the third paper, reported by Malorny (1969), a three-generation study was performed with Calcium formate in Wistar rats. Animals were treated by drinking water at doses of 0 or 200 mg/kg bw/day of test substance. No effects on fertility were observed. Number, weight and length of offspring did not differ in treated animals from controls. A portion of the offspring was also sacrificed shortly after birth for evaluation of developmental toxicity. No statistical differences in organ or bone abnormalities were found. The growth of treated offspring was similar to controls.

The NOAEL for maternal and developmental toxicity was equal or higher than 200 mg/kg bw/day.

The read-across approach is applied and the NOAEL for maternal and developmental toxicity with Calcium Acetate is calculated to be equal or higher than 243.13 mg/kg bw/day (overall effects).

In the last paper, reported by FDA (1974), a one-generation study is presented on female mice, rats and rabbits with Acetic acid. Pregnant animals were dosed daily by oral intubation, beginning on day 6 of gestation. Tested doses were 0, 16, 74, 345, and 1600 mg/kg bw/day. No effects on nidation or on maternal or fetal survival were observed at doses up to 1600 mg/kg bw/day. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring in the controls.

Based on the experimental results 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 in mice, rats, and rabbits.

Justification for classification or non-classification

All these studies have shown no effects on fertility nor on developmental of foetuses, eventhough high doses of chemicals were used, also in a three-generation study with the analogue substance Calcium formate. Based on these negative results, it is considered not necessary to perform more studies on reproduction and developmental toxicity.