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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
2 187.47 mg/kg bw/day
Additional information

Weight of evidence:

Read-across approach from 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 Sodium Acetate is calculated to be equal or higher than 3201.46 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 Sodium acetate is calculated to be 768.35 mg/kg bw/day, and LOAEL > 768.35 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 Sodium acetate is calculated to be 57.44 mg/kg bw/day, and LOAEL > 57.44 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.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
2 187.47 mg/kg bw/day
Additional information

Weight of evidence:

Experimental results:

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.

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

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 Sodium Acetate is calculated to be 3201.46 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 in treated rats. 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 Sodium Acetate is calculated to be equal or higher than 252.18 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 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.

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.