Calcium dipropionate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Calcium dipropionate is not expected to be toxic for reproduction.

Additional information

Read-across approach

Selected endpoints for the human health hazard assessment are addressed by read-across, using a combination of data on the metal cation and the organic acid anion. This way forward is acceptable, since metal carboxylates are shown to dissociate to the organic anion and the metal cation upon dissolution in aqueous media. No indications of complexation or masking of the metal ion through the organic acid were apparent during the water solubility and dissociation tests (please refer to the water solubility and dissociation in sections 4.8 and 4.21 of IUCLID). Once the individual transformation products of the metal carboxylate become bioavailable (i.e. in the acidic environment in the gastric passage or after phagocytosis by pulmonary macrophages), the “overall” toxicity of the dissociated metal carboxylate can be described by a combination of the toxicity of these transformation products, i.e. the metal cation and carboxylate anion according to an additivity approach.

 

Calcium dipropionate is the calcium salt of propionic acid, which readily dissociates to the corresponding divalent calcium cation and monovalent propionate anions. The calcium cation and the propionate anion are considered to represent the overall toxicity of calcium dipropionate in a manner proportionate to the free acid and the metal (represented by one of its readily soluble salts). 

 

A detailed justification for the read-across approach is added as a separate document in section 13 of IUCLID.

 

 

Toxicity for reproduction– effects on fertility

No toxicity data on adverse effects on sexual function and fertility with Calcium dipropionate are available, thus the reproductive toxicity will be addressed with existing data on the dissociation products as detailed in the table below. Further details on the reproductive toxicity of the individual constituents are given below.

 

Table: Summary of toxicity data on adverse effects on sexual function and fertility of calcium dipropionate and the individual constituents.

	calcium substances	Propionic acid (CAS# 79-09-4)	Calcium dipropionate (CAS# 4075-81-4)
Two-generation reproductive toxicity study	not reprotoxic (weight of evidence, human data) not classified	NOAEL(sub-chronic, dog)= 2060 mg/kg bw/day   not classified	no data   not classified

 

Calcium

Only limited data are available on effects of calcium compounds on the reproductive performance of male and female mice and rats, respectively. A preliminary NOAEL for calcium effects on reproduction and development of offspring may be derived from a CaCO3 feeding study in mice (Richards and Greig, 1952). The study design was similar to that of a one-generation reproductive toxicity study. The highest dose of 2 % CaCO3 (corresponding to 1.1 % Ca) resulted in reduced numbers and total weight of litters, and increased both the number and proportion of litter deaths, hence being considered as LOAEL for effects on reproductive performance. The dose level of 0.73 % Ca may be established as NOAEL although there were some sporadic effects without statistical significance. However, no daily dose levels could be calculated due to lack of data on daily food intake.

 

However, with respect to potential hazards of calcium for reproduction the following aspects have to be taken into account:

 

i) Calcium, released as calcium cations in aqueous media is a physiologically essential element and nutrient for all mammals including humans. Comprehensive evaluations of possible adverse health effects of individual nutrients at intakes in excess of dietary requirements have been presented in the scientific opinions of the Scientific Committee on Food (SCF). Where possible, tolerable upper intake levels (UL) for different human populations have been established. The UL is an estimate of the highest level of intake entailing no appreciable risk of adverse health effects. In the opinion on calcium (EFSA 2006), the sources, properties and effects of calcium on animals as well as on different subgroups of the human population have been re-evaluated and a tolerable upper intake level for calcium has been defined. The SCF decided to base the derivation of an UL for calcium on the evidence of different interventional studies of long duration in adults, some of which were placebo-controlled and in which total daily calcium intakes of 2500 mg from both the diet and supplements were tolerated without any adverse effects. Based on the findings, a tolerable upper intake level of 2500 mg of calcium per day for calcium intake from all sources is proposed for adults, corresponding to a dose of about 36 mg calcium/kg bw/d taking into account an average body weight of 70 kg/person. The UL is considered to also cover any potential reproductive effects.

 

ii) Supportive information is available in section 7.12 of the technical dossier (Mortimer, 1988) showing that calcium is essential for the function of human spermatozoa (acrosome reaction), i.e. calcium has a beneficial effect on reproductive performance.

 

iii) Supportive information is available in section 7.12 of the technical dossier (Han, 2000) showing that calcium has a protective effect against lead accumulation in dams and their offspring, i.e. acts beneficially.

 

 

Propionic acid

There are no reproductive toxicity studies available for n-propionic acid. Data from a 100 days repeated-dose study in dogs did not result in toxicity to reproductive organs.

 

In a dog study satisfying GLP requirements and OECD 409 TG, propionic acid (> 99% purity) was administered via diet to male and female Beagle dogs (4/sex/dose) for approximately 100 days at diet concentrations of 0, 3000, 10000 and 30000 ppm propionic acid. A recovery period of 6 weeks was allocated for the groups (4/sex/dose) receiving 0 and 3000 ppm propionic acid in the diet. No mortality occurred during the administration period. No substance related clinical signs of toxicity occurred. Calculated from food consumption, the mean daily dose administered were 214.2, 718.9, 2056.3 mg/kg bw for males and 225.1, 749.2, 2071.8 mg/kg bw for females. Dogs from the high-dose group displayed a decrease in appetite, which was attributed as a response due to unpalatability of the diet. This decrease in food consumption however did not seem to significantly affect body weights or body weight gains. No systemic effects were observed even at the highest dose. There were no significant changes in haematology, urinalysis, or clinical chemistry parameters that could be attributed to the test material. Necropsy of dogs after the administration interval revealed no gross lesions. Examination of tissues revealed no lesions except point-of-contact diffuse epithelial hyperplasia of the mucosa of the oesophagus in several high dose dogs. This effect was reversible after a 6 week recovery period. The incidence of focal epithelial hyperplasia in lower dose animals was comparable to controls. There were no effects observed on male or female reproductive organs. The NOAEL for this study for systemic /reproductive organ effects is 3000 ppm propionic acid in the diet or 2056,3 mg/kg bw for male dogs and 2071.8 mg/kg bw for female dogs (BASF, 1988).

 

Calcium dipropionate

Since no toxicity data on adverse effects on sexual function and fertility is available for calcium dipropionate, information on the individual constituents calcium and propionic acid will be used for the hazard assessment and, when applicable, for the risk characterisation of calcium dipropionate. For the purpose of hazard assessment of calcium dipropionate, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation.

 

Calcium dipropionate is not expected to show adverse effects on sexual function and fertility, since the two constituents calcium and propionic acid have not shown adverse effects on sexual function and fertility in relevant bioassays. Thus, calcium dipropionate is not to be classified according to regulation (EC) 1272/2008 as reproductive toxicant: fertility impairment. Further testing is not required. For further information on the toxicity of the individual constituents, please refer to the relevant sections in the IUCLID and CSR.

Justification for selection of Effect on fertility via oral route:
Information from read-across substances:
human data for calcium: not reprotoxic (weight of evidence)
animal data for propionic acid: NOAEL(dog)=2060mg/kg bw/day

Effects on developmental toxicity

Description of key information

Calcium dipropionate does not show any adverse effects on development of the offspring. 

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline without detailed documentation

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

(documentation deficiencies)

GLP compliance:

no

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: adult
- Average body weight at study initiation: 229.5 g
- Fasting period before study: no data
- Housing: individually
- Diet (e.g. ad libitum): free access
- Water (e.g. ad libitum): tap water, free access
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Animals were housed in temperature and humidity controlled quarters

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: no data

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: no data
- Length of cohabitation: no data
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as day 0
- Any other deviations from standard protocol: no

Duration of treatment / exposure:

days 6-15 of gestation

Frequency of treatment:

daily

Duration of test:

20 days

No. of animals per sex per dose:

24 females

Control animals:

yes, sham-exposed

Details on study design:

- Dose selection rationale: no data
- Rationale for animal assignment (if not random): no data
- Positive control: Acetylsalicyl acid (ASA) administered at 250 mg/kg bw

Maternal examinations:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: Days 0, 6, 11, 15 and 17 of gestation


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Frequency of measurement: daily


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice: on gestation day 20 by surgical anaesthesia
- Organs examined: no data

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes, the number of live and dead foetuses were recorded
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes

Fetal examinations:

- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [one third per litter]
- Skeletal examinations: Yes: [two thirds per litter]
- Head examinations: no

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
The administration of up to 300 mg/kg (body weight) of the test material to pregnant rats for 10 consecutive days had no clearly discernible effect on on dams.

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day (actual dose received)

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
TEST SUBSTANCE:
- The administration of up to 300 mg/kg (body weight) of the test material to pregnant rat for 10 consecutive days had no clearly discernible effect on nidation or fetal survival.
- The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls


POSITIVE CONTROL (ASA)
- Weight reduction in foetuses of dams treated with 250 mg/kg bw with a reduction of the average weight of about 41.4 compared to controls
- Increased number of total resorptions with a total number of resorptions in the positive control reaching 102 as compared to only 6 in the controls. There was also an increased percentage of partial and complete resorption in comparison to negative control animals. The percentage of partial resorptions in positive control animals was 79.2% compared to only 17.4 in negative control animals. Twenty five percent of the embryos were completed resorbed as compared to 0% in the negative control animals.
- An average of 6.6 fetuses/ dam were alive at necropsy in the positive control group totalling 160 in all. In comparison, 10.6 fetuses/ dam were alive in the negative control group making a total of 243 fetuses
- Skeletal investigations revealed malformations and variations of the sternebrae, ribs, verterbrae, skull and extremities in animals of the positive control group (see attachment). Miscellaneous findings included missing and reduced hyoids
- Soft tissue investigations included exencephaly, spina bifida, enterohepatocele

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day (actual dose received)

Basis for effect level:

other: teratogenicity

Abnormalities:

not specified

Developmental effects observed:

not specified

see attachment for summary of results

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

chronic

Species:

rat

Additional information

Calcium dipropionate was fed to pregnant CD-1 mice and Wistar rats during gestation days 6-15 at dose levels of 3, 14, 65, and 300 mg/kg-bw/day. Pregnant rabbits and hamsters were fed calcium propionate at a doses of 0, 4, 19, 86, and 400 mg/kg-bw/day during gestation days 6-18 (rabbits) or 6-10 (hamsters). Body weights of dams were taken at several intervals during gestation. Dams were observed each day for food and water intake and other measures of appearance and behavior. Dams were sacrificed on gestation day 17 (mice), 20 (rats), 14 (hamsters), or 29 (rabbits). Numbers of implantation sites, resorption sites, and live and dead foetuses were recorded. Body weights of live pups were also recorded. All pups were examined grossly for external congenital abnormalities. One-third of the foetuses of each litter underwent detailed visceral examinations; two-thirds were examined for skeletal defects. In all species, there was no effect on maternal or foetal survival, or on foetal or litter size. No increase in foetal or skeletal abnormalities was observed. The NOAEL for maternal toxicity and developmental in rats is 300 mg/kg bw. The NOAEL for maternal toxicity and developmental in mouse is 300 mg/kg bw. The NOAEL for maternal toxicity and developmental in rabbits is 400 mg/kg bw and the NOAEL for maternal toxicity and developmental in hamster is 400 mg/kg bw (FDA 1972). The study is acceptable for assessment with restrictions. The authors provided no reason why tests were not performed up to the limit concentration.

Justification for selection of Effect on developmental toxicity: via oral route:
Key study

Justification for classification or non-classification

Calcium dipropionate is not expected to show adverse effects on sexual function and fertility, since the two constituents calcium and propionic acid have not shown adverse effects on sexual function and fertility in relevant bioassays. Thus, calcium dipropionate is not to be classified according to regulation (EC) 1272/2008 as reproductive toxicant: fertility impairment. 

 

Calcium dipropionate does not show adverse effects on development of the offspring. Thus, calcium dipropionate is not to be classified according to regulation (EC) 1272/2008 as developmental toxicant. Further testing is not required.