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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

There are currently no experimental data available to assess effects on fertility for the test substance. A data waiver is set in place to justify that no further testing on reproductive toxicity is required.

Link to relevant study records
Reference
Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Data waiving:
other justification
Justification for data waiving:
other:
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

There are currently no experimental data available to assess reproductive toxicity for the test substance.

A combined repeated dose and reproduction study (Test Guideline OECD 422) was conducted on dipotassium orthophosphate in the rat on behalf of the National Institute of Environmental Research, and reported publicly in the OECD SIDS (1) dossier for that substance.Since the phosphorus is considered to be the critical part in calcium phosphates (see discussion below) this study is reliable to be used as read across. The OECD study design allows for an evaluation of key aspects of the reproductive cycle including oestrous cycle and spermatogenic cycle, mating performance, fertility, pregnancy and early post-natal offspring development. The test material was administered orally to rats throughout this period of reproduction (approximately 40 - 50 days) at dose levels up to 1000 mg/kg bw per day. There was no evidence to suggest an effect upon reproduction or offspring development and the NOAEL was determined to be >1000 mg/kg bw, considered to be a “limit dose” in the OECD. The lead registrant has sought to access this data however it has not been possible to agree data sharing terms for all co-registrants. As soon as this data is available it will be integrated in the dossier. Nonetheless, the lack of effects on reproduction or offspring development at dose levels well in excess of normal human exposure suggests that calcium and potassium orthophosphates are not a significant risk to the reproduction in females or males and not a significant risk to the developing foetus. Further studies are unlikely to show any significant effects on reproductive performance or development.

Calcium phosphates are approved for use as food additives (the EU food reference / INS number for monocalcium phosphate / calcium bis(dihydrogenorthophosphate) is E341 i). No evidence exists to show that calcium phosphates are likely to pose a risk of reproductive or developmental toxicity. In addition, the Ca2+cation has a similar and essential biological function and excess of this ion results in well documented toxicity; this does not include toxicity to reproduction or developmental toxicity. The World Health Organisation, reports that the maximum tolerable daily intake (MTDI) for phosphates for all individuals is 70 mg P/kg bw (2), this value is considered to be well below that observed for developmental toxicity and as such human exposure is likely to be considerably less that the level required for reproductive toxicity testing. No effects on development were observed at the highest dose tested in animal studies. Reference values for the intake of calcium are considerably higher than that for phosphorus: Adequate intake (AI) value for calcium in 19-30 years old is 1000 mg/day (3). These values indicate that humans will generally be exposed to relatively high daily levels with no adverse effects. In conclusion, an additional extended one-generation reproductive toxicity study in the rat is unlikely to result in providing further evidence of reproductive toxicity as the existing studies have demonstrated a lack of effect at dose levels well in excess of expected human exposure. A study would therefore be scientifically and ethically unjustified.

(1)http://webnet.oecd.org/Hpv/UI/SIDS_Details.aspx?id=545E2F43-CF57-4AED-8784-

C0391BCCC562

(2)Evaluation of certain food additives and contaminants. Twenty-sixth report of the joint FAO/WHO expert committee of food additives. World Health Organisation. Technical Report Series 683. 1982. ISBN92 4 120683 7

(3)Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, of. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride., Press, 1997.

Effects on developmental toxicity

Description of key information

No data are available for calcium hydrogenorthophosphate.

Reliable data is available for calcium dihydrogenorthophosphate monohydrate (CAS 10031-30-8):

Prenatal developmental toxicity (similar to OECD 414), mice: NOAELmaternal ≥ 465 mg/kg bw/day; NOAELdevelopmental ≥ 465 mg/kg bw/day

Prenatal developmental toxicity (similar to OECD 414), rat: NOAELmaternal ≥ 410 mg/kg bw/day; NOAELdevelopmental ≥ 410 mg/kg bw/day

Prenatal developmental toxicity (similar to OECD 414), rabbit: NOAELmaternal ≥ 217 mg/kg bw/day; NOAELdevelopmental ≥ 217 mg/kg bw/day

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
217 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
The available information comprises studies which each alone are regarded insufficient for assessment from a reference substance with similar structure and intrinsic properties. Read-across is justified based on structural similarities of the calciumphosphate compounds and their similarities in PC/ECO/TOX properties (refer to read across justification for further details). However, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex X, 8.7.2, of Regulation (EC) No 1907/2006.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

There are currently no experimental data available to assess developmental toxicity / teratogenicity for calcium hydrogenorthophosphate.

 

For the structural similar substance calcium dihydrogenorthophosphate monohydrate (CAS 10031 -30 -8) three studies are available which were done before guidelines were available (Morgareidge, 1974). These studies were conducted similar to OECD 414 in three different species - mice, rats and rabbits. Although the report is not as detailed as required according to todays standards these three studies are considered reliable in order to assess the developmental toxicity of calcium dihydrogenorthophosphate monohydrate. A reason for the dosage levels are not given which in fact are considered too low since no maternal toxicity was observed. But since the tests were conducted in three different species and in none of these studies developmental effects were observed these studies are considered as reliable on the basis of weight of evidence. 

Mice: Adult female albino CD-1 mice were mated with young adult males. Observation of a vaginal sperm plug was considered as Day 0 of gestation. Dosing by oral intubation with a control (vehicle at level equivalent to group receiving the highest) or test article in a water suspension (10 mL/kg bw) at 4.65, 21.6, 100.0 and 465.0 mg/kg bw was carried out daily on Days 6 to 15 of gestation. Observations of body weight, appearance, behaviour, and food consumption were performed. On Day 17 of gestation all dams underwent Caesarean section. Implantation sites, resorption sites and live/dead foetuses as well as body weights of live pups were recorded. Urogenital tract of each dam were examined for anatomical normality. All foetuses examined grossly for presence of external congenital abnormalities. One third of the foetuses of each litter underwent detailed visceral examination and the remaining two thirds were cleared in potassium hydroxide, stained with alizarin red S dye and examined for skeletal defects. No deaths and no abortion were observed. One full resorption in the highest dose was found which is considered to be a spontaneous occurrence. An increase in incomplete ossification of the sternabrae and extremities were observed but not considered treatment-related since it seems not to be dose-related. The total number of resorptions, number of dams with 1 or more resorption sites and number of dead fetuses was increased in the low dose group and at the two highest concentrations applied. However, due to missing dose-response and considering the fact that no similar effect was observed in rats, the effect is considered rather spontaneous than treatment-related. The administration of up to 465 mg/kg bw of the test material to pregnant mice for 10 consecutive days had no clearly discernible effect on nidation or on maternal 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.

 

Rats: Adult female albino (Wistar derived stock) rats were mated with young adult males. Observation of a vaginal sperm plug was considered as Day 0 of gestation. Dosing by oral intubation with a control (vehicle at level equivalent to group receiving the highest dose) or test article in a water suspension at 4.1, 19.1, 88.5 and 410.0 mg/kg was carried out daily on Days 6 to 15 of gestation. Observations of body weight, appearence, behaviour, and food consumption were performed. On Day 20 of gestation all dams underwent Caesarean section. Number of implantation sites, resorption sites and live/dead foetuses as well as body weights of live pups were recorded. Urogenital tract of each dam examined for anatomical normality. All foetuses examined grossly for presence of external congenital abnormalities. One third of the foetuses of each litter underwent detailed visceral examination and the remaining two thirds were cleared in potassium hydroxide, stained with alizarin red S dye and examined for skeletal defects. No deaths, abortions or full resorption were observed. An increase of wavy ribs in the highest tested dose was observed. This effect was not dose-related and considered not treatment related. One foetus of the lowest dose group had a hydrocephalus which is also considered as a spontaneous occurrence. The administration of up to 410 mg/kg bw of the test material to pregnant rats for 10 consecutive days had no clearly discernible effect on nidation or on maternal 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.

 

Rabbits: Adult female Dutch-belted rabbits were dosed on Day 0 with a single injection of 0.4 mL human chorionic gonadotropin (400 IU) via the marginal ear vein. After three hours each doe was artificially inseminated with 0.3 mL diluted semen from a donor buck using 20E06 motile sperm. Dosing by oral intubation with a control (vehicle at level equivalent to group receiving the highest dose) or test article in a water suspension (10 mL/kg bw) at 2.17, 10.10, 46.7 and 217.0 mg/kg was carried out daily on Days 6 to 18 of gestation. Observations of body weight, appearance, behaviour, and food consumption were performed. On Day 29 all does underwent Caesarean section. Number of corpora lutea, implantation sites, resorption sites and live/dead foetuses as well as body weights of live pups were recorded. Urogenital tract of each dam examined for anatomical normality. All foetuses examined grossly for presence of external congenital abnormalities. Live foetuses of each litter were then placed in an incubator for 24 hours for evaluation of neonatal survival. All pups underwent detailed visceral examination. All foetuses were cleared in potassium hydroxide, stained with alizarin red S dye and examined for skeletal defects. In all groups except the highest dose group animals died during the study. It is also not clear why different group sizes were used which resulted in fewer than 16 rabbits with implantation sites for observation. There were 12, 12, 17, 10 and 10 for control group, 2.17, 10.10, 46.7, and 217 mg/kg bw group, respectively. Two animals died during treatment in the control group and 2.17 mg/kg bw group, 5 in the 10.10 mg/kg bw group and one in the 46 mg/kg bw group but none in the highest dose group. No reasons for these deaths were given in the study report. A decrease in the average number of corpora lutea was observed. However, due to missing dose-response and comparable number of implantation sites and number of fetuses, a treatment-related effect is not considered. No obvious effects in skeletal or visceral malformation were observed. The administration of up to 217 mg/kg bw of the test material to pregnant rabbits for 13 consecutive days had no clearly discernible effect on nidation or on maternal 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.

 

Since all studies performed with the structural analogue calcium dihydrogenorthophosphate monohydrate miss detailed description of effects a weight of evidence evaluation is performed. In all three studies no recurring effects were observed. Therefore, it is considered that calcium hydrogenorthophosphate also does not have a teratogenic potential. It is not considered to be scientifically justified to further investigate the effects of calcium hydrogenorthophosphate on developmental toxicity and as such no classification on developmental toxicity is proposed and no further studies are deemed necessary.

Justification for classification or non-classification

The available data indicate that calcium hydrogenorthophosphate does not meet the classification criteria for reproductive toxicity in accordance with Regulation (EC) No 1272/2008 (CLP) and the Globally Harmonized System of Classification and Labelling of Chemicals (GHS).