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Administrative data

Key value for chemical safety assessment

Effects on fertility

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

There are no studies available for "Reaction product of thermal process between 1000°C and 2000°C of mainly aluminium oxide and calcium oxide based raw materials with at least CaO+Al2O3 >80% , in which aluminium oxide and calcium oxide in varying amounts are combined in various proportions into a multiphase crystalline matrix". As the substance is an UVCB substance with aluminium oxide (Al2O3) and calcium oxide (CaO) as main constituents, data from aluminium and calcium compounds were taken into account by read across following a structural analogue approach.

In terms of hazard assessment of toxic effects, available data on the toxicity to reproduction/development of other aluminium compounds was taken into account by read-across following a structural analogue approach, since the pathways leading to toxic outcomes are likely to be dominated by the chemistry and biochemistry of the aluminium ion (Al3+) (Krewski et al., 2007).

In addition CaO in aqueous media dissociated forming calcium cations and hydroxyl anions, which following oral administration are neutralised in the GI tract and are therefore not relevant for consideration of systemic toxicity. Therefore for assessment of any systemic effects of CaO following administration via the oral route, the calcium ion Ca2+is the chemical species of interest.

 

Animal Studies

 

An adequate two-generation study available to support a rigorous hazard assessment of the developmental effects of aluminium is not available. However, according to REACH, data from existing studies and other OECD Test Guidelines can be used in combination to fulfil the information requirements provided that their suitability (reliability, relevance, adequacy) for use (ECHA, 2008; Chapter 7 a, p.369) has been ascertained. Currently, two GLP studies on reproductive/developmental toxicity of aluminium compounds are available.

A 2-generation study with "Reaction product of thermal process between 1000°C and 2000°C of mainly aluminium oxide and calcium oxide based raw materials with at least CaO+Al2O3 >80%, in which aluminium oxide and calcium oxide in varying amounts are combined in various proportions into a multiphase crystalline matrix" has not been conducted.

In the Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test with theacross substance aluminium chloride basic (CAS No:1327-41-9), no adverse effects on reproductive behaviour, mating criteria and histological structure of examined reproductive organs in males and females of rats. On the other hand calcium oxide ultimately dissociates into Ca2+ and OH-. Calcium, as an essential and abundantly available mineral nutrient, is not toxic to reproduction/fertility. OH- is neutralised in body fluids, hence not relevant in terms of toxicity to reproduction/fertility.

Since CaO is systemically non-toxic and Al2O3 is practically not bioavailable, any effect of "Reaction product of thermal process between 1000°C and 2000°C of mainly aluminium oxide and calcium oxide based raw materials with at least CaO+Al2O3 >80%, in which aluminium oxide and calcium oxide in varying amounts are combined in various proportions into a multiphase crystalline matrix" on reproductive parameters can be precluded.

On the basis of the above exposed a Two-Generation Reproductive Study (OECD guideline 416) with "Reaction product of thermal process between 1000°C and 2000°C of mainly aluminium oxide and calcium oxide based raw materials with at least CaO+Al2O3 >80%, in which aluminium oxide and calcium oxide in varying amounts are combined in various proportions into a multiphase crystalline matrix" is not considered necessary and shall be omitted for reasons of animal welfare.

 

Available information on toxicity to reproduction of aluminium and calcium compounds was taken into account as supporting information.

Read-across from aluminium compounds:

In a GLP study, Beekhuijzen (2007)evaluated the effects of aluminium chloride (basic) (CAS# 1327-41-9) on early postnatal development in rats in a test study performed in accordance with OECD Test Guideline #422. Aluminium chloride (basic) was administered daily by gavage to male and female Wistar rats at doses of 0, 40, 200, 1000 mg/kg/day which contribute 0, 3.6, 18, and 90 mg Al/kg bw/day, respectively. Males were exposed to aluminium for 28 days, 2 weeks prior to mating, during mating, and up to termination; females were exposed for 37 to 53 days, 2 weeks prior to mating, during mating, during pregnancy and up to at least 3 days of lactation. Clinical signs of intoxication, mortality, body weights, food and water consumption, and reproduction process were recorded in both sexes. In addition, haematological and clinical biochemistry analyses were performed on both sexes at the end of study, together with macroscopic and microscopic examinations of the brain, thoracic and abdominal tissues and organs with special attention to the reproductive organs. Gross lesions were recorded for the cervix, clitoral gland, ovaries, uterus, and vagina in all female animals and the coagulation gland, epididymides, prepupital gland, prostate gland, seminal vesicles, and testes in all male animals. Body weights and the weights of the adrenal gland, brain, epididymides, heart, kidneys, liver, spleen, testes and thymus were recorded for 5 animals from each group and sex. For each exposed group the following reproduction parameters were calculated: mating percentage (number of females mated x100/number of females paired); fertility index (number of pregnant females x100/number of females paired ); conception rate (number of pregnant females x100/number of females mated); gestation index (number of females bearing live pups x100/number of pregnant females); duration of gestation (number of days between confirmation of mating and the beginning of parturition); percentage of live males at first litter check (number of live male pups at first litter check x100/number of live pups at first litter check); percentage of live females at first litter check (number of live female pups at first litter check x100/number of live pups at first litter check); percentage of post-natal loss days 0 to 4 post-partum (number of dead pups on day 4 postpartum x100/number of live pups at first litter check) and viability index (number of live pups on day 4 postpartum x100/number of live pups at first litter check). The individual weights of all live pups on days 1 and 4 of lactation were measured and the sex of all pups determined by measuring the ano-genital distance. For offspring, clinical signs of intoxication and behavioural abnormalities were observed daily during at least 4 days of lactation.

No effects on developmental parameters in foetuses and offspring (growth, early development and survival) exposed to aluminium chloride (basic) at doses 3.6, 18 and 90 mg Al/kg bw/day were reported. The NOAEL for reproductive toxicity (lack of effects on early development) proposed by the authors was 90 mg Al/kg bw/day. A Klimisch Score of 2 was assigned to this study.

A GLP study (”One year developmental and chronic neurotoxicity study of aluminium citrate in rats”, ToxTest TEH-113, 2010, GLP, OECD 426 and OECD 452),was designed “to develop data on the potential functional and morphological hazards to the nervous system that may arise from pre-and post-natal exposure to aluminium citrate”. Pregnant Sprague-Dawley dams (n=20 per group) were administered aqueous solutions of aluminium citrate at 3 dosage levels (nominal - 30, 100 and 300 mg Al/kg bw/day. Two control groups received either a sodium citrate solution (citrate control with 27.2 g/L) or plain water (control group). The Al citrate and Na-citrate were administered to dams ad libitum via drinking water from gestation day 6 until weaning of offspring. Litter sizes were normalized (4 males and 4 females) at postnatal day (PND) 4. Weaned offspring were dosed at the same levels as their dams. Male and female rats sacrificed at PND 23. Endpoints and observations in the dams included water consumption, body weight, a Functional Observational Battery (FOB), morbidity and mortality. Endpoints were assessed in both female and male pups that targeted behavioural ontogeny (motor activity, T-maze, auditory startle, the Functional Observational Battery (FOB) with domains targeting autonomic function, activity, neuromuscular function, sensimotor function, and physiological function), cognitive function (Morris swim maze), brain weight, clinical chemistry, haematology, tissue/blood levels of aluminium and neuropathology at the different dose levels.

There were no significant Al-citrate treatment-related effects on mean body weights observed in the dams during the gestation and postnatal periods. The Na-citrate group, however, was significantly lighter than the control group on PND 15 (7.3%; p=0.0316). Eight dams in the high dose aluminium group were found to have diarrhoea compared with none in the other treatment groups. The low and mid-dose Al-citrate groups consumed more water than the control group but the high dose group did not, suggesting that the effect was not simply due to treatment. There were no significant treatment-related differences in gestational length. There were no consistent treatment-related effects observed for the FOB tests in the dams. 

In the female pups, Na-citrate and high dose groups had significantly lower pre-weaning body weights than the control (control versus Na-citrate, p<0.0001; control versus high dose, p=0.0072). In the male pups, the control group mean body weights were significantly greater than the Na-citrate group (p<0.0001) and also significantly greater than the high dose group (p=0.0051). The mid-dose group mean body weight was significantly greater than the Na-citrate group (p=0.0405). In the female pups, the mean number of days to reach vaginal opening was 31.3 (±2.1, SD) in the control group and 39.7 (±5.6, SD) in the high dose Al-citrate group, a significant difference (p<0.0001). In males, the mean number of days to reach preputial separation was 39.6 (±2.1, SD) in the control group and 42.5 (±3.2, SD) in the high dose group, also a significant difference in the pair-wise comparisons (p<0.0001). FOB observations showed no clear treatment-related effect among the neonatal pups that were assessed at PND 5 and 11 or in the juvenile pups assessedca.PND 22. No consistent treatment-related effects were observed in ambulatory counts (motor activity) and no significant effects were observed for the auditory startle response, T-maze tests (pre-weaning Day 23 cohort). Haematology parameters showed no significant treatment-related effects in the Day 23 cohort. Serum biochemistry changes associated with aluminium toxicity such as elevated alkaline phosphatase were observed at PND 23. The authors state the levels remained within the normal range. Whole body Al levels in neonatal pups from high dose females and males were greater than those in the control groups. There were no significant sex differences. Concentrations of Al in bone showed the strongest association with Al dose and some evidence of accumulation over time in all of the Al-treated groups. Of the central nervous system tissues, Al levels were highest in the brainstem. Although levels of Al were relatively low in the cortex (< 1µg/g), they were positively associated with Al levels in the liver and femur.  

The study showed no treatment related effects of Al-citrate on maternal body weight, neurobehavior and gestational length. No dose and treatment-relevant effects of Al-citrate on neuromotor maturation and neurobehavioral activity, learning and memory, haematological and clinical biochemistry parameters, post-mortem structure of the internal organs followingin-uteroand lactation exposure were observed. Delayed development of both male and female pups was observed in the high dose Al-citrate group and also in the Na-citrate group. The effect is considered treatment-related but whether the effect is secondary to decreases in body weight is not clear. In addition, as an effect was observed in the Na-citrate group, the role of aluminium in causing this effect can not be concluded (nor excluded). Reported results suggest the possible transfer of Al from dams to pupsin- utero, although a contribution from breast milk PND 0 to 4 is also possible.

Neurodevelopmental Deficits

Neurodevelopmental deficits have been reported in both mice and rats exposed via the oral route to aluminium at different life stages. The most commonly observed effects included decreased grip strength (Golub et al., 1992; 1995, Golub and Keen, 1999), reduced temperature sensitivity (Donald et al., 1989; Golub et al., 1992), reduced auditory startle responsiveness (Mishawa and Shigeta, 1993; Golub et al., 1994) and impaired negative geotaxis response (Bernuzzi et al., 1986; 1989; Muller et al., 1990; Golub et al., 1992). Decreased locomotor coordination, general motor activity level and impaired righting reflex have also been reported (Bernuzzi et al., 1986; Cherroret et al., 1992; Misawa and Shigeta, 1993). However, no treatment-related effects on locomotor activity and auditory startle response were reported in weanling male and female rats at the end of the lactation period following prenatal and postnatal (lactation) exposure to Al citrate (ToxTest, TEH-113, 2010). In the same study, no Al-citrate treatment-related effects were observed in the Functional Observational Battery tests performed on male and female rats at PND 5 and 11 (during the neonatal period) and on PND 22 (as juvenile pups).

Human Studies

There are few human studies on the reproductive/developmental effects of ingested aluminium compounds. Several case studies have focused on children and pre-term infants receiving parenteral nutrition. A detailed discussion of these human case studies is presented in the comprehensive reviews by Krewski et al.(2007) and ATSDR (2008). 

Gilbert-Barness et al. (1998) reported the case of a girl who, at the age of 4 months, was diagnosed with severe mental retardation. A high Apgar score was allocated to the girl at birth and there was no recorded neonatal distress. Autopsy at age 9 revealed CNS cortical atrophy, small basal ganglia, and hypomyelination of the spinal cord, cerebral cortex, subcortex and cerebellar white matter. Later it was found that the mother had taken an average of 75 Maalox tablets (containing 200 mg of aluminium hydroxide per tablet) each day during pregnancy. It was suggested that the high levels of aluminium intake by the mother, during critical periods of the foetus’ brain development resulted in neurological damage to the infant (Krewski et al., 2007).

Bishop et al. (1997) reported that the Bayley index was significantly lower in the 39 pre-term infants who received more than 10 days of intravenous feeding of the standard solution than in the 41 pre-term infants who received more than 10 days of intravenous feeding of the Al-depleted solution. The standard and aluminium-depleted solutions delivered median daily aluminium intakes of 187 and 28μg respectively.

No statistically significant adverse pregnancy outcomes were observed in women accidentally exposed to high concentrations of aluminium sulphate in drinking water (concentrations were not specified in the paper) in northern, (Golding et al., 1991). The authors compared pregnancy outcomes in the affected area (n=68) after the incident with outcomes in a neighbouring unaffected area (n=193). Except for a statistically significant increased prevalence of children showing talipes (4 cases vs. one control from the same area; p=0.014), no exposure-related effects of aluminium were found with regard to perinatal deaths, low birth weight, preterm delivery, or severe congenital malformations. No follow-up studies have been conducted to investigate the possible long-term developmental effects in children born to mothers who were exposed to the high aluminium concentrations during pregnancy.

Overview of Epidemiological and Toxicological Studies on aluminium compounds

 

Studies of soluble aluminium compounds are relevant to this hazard assessment if it is assumed that, following oral exposure, the targeted aluminium compounds are solubilised in the gastrointestinal tract (GIT) in the presence of stomach and organic acids and that Al3+is an active moiety for systemic effects; it is recognized that the bioavailability of the sparingly soluble target compounds might be an order of magnitude less than these more soluble aluminium salts (Priest, 2010).

 

Read across from calcium compounds

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 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 in daily food intake. However, with respect to the potential hazards of calcium for reproduction it should be noted that calcium cations and hydroxyl anions which are formed in aqueous media from calcium oxide are physiologically essential elements and nutrients for all mammals including humans.

Supportive information is available in section 7.12 on the technical dossier (Han, 2000) showing that calcium has a protective effect against lead accumulation and their offspring. Moreover Mortimer (1988, section 7.12 of the technical dossier) showed that calcium is essential for the function of human spermatozoa (acrosome reaction). In fact it was shown that calcium has a beneficial effect on reproductive performance.

 


Short description of key information:
Read-across from Aluminium compounds:
-Beekhuijzen, 2007
[Al chloride (basic), rats, Klimisch Score 2]
NOAEL is > 90 mg Al/kg (rat, male, female, lack of pre-natal and neonatal developmental toxicity)

Effects on developmental toxicity

Description of key information
Read-across from Aluminium compounds:
-Gomez et al.(1990) [Al hydroxide, rat, Klimisch Score 2]
NOAEL is > 266 mg Al/kg ( rat, relevant embryotoxic and teratogenic effects)
Read-across from Calcium compounds:
Bailey et al., 1974 [Calcium oxide (FDA 73-41), rat/mouse]
NOAEL (rat) = 680 mg/kg bw/day
NOAEL (mouse) = 440 mg/kg bw/day
Additional information

There are no studies available for "Reaction product of thermal process between 1000°C and 2000°C of mainly aluminium oxide and calcium oxide based raw materials with at least CaO+Al2O3 >80% , in which aluminium oxide and calcium oxide in varying amounts are combined in various proportions into a multiphase crystalline matrix"

As the substance is an UVCB substance with aluminium oxide (Al2O3) and calcium oxide (CaO) as main constituents, data from aluminium and calcium compounds were taken into account by read across following a structural analogue approach.

 

Read-across from aluminium compounds:

In terms of hazard assessment of toxic effects, available data on developmental toxicity/teratogenicity of aluminium compounds was taken into account by read-across following a structural analogue approach, since the pathways leading to toxic outcomes are likely to be dominated by the chemistry and biochemistry of the aluminium ion (Al3+) (Krewski et al., 2007).

Five developmental toxicity studies are available on aluminium hydroxide in mice and rats.

Domingo et al. (1989) investigated the embryotoxic and teratogenic potential of Al(OH)3administered orally to pregnant Swiss mice. Mated female mice (20 animals per group) were administered (oral, gavage) 0, 66.5, 133 or 266 mg Al (OH)3/kg bw/day (equivalent to 23, 46, and 92 mg Al/kg bw/day) from gestation day 6 through 15. Dams were sacrificed on gestation day 18. No sign of maternal toxicity was observed in any group based on changes in maternal weight gain, food consumption and gross signs of abnormalities at post-mortem examination. The number of total implantations, the foetal sex ratio, body weights and lengths of foetuses were not significantly affected at any of the administered doses of aluminium hydroxide. The number of early resorptions/litter was increased in all Al (OH)3 treated groups (3.0 - in the 23 mg Al/kg group, 2.4 - in the 46 mg Al/kg group, and 1.3 – in the 133 mg Al/kg group versus 0.4 in the control group) and the number of live foetuses decreased in all groups (11.1 in the control group, 9.4 in the 23 mg Al/kh group, 9.2 in the 46 mg Al/kg group and 9.8 in the 92 mg Al/kg group) (n=18-20 litters per group). Observed effects were not considered as treatment related effects as there was no dose-response relationship observed. The Al-treated foetuses did not exhibit any marked differences in external malformations, internal soft-tissue or skeletal abnormalities compared to the controls. Suggested NOAEL is 266 mg Al/kg (lack of embryo/fetal toxicity or teratogenicity). The authors suggested that the lack of developmental toxicity of Al(OH)3 was likely due to lower gastrointestinal absorption of this compound compared with other forms of aluminium. 

 A similar study was conducted by Gomez et al. (1990) in rats. Aluminium hydroxide was administered by gavage (2 times, daily) to pregnant Sprague-Dawley rats at dose levels of 192 (n=18 animals per group), 384 (n=18 animals per group) and 768 (n=10 animals per group) mg/kg (equivalent to 66.5, 133 and 266 mg Al/kg bw/day, respectively) from day 6 through 15 of gestation. The animals were killed on day 20 of gestation. No adverse effects were reported on animal appearance, behaviour, maternal body weight, or absolute and relative organ weight (uterine, kidney and liver). No differences were observed for haematological and biochemical parameters but detailed results for these outcomes were not provided in the publication. Although not statistically significant, the incidence of early resorptions was higher in all Al (OH)3-treated groups than in the control group (0.4 - in the 46 mg Al/kg group, 1.3 - in the 92 mg Al/kg group, and 0.6 – in the 266 mg Al/kg group versus 0.0 in the control group). Increased post-implantation loss (%) was observed compared to the control group(3.6 - in the 46 mg Al/kg group, 12.5 - in the 92 mg Al/kg group, and 5.0 – in the 266 mg Al/kg group versus 0.6 in the control group). Observed changes were not considered as treatment related effects because no relationship to dose was observed. Increased post-implantation loss (2.2 times compared to the control group) was observed only in the dose 92 mg Al/kg group. Statistically significant decrease in maternal food consumption was not associated with decreased maternal body weight and no dose-response relationship was found. No Al-treatment related effects were observed on critical gestational parameters such as number of litters, corpora lutea, number of total implantations, number of live foetuses, sex ratio, or foetal body weight at any dose administered. During foetal examination, no external and visceral abnormalities or skeletal malformation was detected. No significant differences in placental concentrations of aluminium were observed between the different groups. Suggested NOAEL is 266 mg Al/kg bw/day (lack of embryo/fetal toxicity or teratogenicity).

The influence of citric acid on the embryonic and/or teratogenic effects of high doses of Al(OH)3in rats was investigated by Gómez et al. (1991). Three groups of pregnant rats were administered daily doses (gavage) of Al(OH)3(384 mg/kg bw/day, equal to 133 mg Al/kg bw/day , n=18), aluminium citrate (1064 mg/kg bw/day, n=15), or Al(OH)3(384 mg/kg bw/day, equal to 133 mg Al/kg bw/day) concurrently with citric acid (62 mg/kg bw, n=18) on gestational days 6 to 15. A control group received distilled water during the same period (n=17). There were no treatment-related differences on critical gestational parameters such as numbers of litters, corpora lutea, number of total implantations, number of live foetuses, sex ratio, or foetal body weight in the group treated with Al(OH)3. No external and visceral abnormalities or skeletal malformation were detected on foetal examination. Maternal and foetal body weights were significantly reduced, the number of foetuses with delayed sternabrae and occipital ossification was significantly increased (p<0.05), the number of foetuses with absence of xiphoides was increased in the group treated with Al(OH)3and citric acid as compared to the control group. No significant differences in the number of malformations were detected between any of the groups (authors did not provide the quantitative data). 

Colomina et al. (1992) evaluated the influence of lactate on developmental toxicity attributed to high doses of Al(OH)3in mice. Oral (gavage) daily doses of Al(OH)3(166 mg/kg bw, n=11), aluminium lactate (627 mg/kg b, n=10), or Al(OH)3(166 mg/kg bw) with lactic acid (570 mg/ kg bw, n=13) were administered to pregnant mice from gestational day 6 to 15. An additional group of mice received lactic acid alone (570 mg/kg bw). A control group (n=13) received distilled water during the same period. No signs of maternal toxicity (no statistically significant changes in food consumption, maternal body and organ weight) were observed in the dams treated with Al(OH)3. No statistically significant treatment-related differences oncritical gestational parameters such as number of litters, corpora lutea, number of total implantations, number of live foetuses, sex ratio, or foetal body weight were observed in the Al (OH)3-treated group and no external abnormalities or skeletal malformation were detected on foetal examination. However, aluminium concentrations were significantly higher in the bones of dams, and aluminium was detected in the whole foetus of the Al(OH)3-treated animals. Concurrent administration of Al(OH)3and lactic acid resulted in significant reductions in maternal weight compared to the control group. In the group given lactate only, aluminium was detected in whole foetuses; however, this was not statistically different from the mean level found in the control group. Aluminium lactate administration resulted in significant decreases in maternal body weight and food consumption, foetal body weight accompanied by increases in the incidence of cleft palate. Delayed ossification was also observed in the aluminium lactate-treated animals. Although not statistically significant, the incidence of skeletal variations was higher in the group concurrently administered Al (OH)3and lactic acid than in the control group. No other signs of developmental toxicity were detected in the Al (OH)3and lactic acid group.

In a similar experiment, Colomina et al. (1994) assessed the effect of concurrent ingestion of high doses of Al(OH)3and ascorbic acid on maternal and developmental toxicity in mice. Three groups of pregnant mice were given daily doses (gavage, 2 times daily) of Al(OH)3(300 mg/kg bw or 103.8 mg Al/kg), ascorbic acid (85 mg/kg bw), or Al(OH)3 concurrent with ascorbic acid (85 mg/kg bw) from gestational day 6 to day 15. A fourth group of animals received distilled water and served as the control group. The animals were killed on gestation day 18. The number of litters, corpora lutea, number of total implantations, number of live foetuses, sex ratio, and foetal body weight did not differ between the control and Al(OH)3-treated groups. No external and visceral abnormalities or skeletal malformations were detected on foetal examination. Placenta and kidney concentrations of aluminium were significantly higher in mice receiving Al(OH)3 and Al(OH)3 plus ascorbic acid than in controls. No information was provided on the number of dams and litters in the Al-treated and control groups.

In summary, available studies indicate that aluminium hydroxide did not produce neither maternal nor developmental toxicity when it was administered by gavage during the critical period of embryogenesis (GD 6-15) to mice at doses up to 92 mg Al/kg bw/day (Domingo et al., 1989) or to rats at doses up to 266 mg Al/kg bw/day (Gomez et al., 1990). The developmental toxicity of aluminium following the oral route of exposure is highly dependent on the form of aluminium and the presence of organic chelators that influence bioavailability.

For all the studies with aluminium hydroxide, dose administration was by gavage, which would be expected to result in higher blood levels than dietary administration or administration via the drinking water, and very high dosages were used (ca. 200 – 2000x normal human exposure). Part of the reason for using such high dosages was the low solubility and bioavailability of aluminium hydroxide and the limited sensitivity of available analytical methods to determine small changes from endogenous levels of aluminium. However, the achieved dose of aluminium in maternal plasma was not measured in any of the studies reviewed. In the studies with aluminium administered in the diet or drinking water, dosages were generally identified in terms of the target dose, e.g. 1000 µg Al/g diet, without calculation of the actual dose administered based on the food or water consumption. Further, for the majority of the studies, there was no assessment of the background levels of aluminium in the food and water provided for the animals.

These factors generally lead to the conclusion that the dosages used in reproductive toxicity studies to date have been much greater than those that would be encountered in the human consumer or worker situation. In addition, the actual dose administered has usually been under-estimated because background aluminium levels in the diet and drinking water provided for the animals have not been taken into account. 

None of the studies on aluminium hydroxide showed any clear evidence of dose related developmental toxicity despite using daily dose levels up to 2000 fold higher than the normal aluminium levels of intake. Since bioavailability studies have shown that the absorption of aluminium oxide is less than that of aluminium hydroxide, it is unlikely that these would show any evidence of developmental toxicity at similar dose levels (Sullivan, 2010).

 

 

Read-across from calcium compounds:

The developmental toxicity of FDA 73-41 (Calcium oxide) was evaluated in mice and rats in a GLP study performed comparable to the OECD Guideline 414 (Bailey et al., 1974). Calcium oxide was administered by gavage to 5 groups of CD-1 mice from gestation days (GD) 6 to 15 at daily doses of 0, 4.4, 20.4, 94.8, and 440 mg/kgbw/day. In a second experiment the test item was administered by gavage to 5 groups of Wistar rats from gestation days (GD) 6 to 15 at daily doses of 0, 6.8, 31.5, 146.5, and 680 mg/kg bw/day. In both experiments day 0 of pregnancy was designated as the day of confirmed mating. The administration of Calcium oxide up to 440 mg/kg bw/day to pregnant mice and up to 680 mg/kg bw/day to pregnant rats for 10 consecutively 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.

Therefore, the NOAEL for developmental toxicity for mice was found to be 440 mg/kg bw/day and the NOAEL for rats was found to be 680 mg/kg bw/day.

Further pre-natal developmental toxicity studies establishing a dose- response relationship of potential adverse effects of calcium after oral administration of calcium carbonate to rats and mice were identified (Shackelford et al., 1993). The design of these three studies was comparable to the OECD guideline 414. In all studies no adverse developmental, foetotoxic or teratogenic effects were noticed up to and including the highest dose levels tested. These studies allow the derivation of a NOAEL value for developmental effects of calcium.

From the study on rats given CaCO3 in feed (Shackelford et al., 1993) the highest dose of 1.25 % Ca is established as the NOAEL for developmental effects, corresponding to a daily dose of 938 mg Ca/kg bw/day.

Lack of developmental/teratogenic effects or even beneficial effects of calcium supplementation on foetal development is further supported by human data [RA-A, CaCO3, supporting, Villar et al., 1990, medical monitoring (developmental toxicity / teratogenicity), general population, RL2; RA-A, CaCO3, supporting, Levine et al., 1997, medical monitoring (developmental toxicity / teratogenicity), general population, RL2; RA-A, CaCO3, supporting, Koo et al., 1999, medical monitoring (developmental toxicity / teratogenicity), general population, RL2].  

 

Justification for classification or non-classification

Classification and Labelling for Fertility Effects, Developmental Effects or Adverse Health Effects on or via Lactation

Overall, based on the read-across from aluminium and calcium compounds for the toxicity to reproduction or development of "Reaction product of thermal process between 1000°C and 2000°C of mainly aluminium oxide and calcium oxide based raw materials with at least CaO+Al2O3 >80% , in which aluminium oxide and calcium oxide in varying amounts are combined in various proportions into a multiphase crystalline matrix", no classification is required according to DSD or CLP classification criteria.

 

Additional information