Reaction mass of aluminium and aluminium oxide and calcium oxide and magnesium oxide

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Additional information

There is no information availableon the toxicity to reproduction or development of aluminium oxide.

According to the REACh Regulation Annex IX, Section 8.7, Column 2, reproductive toxicity studies do not need to be conducted if the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available), it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure and there is no or no significant human exposure.

The oral biovailability of Al metal is negligible, the acute oral toxicity studies conducted with aluminium oxide have shown no effects and there is no systemic exposure to aluminium metal from its intended uses. The criteria for not conducting reproductive studies are thus fulfilled.

However, 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;).

Overview of Epidemiological and Toxicological Studies

 

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).

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 28 μg respectively.

No statistically significant adverse pregnancy outcomes were observed in women accidentally exposed tohigh concentrations of aluminium sulphate in drinking water (concentrations were not specified in the paper) in northern Cornwall, England(Golding et al., 1991). The authors compared pregnancy outcomesin 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.

Animal Studies

Test guidelines for assessing reproductive endpoints include the Reproductive/Developmental Toxicity Screening study (OECD Test Guideline #421), the combined Repeated Dose Toxicity Study and Reproductive/Developmental Toxicity Screening study (OECD Test Guideline #422), the One–Generation Reproductive Toxicity Study (OECD Test Guideline #415) and the Two–Generation Reproductive Toxicity Study (OECD Test Guideline #416). Of these, only the Two–Generation Reproductive Toxicity Study (OECD Test Guideline #416) provides adequate and complete information (ECHA, 2008, Chapter 7a) to meet the information requirements of REACH for an Annex X substance.

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 GLP study (”One year developmental and chronic neurotoxicity study of aluminium citrate in rats”, ToxTest TEH-113, 2010),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.  

This study was conducted according to GLP with a design based on OECD TG #426. The study used adequate numbers of animals and randomization to reduce bias, assessed endpoints in both female and male offspring, and studied a wide range of neurotoxicity endpoints. Haematology, clinical chemistry, pathology and general toxicity endpoints were also assessed. Three dose levels were used although the highest was close to the MTD. The results from this study are informative for developmental and neurotoxic effects due to prenatal and early postnatal exposure of rats to high doses of aluminium (30 mg Al/kg bw/day, 100 mg Al/kg bw/day and 300 mg Al/kg bw/day).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 pups in utero, although a contribution from breast milk PND 0 to 4 is also possible. A Klimisch Score of 2 was assigned to this study

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[1]. 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.

Results of other developmental toxicity studies in which prenatal, perinatal and/or post-weaning exposure of rats and mice to aluminium (as the hydroxide, chloride (basic), chloride, nitrate, and lactate) in the diet or drinking water were investigated are summarized below. 

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).

Short description of key information:
-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

-Gomez et al.(1990) [Al hydroxide, rat, Klimisch Score 2]
NOAEL is > 266  mg Al/kg ( rat, relevant embryotoxic and teratogenic effects)

Additional information

There is no information availableon the toxicity to reproduction or development of aluminium oxide.

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;).

A few (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)₃treated 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 anomalities 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 ofAl(OH)₃was likely due to lower gastrointestinal absorption of this compound compared with other forms of aluminium. A Klimisch Score of 2 was assigned to this study.

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 anomalities or skeletal malformation was detected. No significant differences in placental concentrations of aluminium were observed between the different groups. A Klimisch Score of 2 was assigned to this study. Suggested NOAEL is 266 mg Al/kg bw/day (lack ofembryo/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 oncritical gestational parameters such as numbers of litters, corpora lutea, number of total implantations, number of live foetuses, sex ratio, or foetal body weightin 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). A Klimisch Score of 2 was assigned to this study.

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 observedin the Al (OH)₃-treated group andno 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 theAl (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 administerd 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. A Klimisch Score of 2 was assigned to this study.

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)₃concurrent 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. Thenumber of litters, corpora lutea, number of total implantations, number of live foetuses, sex ratio, and foetal body weightdid 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)₃and Al(OH)₃plus ascorbic acid than in controls. No information was provided on the number of dams and litters in the Al-treated and control groups. A Klimisch Score of 2 was assigned to this study.

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.

Weight of Evidence for Reproductive/Developmental Effects in Humans

Epidemiological studies of the effects of oral exposure to aluminium or its compounds on reproductive (developmenta) outcomes have not been conducted. The evidence from human studies is insufficient.

It is assumed that the aluminium ion, Al³⁺, is “the biologically active moiety” once the target substances are absorbed (following inhalation, ingestion or dermal contact)and “…likely to be similar or follow a similar pattern as a result of the presence of a common metal ion (or ion complex including a hydrated metal ion)” (Guidance on Grouping of Chemicals, OECD, 2007)[1].The cumulative weight of evidence based on the extensive database from animal studies examining various effects of soluble aluminium compounds on reproduction is modest. 

No reproductive toxicity studies are available for on the developmental toxicity of aluminium oxide or aluminium metal. Five studies on the developmental toxicity of aluminium hydroxide are available (Domingo et al., 1989; Gomez et al., 1990, 1991; Colomina et al., 1992, 1994). No clear evidence of dose-related developmental toxicity available based on these studies.

The weight of evidence for the association between exposure to aluminium metal, aluminium oxide and aluminium hydroxide and developmental toxicity in humans is limited.

 

Inhalation Exposure

Overview of Epidemiological and Toxicological Studies

 

Aluminium metal, aluminium oxide and aluminium hydroxide

Human Studies

The effects of inhaled aluminium metal, aluminium oxide and aluminium hydroxide on reproductive/developmental outcomes have not been investigated directly in epidemiological studies.

Mur et al. (1998) reported a higher birth-rate among 692 French aluminium potroom workerswho had always worked as potroom workersthan among a control group of 588 maleblue-collarworkers who were employed in maintenance operations in the same 11 facilities. The control group had never worked in potrooms.Eligibility criteria to enroll in the study included: French nationality (to avoid cultural differences in sexual habits), marriage after entering the company (to ascertain the number of children born after the start of occupational exposure), and a length of employment of at least 1 year in the company, without any major change in the type of activity.The fertility data of the workers were obtained exclusively from the administrative files of the company. Based on the date of birth of the last child (dates of birth for all the children of each couple were not available), the annual birthrates of each couple after the marriage were calculated by dividing the total number of children of the couple by the number of years between the marriage date and the date of birth of the last child. No significant differences were observed between the ‘exposed’ and ‘control’ groups for the average year of marriage, the average age of the workers and of their spouses at the time of marriage, and the length of employment. Potroom workers were heavier smokers compared to the control group. The average number of live births in the potroom group was greater than that in the ‘control’ group; in addition, the average number of live births in both groups of aluminium industry workers was greater than the national average. After 30 years of marriage, the average numbers of live births were 2.63 (61.34) for the ‘control’ group, and 3.11 (61.74) for the ‘exposed’ group (P<0.05), the reference value for the entire French population being 2.28. The standardized birth ratio (SBR) in the control group was 1.04 (95% CI: 0.98–1.09) and 1.17 (95% CI: 1.12–1.23) in the potroom workers.The birthrate was higher in the exposed than in the unexposed group (birthrate ratio=1.13; p<0.001). The aim of this study was toevaluate the potential effects of occupational exposure to heat and static magnetic fields on male fertility. Exposure to aluminium compounds was not assessed. In addition, it was not possible to take into account a range of non-occupational and socio-economic factors that could influence fertility and birth-rate, for example income level, health status of male workers and their wives, and contraceptive practices. A Klimisch Score of 3 was assigned to this study.

 

Prasad et al. (2002)studied reproductive performance in 160 non-smoking aluminium foundry workers. These workers were engaged in melting aluminium ingots and alloying with magnesium and silicon followed by casting, rolling and coiling of aluminium wire, rods and conductors used for power transmission. The age range of the workers was 20-50 years and the duration of their employment in the factory ranged from 1 to 14 years. The exposed workers were compared with 150 male workers (control group) matched for age, smoking, drinking and socio-economic status with no occupational exposure to any known physical or chemical agents. Information onage, sex, duration of employment, health, medication, type of marriage (whether affinal or consanguineous), and reproductive historywas collected by using a standard questionnaire.The reproductive parameters studied included the number of pregnancies in the workers’ wives, live births, stillbirths, abortions and the number of congenital defects, premature births, and neonatal deaths in their offspring.Air sampling was not undertaken in this study.There was no significant difference in fertility between the exposed and unexposed workers (99.33 versus 99.13, respectively, p<0.05).There was a significant increase in the percentage of abortions (6.60% vs. 3.79%, compared to the control group, P<0.05) and a decrease in the percentage of live births (89.28% vs. 93.94%, compared to the control group, P<0.05) among the workers’ wives and more congenital defects in the offspring of the exposed workers than in the controls (1.03% vs. 0.03%, P<0.05). Although there was an increase in the percentage of stillbirths and neonatal deaths in the offspring of the exposed, this increase was not statistically significant when compared with controls. No premature births were recorded in either the exposed or the control group. The authors mentioned that workers were exposed topolycyclic aromatic hydrocarbons, fluoride, fume of other metals, burnt gases,heat and static magnetic fields and high temperature. However, possible effects of these other hazardous compounds on male fertility were not assessed. Very limited details were provided on the study design and results. In addition, because of possible exposure to a range ofconfounding factors,the contribution of aluminium (from the foundry) to the reported adverse reproductive outcomes is unclear. A Klimisch Score of 3 was assigned to this study.

Hovatta et al. (1998)studied semen parameters (concentration, motility and morphology) and concentrations of aluminium, cadmium and lead in spermatozoa and seminal plasma from a group of workers in a refinery and a polyolefin factory(n=27, mean age 34 years, range 27 to 46 years)and a group of sperm bank donor candidates (n=45, mean age 28 years, range 20 to 45 years).  The authors stated that the factories were located in a rural area of Finland with most of employees residing in the countryside while sperm bank donor candidates came from urban Helsinki. The concentration of aluminium in spermatozoa was lower in the group of employees than in the sperm donor candidates (0.93±0.69 (mean±s.d. mg/kg) compared with 2.52±4.14 mg/kg; p<0.05). There was no significant difference between the groups with respect to aluminium content of seminal plasma. A weak but statistically significant inverse relation (Pearson r =-0.28; p<0.01) was observed between aluminium concentrations in the spermatozoa and sperm motility. A marginally significant inverse relationship was observed between sperm morphology and aluminium levels in the spermatozoa of men in the highest quartile of aluminium concentrations. Cadmium and lead levels did not show any statistically significant correlations with sperm parameters. The authors did not provide details of occupational exposures. Although the study provides some evidence for an association between aluminium levels in spermatozoa and sperm parameters, the small study size, the selected nature of the participants, and the lack of adequate characterization of possibly confounding occupational and environmental exposures limit its usefulness for hazard assessment.A Klimisch Score of 3 was assigned to this study.

 

Dawson et al. (1998) compared the levels of lead, cadmium and aluminium in relation to live sperm in semen samples from 64 healthy21 to 35 year-oldmen.Spearman’s rank correlation between sperm viability and the semen plasma metal levels showed an inverse relation to aluminium (p<0.01).The seminal plasma aluminium concentration was significantly higher in those with low sperm viability. Average concentrations were 1.01, 0.59 and 0.18 mg/L in the 18, 26 and 20 subjects with low, medium and high sperm viability, respectively.A Klimisch Score of 3 was assigned to this study.

Sakr et al. (2010) conducted a cross-sectional survey to examine reproductive outcomes in 710 active workers, both men and women, at a North America aluminium smelter. An anonymous questionnaire was developed to obtain information on the workers including age, level of education, occupational history and reproductive history (e.g., the pregnancies the workers had produced).  Participants were asked about the occupation of their partner during all pregnancies, the outcome of each pregnancy (pregnancy term, single live birth, multiple live birth, ectopic, abortion, spontaneous abortion, stillbirth, and molar), medical conditions experienced by mothers during the pregnancy (hypertension, diabetes, pre-eclampsia or eclampsia, thyroid disorder, systemic lupus, or other), age, smoking, and drinking habits. Normal live birth, miscarriage, live birth with congenital abnormally, and premature birth were selected for the analysis. Congenital anomalies were classified as major (an anomaly of surgical or cosmetic consequence) and minor (an anomaly with a little impact on individual well-being) by a nosologist (level of experience of a nosologist not provided) who was blinded to the employment status at the time of each pregnancy. All jobs at the aluminium smelter based on job titles were grouped into 3 categories: production, administration and laboratory. Random personal industrial hygiene samples for total dust, respirable dust, aluminium oxide, aluminium, asbestos, ammonia ,carbon monoxide, metallic and trivalent chromium, coal tar pitch volatiles as BSM, copper, cyanide (as CN), cyclohexane, fluorides (total), fluoride (particulate), fluoride gas (as HF), magnesium, manganese, metal and compounds, methanol, naphthalene, nickel, nickel compounds, RCF, crystalline silica, sulphur dioxide, and EMF were obtained through personal monitoring in the breathing zone of workers outside of any personal protective equipment.

To assess the occurrence of reported pregnancy outcomes among particular job categories, the authors identified reference groups in which all pregnancies had occurred during the pre-employment period (no details available on the selection and exclusion criteria of the reference groups). For each outcome, the proportion of pregnancies occurring during employment among the reference group was compared. The difference in proportions across employment groups was examined using the Chi square test. Logistical regression was used to account for the potential covariates. Data were stratified by gender. For the analysis of miscarriage, the data were stratified into pre-1999 and post-1999 due to increased awareness among workers in 1999 of the adverse pregnancy outcomes. The significance of the results was reported at P value less than 0.05.

 The overall participation rate for the survey was 85% (621 of 730 workers); a higher proportion of women participated, 94% (106 of 113 workers) compared with 83% (515 of 617 workers) for men. All men and women who reported one or two pregnancies were included in the analysis (343 men and 76 women). The mean age at the time of the survey was 43.7 ± 6.3 years (mean ± SD) for men and 42.6 ± 7.3 for women. Most of men were involved in production-related jobs (80.5%) and 50% of the women held administrative positions. Most men had high school education (53.9%) whereas the majority of women had a college education (61.8%). Cigarette smoking and drinking were more prevalent before employment for both men and women.

The proportion of miscarriages reported by women and men was significantly lower in the pre-1999 than in the post-1999 period (76/759 or 10.01% vs. 37/160 or 23.13%; P<0.0001, respectively). Female workers had higher proportions of miscarriages than the spouses of male workers (34/184 or 18.48% vs. 79/735 or 10.75%, P=0.004, respectively). Working in the laboratory was significantly associated with the occurrence of congenital anomalies (OR, 7.89, CI 95%=1.16-53.77). In women workers, the relationship between premature birth and most of the potential co-factors was not evaluated due to small number of reported cases (Table 3). For spouses of male workers, year of conception was also significantly associated with increased miscarriage (OR, 2.00, CI 95%=1.05 to 3.80 for year of conception after 1999 compared to pre-1999 period). Working in a laboratory was associated with increased miscarriage for male workers but the difference in rate was not statistically significant (OR, 2.48, CI 95%=0.74 to 8.31). For males, work in the production area was significantly associated with premature birth outcomes for their wives (OR, 2.85, CI 95%=1.25-6.49). No statistically significant differences between rates of congenital anomaly in pregnancies fathered by male workers were reported. Overall, the results provide some evidence that both male and female workers of reproductive age and actively employed in the aluminium smelter experienced adverse reproductive outcomes during the period of employment (miscarriages, premature birth outcomes, and congenial abnormality). Prasad et al. (2002) reported increased congenial defects in offspring born to mothers/wives of the Al -exposed male workers employed at the aluminium foundry compared to the control group (P<0.05); however, reported percentages were small (1.03% versus 0.03%, respectively). Since both female and male workers were exposed to other hazardous substances (burnt gases, SO₂, coal-tar pitch volatiles, fluorides, etc.), in the workplace, the possibility that co-exposures to other toxicants resulted in the adverse effects cannot not be excluded. Study limitations include lack of data on the socio-economic status of the participants, previous exposure to hazardous substances, habits with regard to, and/or frequency of, use of contraceptive devices, and occurrence of genetic diseases in the families; also, the limited number of participants decreases the significance of reported findings. A Klimisch score 2 was assigned to this study.

Animal Studies

No adequate animal studies regarding the effect of the target aluminium compounds (aluminium metal, aluminium oxide and aluminium hydroxide) on developmental outcomes from exposure via inhalation were located. 

Other aluminium compounds

No histological changes were observed in reproductive organs and tissues (testes/ovaries, prostate/uterus, seminal vesicle) of Fischer 344 rats (male, female/10 animals per group) Hartley guinea pigs (male, females/10 animals per group) exposed by inhalation to 6.1 mg Al/m³as aluminium chlorhydrate for 6 months, 6 hours per day, 5 days per week (Steinhagen et al., 1978). However, the authors did not examine reproduction function of the Al exposed animals.

Examination of reproductive function in male and female rats exposed by inhalation to 15.6±0.84 mg/m³of aluminium sulphate for 4 months did not reveal gonadotoxic or embryotoxic effects at the end of study (Grekhova et al., 1994).The authors provided only a very brief description of the study design and results which limits its reliability and usefulness for hazard assessment.

 

Oral exposure

It is likely that, once Al³⁺has reached systemic circulation, its distribution is independent of the exposure route; therefore data obtained from studies of reproductive effects following oral exposure can be considered for assessment of this hazard following inhalation exposure. A few (five) developmental toxicity studies are available on aluminium hydroxide in mice and rats. For the exposure situations specified for the inhalation route, the most relevant studies are those in which either the target compounds have been administered (Domingo et al., 1989; Gomez et al., 1990; 1991; Colomina et al., 1992; 1994). A brief description of these studies and results is provided in the oral exposure section.

 

Weight of Evidence for Reproductive Effects in Humans

Epidemiological studies of developmental toxicity associated with inhalation exposure to aluminium oxide, aluminium hydroxide and aluminium metal were not identified.The evidence from human studies is insufficient.

No animal studies were identified that investigated the effects of exposure to the the target aluminium compounds via inhalation on reproductive toxicity (developmental effects). As reproductive toxicity is a systemic effect, results from studies of effects from exposure via the oral route are relevant. Based on the reviewed animal studies, it is concluded that evidence of an association between inhalation exposure to the target aluminium compounds and developmental effectsin both males and femalesis limited.

Overall, the weight of evidence for an effect of inhalation exposure to aluminium on developmental endpoints is insufficient.

 

 

Justification for classification or non-classification

Classification and Labelling

 

According to Regulation (EC) No 1272/2008, classification as a reproductive toxicant is to be based on an assessment of the total weight of evidence. A substantial number of studies using different animal models support the association between oral exposure to Al and developmental effects (Krewski et al., 2007; WHO, 2007; EFSA, 2008; ATSDR, 2008; Health Canada, 2010).

Given that a critical factor influencing developmental toxicity is the concentration of the substance at the actual target site (ECHA, 2008, Chapter 7.12, p.148), “the human health hazard assessment shall consider the toxicokinetic profile (i.e. absorption, metabolism, distribution and elimination, ADME) of the substance” (Annex I, Section 1.0.2.). The occurrence and severity of reproductive effects of ingested aluminium compounds are a function of the bioavailability of the Al ion (Domingo, 1995; Golub & Domingo, 1996; Domingo et al., 2000; Krewski et al., 2007; ATSDR, 2008) and bioavailability is therefore relevant assessing the hazards of the target substances.Gastrointestinal absorption of the water soluble forms of aluminium compounds - aluminium nitrate nonanydate, aluminium chloride, and aluminium citrate - has been shown to be considerably higher than that of the sparingly soluble aluminium oxide, aluminium metal and aluminium hydroxide (Priest 2010).

Five reproductive toxicity studies with aluminium hydroxide were conducted with administration of high doses of aluminium hydroxide via the oral route of exposure. Collectively, these studies provide no clear evidenceof treatment-related developmental toxicity following oral exposure to aluminium hydroxide.A weight of evidence assessment based on the available reproductive toxicity studies with aluminium hydroxide does not support Classification and Labelling (EC No.1272/2008) requirements for developmental toxicity following oral exposure to aluminium hydroxide.

No studies on the reproductive toxicity of aluminium metal or aluminium oxide were located. However, the relatively similar aluminium bioavailability of all three targeted compounds (aluminium hydroxide, aluminium oxide and aluminium metal) following oral administration to laboratory animals (Piest, 2010) suggest that the availability of the aluminium ion for systemic effects will be similar for all compounds and aluminium metal and aluminium oxide also have a low potential to cause adverse developmental effects. 

Classification and Labelling for Adverse Health Effects on or via Lactation

In the current REGULATION (EC) No 1272/2008 on Classification and Labelling (page 109), effects on, or via, lactation are allocated to a separate single category; therein it is stated: “…….substances which are absorbed by women and have been shown to interfere with lactation, or which may be present (including metabolites) in breast milk in amounts sufficient to cause concern for the health of a breastfed child, shall be classified and labelled to indicate this property hazardous to breastfed babies”.

Classification can be assigned on the basis of:

(a) human evidence indicating a hazard to babies during the lactation period; and/or

(b) results of one or two generation studies in animals which provide clear evidence of adverse effects in the offspring due to transfer in the milk or adverse effect on the quality of the milk; and/or

(c) absorption, metabolism, distribution and excretion studies that indicate the likelihood that the substance is present in potentially toxic levels in breast milk (EC, No 1272/2008).

Based on available data, there is evidence to suggest that aluminium absorbed bywomen can interfere with lactation (Yokel, 1984, 1985), and may be present in breast milk in amounts sufficient to cause concern for the healthof a breastfed child. However, currently, no data are available to confidently evaluate the toxicological significance and potential adverse health outcomes of aluminium levels found in breast milk (Krewski et al., 2007, p. 199).  

The magnitude of the contribution to the aluminium in breast milk from REACH-relevant exposures to aluminium metal, aluminium hydroxide or aluminium oxide is likely to be very small.

Based on the read-across from aluminium compounds for the toxicity to reproduction or development, no classification is required according to DSD (67/548/EEC) or CLP (1272/2008/EC) classification criteria.