Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 1 and 2) and consistent studies from the target substance and a reference substances with similar structure and intrinsic properties. Read-across is justified based on common functional group(s), common precursors/breakdown products, similarities in PC/ECO/TOX properties (refer to endpoint discussion for further details). The available studies are thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No. 1907/2006.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproductive toxicity

In accordance with Article 13(1) of Regulation (EC) No 1907/2006, information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met. This includes information from structurally related substances (grouping or read-across).

In accordance with Annex XI, Section 1.5, substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. Application of the group concept requires that physicochemical properties, human health effects and environmental effects or environmental fate may be predicted from data for reference substance(s) within the group by interpolation to other substances in the group (read-across approach).

The similarities may be based on:

(1) a common functional group;

(2) the common precursors and/or the likelihood of common breakdown products via physical and biological processes, which result in structurally similar chemicals; or

(3) a constant pattern in the changing of the potency of the properties across the category.

 

Reproductive toxicity of Aluminium dihydrogen triphosphate (EC 237-714-9) was evaluated in a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test according to OECD 422. In addition, to comply these substance-specific data, read across to the water soluble aluminium salt Aluminium sulfate (CAS 10043-01-3) was conducted. In general, bioavailability of aluminium appears to be correlated to water solubility although oral absorption of aluminium can vary 10-fold based on chemical form, available dietary ligands and complexing agents (ATDSR, 2008) (for more details, please refer to the Analogue Justification). Therefore, based on the higher water solubility of Aluminium sulfate, the available data on Aluminium sulfate are considered to allow a weight-of-evidence approach covering a worst-case assumption considering a higher bioavailability of the aluminium moiety of Aluminium sulfate.

The similarity between the source and target substance is based on:

(1) common functional groups: aluminium sulfate and aluminium dihydrogen triphosphate are both inorganic salts of aluminium (Al3+) cations and sulfate (SO42-) or dihydrogen triphosphate (H2P3O103-) anions, respectively; the latter anion being composed of orthophosphate moieties.

(2) likelihood of common breakdown products via physical and biological processes, which result in structurally similar chemicals: both the source and target substance are ionic compounds which release the common breakdown products aluminium (Al3+) cations and sulfate (SO42-) or (PO43-) anions following chemical or biological hydrolysis and dissolution of the ionic bonds.

(3) constant pattern in the changing of the potency of the properties across the category:

in general, independently of the cation under consideration, the bioavailability increases with water solubility of aluminium compounds.

 

In accordance with the provisions set out in Annex XI, Section 1.5, the results of the studies used for assessment and read-across are adequate for the purpose of classification and labelling and/or risk assessment; have adequate and reliable coverage of the key parameters addressed in the corresponding test method; cover an exposure duration comparable to or longer than the corresponding test method; and adequate and reliable documentation of the applied method is provided in the technical dossier.

A detailed read-across justification is provided in Section 13 of the technical dossier.

 

 

Reproductive toxicity

Aluminium dihydrogen triphosphate (EC 237-714-9)

 

Aluminium dihydrogen triphosphate was tested for reproductive toxicity in a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test according to OECD 422 and under GLP conditions (Sunaga, 2002). A group of 10 male and 10 female rats were exposed to Aluminium dihydrogen triphosphate at 100, 300 and 1000 mg/kg bw/day via gavage. The doses were selected based on the results of a preliminary 14-day experiment. Males were exposed over a time period of 46 days, starting 14 days prior to mating and covering the mating and gestation period up to day 4 of nursing. Females received the test item 14 days prior to mating, through mating, gestation and delivery up to Day 4 of lactation. A concurrent control group receiving the vehicle (0.5% carmellose sodium in purified water ) was included in the study. Uniformity, stability and concentration of test item solutions were verified analytically. No mortality or signs indicative for clinical toxicity were observed. in the high-dose group, central abdominal swelling and soiling of the perioral fur was observed in 1/10 males of the high-dose group on the day of autopsy. Furthermore, 1/10 females of the mid-dose group showed a subcutaneous mass on day 13 of pregnancy and thereafter. Body weight and weight gain were comparable among the groups. Organ weights of males of any dose group were unremarkable. In females, absolute and relative weights of the spleen were significantly decreased in the low- and high-dose groups compared to the control group. Organ weights in the mid-dose group were not affected by treatment. Thus, due to a missing correlation to a dose-response, the alterations in spleen weights are not considered as adverse.

No effects on estrous cycle were noted in females of any dose group despite one mid-dose female, which showed continuous diestrus. The respective female became pregnant during the second week of mating. However, all pups from this dam died at birth. Due to the incidental occurrence of irregular estrous cycle observed in the mid-dose group (only 1/10 females affected), no adverse effects on estrous cycle induced by treatment are considered.

In regard to fertility, no test item-related adverse effects were observed. In detail, copulation, gestation and nursing indices were comparable among the groups. In the mid-dose group, 1/10 dams did not give birth up to day 25 of pregnancy. 2 dead fetuses and 5 surviving fetuses were found within the uterus of this dam at autopsy (day 26 of pregnancy). As surviving fetuses were present in the uterus and no comparable effect was observed in the higher dose group, this effect is not considered as adverse but rather as a spontaneous effect. Further, all pups delivered by 1/10 mid-dose dams died at birth on day 25 of pregnancy thereby reducing the gestation index to 90% compared to 100% in the control and remaining treatment groups, including the high-dose group. Due to the incidental occurrence in the mid-dose group, the decrease in gestation index is not considered as adverse. Fertility indices in the control, low- and mid-dose group reached 100% although 2 control and 4 mid-dose males revealed testis atrophy in histopathology. A decrease in fertility index was determined in the high-dose group, which might be related to infertility of 1/10 males showing severe testis atrophy and vaginal closure/inflammation in the uterus horn in 1/10 female. Thus, due to the low incidence of infertility (1/10 males and 1/10 females), spontaneous occurrence rather than a treatment-related effect on fertility is considered as reason for infertility. Moreover, based on a comparison with historical control data (Ema et al., 2014), the decreased fertility index observed in the high-dose group is not considered to be of biological significance as pregnancy rates ranging from 80 - 100% were evaluated for the respective tester strain and study period (depending on the feed source). Number of corpora lutea, number of implantations, implantation index, delivery index and total number of offspring were not affected by treatment in any dose group. The mid-dose group revealed slightly reduced results in regard to several parameters (incl. number of corpora lutea, number of implantations, number of dams with live offspring, total number of offspring, surviving number and delivery index). However, due to a missing dose-response, the observed alterations are considered as incidental and not-treatment related, especially as most parameters fall into the range of historical control data (Ema et al., 2014).

In gross pathology, deformity of the liver and multifocal fine yellowish-white spots were seen in 1/10 males in the low-dose group. Further, 1/10 mid-dose and 1/10 high-dose males showed atrophy of the bilateral testes and epididymides. Umbilical hernia and a dark red protrusion in part of the ileum was observed in a further high-dose male. The mid-dose male showing atrophy of the testes proved to be fertile after mating. In contrast, the high-dose male showing atrophy of the testes was not able to mate successfully.

In females, in the low-dose group, 1/10 dams showed dilation of both cerebral ventricles. Further, 1/10 mid-dose dams revealed swelling of the spleen and a subcutaneous white mass. Dark reddish macules were seen in the glandular stomach in the mid-dose dam which delivered only dead pups at birth. Further, one mid-dose female revealed swelling of the liver, deformity of the spleen, adhesion of the intraperitoneal organs (spleen, pancreas, panniculus and retroperitoneum). This dam did not give birth up to day 25 of gestation. In the high-dose group, 1/10 dams showed an ileal diverticulum. Further, the high-dose female which did not became pregnant showed closure of the vagina, dilation of the uterus and retention of a yellowish-white fluid indicative for an inflammation reaction within the uterus.

In histopathology, the male without proven fertility showed severe atrophy and interstitial oedema in the seminiferous tubules in the testes, a severe decrease in sperm in the epididymides and intermediate intraluminal cell debris. Moreover, atrophy of testes of milder severity was observed in 2 control and 4 mid-dose males. However, as all affected control- and mid-dose males were fertile, including the mid-dose male with intermediate atrophy of the seminiferous tubules in the testes and an intermediate decrease in sperm in the epididymides, atrophy of testes observed in the control and mid-dose group is not considered as adverse. Due to a missing dose-response and occurrence in the control group, atrophy of testes observed in the high-dose group is considered rather incidental than treatment-related. Mild myocardial degeneration was seen in a further high-dose male in which pregnancy with a paired female was not established, most probably due to vaginal closure or inflammation in the uterus of the paired female. In the low dose group, no histopathological alterations were observed in males. In females, in the low-dose group, 1 dam showed dilation of the cerebral ventricles. At the next higher dosage level, 1 dam showed mild extramedullary haemopoiesis in the spleen and adenoma in the mammary gland. A further dam, in which delivery was not seen, mild extramedullary haemopoiesis in the liver and spleen and intermediate necrosis in the spleen were seen. The female that delivered only dead pups, showed mild ulceration of the glandular stomach. Localized necrosis of the liver and atrophy of the thymus were sporadically present in the high-dose group. The females which were not able to establish pregnancy showed mild vitreous casts in the kidneys (1/2 females), mild inflammation of the uterine horn and neck of the uterus and vaginal closure (1/2 females). As inflammatory changes were not seen for the vaginal closure, this was judged to be congenital.

 

No treatment-related effects on the offspring were observed. In detail, the number of surviving offspring on day 0 of nursing, live birth index, number of surviving offspring on day 4 of nursing and viability indices were comparable among the groups. Neonatal deaths at the end of delivery were observed in the control group (2 males and 1 female from 3 different litter) and in the mid-dose group (8 pups from 2 litter (7/7 fetuses in one litter) . Mortality up to day 4 of nursing was observed in the control group (4 males and 2 females), in the low- (1 male) and high-dose group (1 female). The general condition of offspring was not affected by treatment. No effect on body weight was noted in any dose group. At autopsy, no abnormalities were noted in neonates despite, injury to the lower jaw and a skin crust observed in 1 female in the low-dose group and loss of the tail in 1 female in the high-dose group.

 

In summary, based on the results of the conducted study, Aluminium dihydrogen triphosphate is not considered to negatively affect fertility in male and female rats. Due to the sporadic occurrence of irregular estrous cycle (observed 1/10 mid-dose females), the isolated decrease in gestation index (observed in the mid-dose group), comparable number of corpora lutea, number of implantations, implantation index, delivery index and total number of offspring and fertility rates lying inside the range of historical control data (published by Ema et al., 2014), the observed findings are not considered as treatment-related. Therefore, a NOAEL of 1000 mg/kg bw/day was defined for fertility.

 

Aluminium sulfate (CAS 10043-01-3)

Reproductive toxicity of Aluminium sulfate was tested in a two generation reproduction toxicity study according to OECD Guideline 416 (Hirata-Koizumi et al., 2011). 24 Crl:CD(SD) rats/sex/generation (F0 and F1 generation) were exposed to 120, 600 and 3000 ppm aluminium sulfate via drinking water based on the results of a dose-range finding study. Control animals received the vehicle (ion-exchanged water; a total dose of 1.62 (F0 males), 2.29 (F0 females), 1.93 (F1 males) and 2.35 (F1 females) mg Al/kg bw/day was administered via food and water). The concentrations of aluminium sulfate in drinking water were verified in the first and last preparations and once every 3 months (quantitation limit: 5 µg/mL). The animals were exposed to the test substance beginning at 5 weeks of age for 10 weeks until mating, during mating, throughout gestation and lactation. Normalisation of litters was performed on PND 4. Selection of parental animals in the F1 generation took place on PNDs 21 to 25, based on an equal distribution of body weights across the groups.

No clinical signs of toxicity were observed in the P generation. One unscheduled death was determined in the P mid-dose group at 2 weeks of gestation, the respective dam showed a subcutaneous mass in the abdominal region starting 5 weeks of dosing. Body weights in high-dose males and females was significantly decreased in the first 2 - 3 weeks of dosing without showing a direct correlation to food consumption, which was reduced in mid- and high-dose animals at several time points (P mid-dose males - during the first week of dosing, high-dose males: during weeks 1, 8 and 13-14; P mid-dose females: during week 3 of lactation, high-dose females: 1 week of dosing and during week 3 of lactation). No significant alterations in estrous cycle were observed in P and F1 females during the premating period. However, persistent diestrus was determined in a few control and test animals. A significantly decreased number of cauda epididymal sperm (253.8 ± 61.3 × 1E+6/cauda compared to 286.3 ± 40.3 ×1E+6/cauda in test and control animals, respectively) was determined in high-dose males. However, after normalization to epididymal weight, the number of relative cauda epididymal sperm was comparable among the groups and hence, the effect is considered as non-adverse. No significant differences on reproductive function or performance were observed including copulation, fertility, gestation index, precoital interval, gestation length, delivery index, number of implantations and number of litters or pups. Reduced liver (absolute and relative weight) and spleen (absolute weight) weights were determined in high-dose males. No alterations were observed in females. In pathology, no dose-related gross lesions were found in any animal and dose group. In the offspring, viability was comparable on PND 0, 4 and 21 among the groups in any generation (F1 and F2). In the F1 generation, no signs indicative for clinical toxicity were observed. In 1 control and 1 low-dose pup, trauma in the perianal region and tail or hemimelia and oligodactyly were observed. Due to the low incidence, these findings are not considered as adverse. In the F2 generation, no signs indicative for clinical signs were observed. In the F1 and F2 generation, significantly reduced body weights were observed on PND 21 and at sacrifice in the high-dose group. Sexual maturation was significantly delayed in high-dose females (vaginal opening observed 31.4 ± 1.7 compared to 29.5 ± 2.1 days in control) correlating to a slightly increased body weight compared to controls (119.0 ± 13.3 versus 109.6 ± 11.6 g)). No significant differences were noted in the age of preputial separation. No changes in body weights at the time of preputial completion were noted. High-dose animals of the F1 generation revealed significantly decreased liver (absolute and relative organ weight), spleen, thymus, kidney, testes and epididymides weights (absolute weights) and increased relative brain weights. Furthermore, absolute uterus weights were decreased in high-dose F1 females. In the F2 generation, weights of the thymus, spleen (absolute and relative weights), liver and epididymides (absolute) were significantly reduced. Relative brain weight was increased in high-dose males. Reduced absolute brain weight was observed in females of the mid-dose group. No treatment-related alterations were observed in gross and histopathology.

In the offspring, sex ratio was comparable among all test groups in the F1 or F2 generation and developmental landmarks were reached without significant differences compared to the control, except a significantly lower completion rate of pinna unfolding on PND 2 determined in females of the mid-dose group compared to respective controls. Furthermore, the anogenital distance (AGD) and AGD per cube root of body weight ratio were comparable among the groups in the F1 and F2 generation. No adverse effects were noted on neuromotor development.

In the F1 parental generation, no clinical signs of toxicity were observed. Incidental death of single animals occurred in the low- and high-dose group. Statistically reduced water consumption was determined in the F1 generation in all dose groups. Significantly reduced food consumption was determined in the mid- and high-dose group. Body weights were comparable among the groups except for F1 low-dose females which revealed an increased body weight during week 6 - 8 compared to controls. Estrous cycles were comparable in F1 females although some control and test animals had persistent diestrus. No effects on the evaluated sperm parameters were determined. Furthermore, reproductive performance was comparable among the groups as copulation, fertility, gestation index, the precoital interval, gestation length, delivery index, the number of implantations, number of litters or pups delivered were not affected by treatment. In adult F1 males of the high-dose group, absolute organ weight of adrenals was significantly decreased compared to control animals. Mid-dose males showed significantly reduced absolute testis weight. Organ weights of F1 females did not differ from controls. No dose-related gross lesions were observed in the F1 generation. Reproductive organs revealed no compound-related alterations in adults of the F1 generation.

 

Based on the results of the conducted study, a NOAEL of 8.06 mg aluminium/kg bw/day (600 ppm aluminium sulfate) was derived for systemic toxicity in the parental generation. As no effects on fertility were observed in either the parental or F1 generation, a NOAEL ≥ 55.6 mg aluminium/kg bw/day (3000 ppm aluminium sulfate) was derived for fertility. Due to the effects observed in the F1 and F2 generation, a NOAEL of 9.78 aluminium/kg bw/day (600 ppm aluminium sulfate) was set for developmental toxicity.

However, no data are available that enable evaluation of decreased water intake in the absence of aluminium sulfate treatment. Hence, reduced water consumption cannot be excluded as reason for the observed developmental effects and thus, the suggested NOAEL for developmental toxicity was defined rather conservative. Moreover, the statistically significant delay in vaginal opening observed in F1 females was not accompanied by adverse changes in estrous cyclicity, anogenital distance or further reproductive performance. Thus, delayed vaginal opening represents a rather isolated finding. Further, the reduced water consumption might be due to reduced pH (3.57 to 4.2) of the drinking water supplemented with high aluminium dosages caused by reduced palatability of the drinking water. In addition, F0 and F1 females also decreased their food consumption during week 3 of lactation compared to the controls. Thus, it is not possible to exclude secondary effects due to maternal dehydration and reduced nursing. Therefore, utility of the available study for risk assessment is limited.

 

In summary, two studies are available for the evaluation of reproductive toxicity caused by Aluminium dihydrogen triphosphate. For the target substance, a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test according to OECD 422 is available from which a NOAEL of 1000 mg/kg bw/day was defined for fertility. Furthermore, a Two-Generation study was performed with Aluminium sulfate, which did not adversely influence fertility up to the highest dose level tested (3000 ppm aluminium sulfate) and hence, a NOAEL ≥ 31.2 mg aluminium/kg bw/day is considered for fertility.

In conclusion, based on the available data on the target and source substance, Aluminium dihydrogen triphosphate is not considered to exhibit reproductive toxicity.

 

References not included in IUCLID:

 

ATSDR, 2008. Toxicological Profile for Aluminum. Agency for Toxic Substances and Disease Registry. U.S. Department of Health and Human Services. http://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=191&tid=34

 

Ema et al., 2014. Historical control data on developmental toxicity studies in rodents. Congenital Anomalies 54 :150–161.


Short description of key information:
NOAEL (fertility, 46 days, rats): 1000 mg/kg bw/day (Aluminium dihydrogen triphosphate (EC 237-714-9), OECD 422, GLP )
NOAEL (fertility, two generation study, rats): ≥ 31.2 mg aluminium/kg bw/day (read-across from Aluminium sulfate (CAS 10043-01-3), OECD 416, GLP)

Justification for selection of Effect on fertility via oral route:
No study was selected as hazard assessment is conducted by a weight-of-evidence approach. All available studies are adequate and reliable based on overall assessment and, in case of read across, identified similarities in structure and intrinsic properties between the source and target substance (refer to the endpoint discussion for further details).

Effects on developmental toxicity

Description of key information
NOAEL (developmental toxicity, rats): 300 mg aluminium/kg bw/day (read-across from Aluminium citrate (CAS 31142-56-0), OECD 426/452, GLP )
NOAEL (fertility,GD 6 - 15, rabbits, rats, mice): > 217, 410 and 465 mg/kg bw/day (read-across from Calcium dihydrogenorthophosphate monohydrate (CAS 10031-30-8))
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 1 and 2) and consistent studies from the target substance and a reference substances with similar structure and intrinsic properties. Read-across is justified based on common functional group(s), common precursors/breakdown products, similarities in PC/ECO/TOX properties (refer to endpoint discussion for further details). The available studies are thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.7, in accordance with Annex XI, 1.5, 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

Developmental toxicity

In accordance with Article 13(1) of Regulation (EC) No 1907/2006, information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met. This includes information from structurally related substances (grouping or read-across).

In accordance with Annex XI, Section 1.5, substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. Application of the group concept requires that physicochemical properties, human health effects and environmental effects or environmental fate may be predicted from data for reference substance(s) within the group by interpolation to other substances in the group (read-across approach).

The similarities may be based on:

(1) a common functional group;

(2) the common precursors and/or the likelihood of common breakdown products via physical and biological processes, which result in structurally similar chemicals; or

(3) a constant pattern in the changing of the potency of the properties across the category.

 

There are no or no studies available in which developmental toxicity of Aluminium dihydrogen triphosphate has been investigated. Therefore, in order to fulfil the standard information requirements, assessment of this endpoint/property is conducted by means of read-across from the following reference substances:

Aluminium citrate (CAS31142-56-0)

Calcium dihydrogenorthophosphate monohydrate (CAS 10031-30-8).

Read across to both source substances is justified based on structural similarities. The source substances are ionic and will readily dissociate to their ionic forms in aqueous environments, thereby leading to the release of either Al cations or phosphate anions, both representing functional groups of the target substance.

In general, bioavailability of aluminium appears to be correlated to water solubility although oral absorption of aluminium can vary 10-fold based on chemical form, available dietary ligands and complexing agents (ATDSR, 2008) (for more details, please refer to the Analogue Justification). Therefore, based on the higher water solubility, the available data on Aluminium citrate are considered to allow a worst-case assumption considering a higher bioavailability of the aluminium moiety of Aluminium citrate. The orthophosphate ion can undergo ionisation with loss of H+from each of the three –OH groups. The degree of ionisation is dependent upon the associated cation and the ambient pH (if in solution). Moreover, orthophosphate salts of these types are not considered to differ in their systemic toxicity profiles.

 

The similarity between the source and target substance is based on:

(1) common functional groups: Aluminium citrate and Calcium dihydrogenorthophosphate monohydrate are both inorganic salts of aluminium (Al3+) cations or phosphate anions, respectively; the latter anion being composed of orthophosphate moieties.

(2) likelihood of common breakdown products via physical and biological processes, which result in structurally similar chemicals: both the source and target substance are ionic compounds which release the common breakdown products aluminium (Al3+) cations or phosphate anions following chemical or biological hydrolysis and dissolution of the ionic bonds.

(3) constant pattern in the changing of the potency of the properties across the category:

Bioavailability of aluminium compounds increases with increasing water solubility of aluminium compounds. In regard to the phosphate anion, orthophosphate salts are not considered to differ in their systemic toxicity profiles.

 

In accordance with the provisions set out in Annex XI, Section 1.5, the results of the studies used for assessment and read-across are adequate for the purpose of classification and labelling and/or risk assessment; have adequate and reliable coverage of the key parameters addressed in the corresponding test method; cover an exposure duration comparable to or longer than the corresponding test method; and adequate and reliable documentation of the applied method is provided in the technical dossier.

A detailed read-across justification is provided in Section 13 of the technical dossier.

 

 

Developmental toxicity

Aluminium citrate (CAS 31142-56-0)

Developmental toxicity of Aluminum citrate was evaluated in a double-blind neurodevelopmental toxicity study performed equivalent to OECD 426 and 452 according to GLP criteria (Poirier, 2011). 20 pregnant Sprague Dawley rats were exposed from Day 6 of gestation (GD) until postnatal day (PND) 21 to 30, 100 and 300 mg Al/kg bw/ day dissolved in filtered drinking water. On PND 4, normalization to 4 males and 4 females per litter was performed and pups were assigned to 4 sacrifice groups including a total of 80 pups per sex: exposure in utero and through lactation (GD 6 -21 and PND 1 – 22, group 1) or exposure in utero, through lactation followed by exposure via drinking water until PND 64 (GD 6 -21 and PND 1 – 64, group 2), PND 120 (GD 6 -21 and PND 1 – 120, group 3) or PND 364 (GD 6 -21 and PND 1 – 364, group 4). Control animals received a placebo control solution containing 27.2 g/L sodium citrate, which mimics the citrate ionic strength of the highest test concentration. During the study period, exposure via drinking water resulted in significantly lower actual ingested dosages compared to the target concentration for all dose-groups as a result of reduced water consumption.

No mortality was observed in the dams until the end of the study period. Evidence of systemic toxicity was observed in dams of the high-dose group determined mainly by diarrhea. Furthermore,animals of all dose groups, including the control and Na-citrate group, exhibited clinical signs like alopecia and porphyrin staining. One dam from the Na-citrate group stopped nursing and was euthanized early.Body weights of dams were unremarkableduring gestation and the postnatal period.A dose-dependent increase in fluid consumption was observed inthe Na-citrate group, low- and mid-dose group during gestation and lactation.

In pups,a number of animals from each dose and sacrifice group died or were euthanized during the study prior to the planned sacrifice. The major findings were urinary tract lesions of hydronephrosis, ureteral dilation, obstruction and/or presence of calculi in pups which were observed especially in males of the mid- and high-dose groups. Post mortem signs of urinary tract pathology lead to the decision to euthanize the remaining high-dose males. Clinical signs including diarrhea and bloat, thinness, poor hair coat and hematuria were visible in the high-dose group. Furthermore, 3 animals of the Na-citrate group were thin and with poor hair coats. One control female was bloated, had diarrhea and was euthanized. Decreased pre-and post-weaning weights were observed in the Na-citrate group and in high-dose animals of both sexes: at the time of weaning, male pups of the Na-citrate group had 17% lower body weights relative to controls but recovered. High-dose males had 12% lower weights in comparison to controls and continued to lose weight. By PND 84 the mean weight of male high-dose pups was 30% below controls (animals were euthanized due to renal pathology), considering the effect to be adverse. Increased fluid consumption was determined in Na citrate, low-and mid-dose groups which indicates that dosing with either Aluminium citrate or sodium citrate induced significant increases in fluid consumption.

Delayed sexual maturation determined by vaginal opening and preputial separation was present in high-dose males and females. However, a similar or less pronounced effect was observed in the Na citrate group. Thus, a general ionic effect due to alterations in water and food consumption cannot be excluded as reason for the retardation in sexual maturation. 

Neurobehavioral tests including a functional observation battery (FOB), motor activity, Morris water maze and T-maze did not reveal significant differences among the groups. Therefore, exposure to aluminium citrate was not associated with significant alterations in learning, autonomic and sensimotor functions. In contrast, mid-and high-dose animals, especially young animals revealed a significantly impaired neuromuscular function. Older animals seemed to recover over time, most probably due to the fact that they got larger and stronger over time.

Despite a statistically significant decreased mean cell volume (MCV) in low-dose females and high-dose males, haematology did not reveal statistically significant differences among the groups.

Clinical chemistry revealed slight effects on albumin, alkaline phosphatase (ALP), serum calcium (CA), chloride (CL), creatinine (CRE), gobulin (GLOB), gluatmin (GLU), sodium (NA), serum phosphatase (PHOS), triglycerides (TG), total protein (TP) and urea values in males of the Day 64 group. Further, elevated ALP and CA levels were determined especially in the Day 64 group and are interpreted as features of aluminium toxicity. High-dose animals of both sexes were less robust and parameters such as total protein, albumin and globulin were slightly decreased especially in the Day 64 group. Creatinine and urea levels were elevated in the Day 64 group males which might be due to renal calculi. Despite a lower mean brain weight in high-dose males of the Day 64 group and high-dose females of the Day 120 group, no differences in organ weights were determined in gross pathology. As total body weights tended to differ more among the groups than brain weights, the biological significance of this effect is questionable. Macroscopic examinations determined white precipitates in the urinary tracts of male and females. Moreover, high-dose males revealed hydronephrosis and ureteral dilation. Further, fluid colonic content was detected in some high-dose group animals, especially males (5/20 from Day 64 group, 2/20 from Day 120 group and 2/20 from Day 364 group). Single females in the Day 23 and 364 group and a single male in the vehicle group each revealed a similar finding. Histopathology revealed no treatment-related abnormal microscopic findings.

In summary, based on the results of the conducted study, no adverse effects on dams were determined and hence, a NOAEL of 300 mg Al/kg bw/day was determined for maternal toxicity. Furthermore, taking into account that 1)no adverse effects were observed in the pups which are related to maternal treatment during pregnancy and lactation, 2) clinical signs indicative for systemic toxicity were observed at later age, including post-weaning exposure, 3) effects on body weight and sexual maturation were observed in aluminium citrate and Na citrate treated animals, and hence a generic ionic effect cannot be excluded and 4) alterations in neuromuscular function seem to be reversible over time,a NOAEL of 300 mg Al/kg bw/day was considered for developmental toxicity.

 

Calcium dihydrogenorthophosphate monohydrate(CAS 10031-30-8)

Developmental toxicity of Calcium dihydrogenorthophosphate monohydrate was tested in rats, rabbits and mice in a non-GLP Guideline study. In detail, pregnant females were exposed to the test substance at concentrations ranging from 2 – 465 mg/kg bw/day by oral intubation during Days 6 to 15 of gestation (exact dose levels differed between the different species; mice: 4.65, 21.6, 100 and 465 mg/kg bw/day, rabbits: 2.17, 10.1, 46.7 and 217 mg/kg bw/day, rats: 4.1, 19.1, 88.5 and 410 mg/kg bw/day). A sham-exposed control group was included in the study. A further control group receiving aspirin at 250 mg/kg/bw/day was included (vehicle at level equivalent to the high dose group). Observations of body weight, appearance, behavior, and food consumption were performed. Daily room temperature was recorded. On Day 20 of gestation all dams underwent Caesarean section. Number of implantation sites, resorption sites and live/dead fetuses recorded. Body weights of live pups recorded. Urogenital tract of each dam examined for anatomical normality. All fetuses examined grossly for presence of external congenital abnormalities. One third fetuses 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.

 

In rats, no signs indicative for maternal or embryo toxicity were observed. Administration of the highest dose to pregnant rats for 10 consecutive days during pregnancy had no discernible effects on nidation or on maternal and fetal survival. No treatment-related effects on in utero development were observed in any species tested. Number of litters, implantation sites, resorptions, live fetuses and sex ratio were comparable among the sham-exposed control group and test substance groups in all species tested. In mice, 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. In rabbits, a tendency towards decreased number of corpura 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. Aspirin exhibited embryo toxic properties by increasing the number of resorptions and decreasing fetal survival. In addition, the number of skeletal abnormalities increased after Aspirin in utero exposure, thereby pointing to validity of results. 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. Under the conditions of the study, the test material administered to pregnant rats for 10 days up to the highest dose level tested showed no maternal or developmental toxicity. Thus, NOAELs of > 217, 410 and 465 mg/kg bw/day were derived for maternal and developmental toxicity in rabbits, rats and mice, respectively.

 

In summary, in utero exposure to the target substances Aluminium citrate and Calcium dihydrogenorthophosphate monohydrate did not reveal evidences indicating maternal or embryotoxic properties. Thus, the target substance Aluminium dihydrogen triphosphate is not considered to exhibit developmental toxicity.

 

References not included in IUCLID:

 

ATSDR, 2008. Toxicological Profile for Aluminum. Agency for Toxic Substances and Disease Registry. U.S. Department of Health and Human Services. http://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=191&tid=34

 


Justification for selection of Effect on developmental toxicity: via oral route:
No study was selected as hazard assessment is conducted by a weight-of-evidence approach. The studies are adequate and reliable studies based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Justification for classification or non-classification

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

CLP

Reproductive/Developmental toxicity: not classified

GHS

Reproductive/Developmental toxicity: not classified

Additional information