Registration Dossier

Diss Factsheets

Administrative data

Description of key information

NOAEL (46 days, rats): 300 mg/kg bw/day (Aluminium dihydrogen triphosphate (EC 237-714-9), OECD 422, GLP )
NOAEL (90 days, dogs): 322.88 mg/kg bw/day (read-across from Sodium aluminium phosphate (CAS 7785-88-8))

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Meets generally accepted scientific standards with acceptable restrictions: The test substance identity has not been clarified in the study report, however composition of the test material is known and the study is considered to be reliable for use as a key study. The reliability has been amended in accordance with 'practical guide 6: How to report read-across and categories' which states that the maximum reliability for a read-across study is 2. The study is considered to be adequate and reliable for the purpose of registration under REACH (Regulation (EC) No. 1907/2006). Read across from sodium aluminium phosphate to the following aluminium orthophosphates; - Aluminium tris(dihydrogen phosphate) - Aluminium orthophosphate Can be justified on the following basis; All members of the group are structurally similar ionic inorganic compounds consisting of aluminium cations and phosphates anions. No members of the group are classified for acute toxicity and generally exhibited no mortalities at the classification limit. Two members of the group are classified for local effects only (i.e. skin/eye irritation) which will not have an impact on the systemic toxicity of the compounds. An expert review of the toxicology of aluminium(1) found limited data to suggest that oral exposure to aluminium was harmful in humans. The oral toxicity of aluminium in animals is well-studied, although many of the studies are limited by a lack of reported information on aluminium content in the base diet and no specific target organs for toxicity have been identified. Further, Major sources of human oral exposure to aluminium include food (due to its use in food additives, food and beverage packaging, and cooking utensils), drinking water (due to its use in municipal water treatment), and aluminium-containing medications (particularly antacid/antiulcer and buffered aspirin formulations). Medicinal formulations containing aluminium are considered safe in healthy individuals at recommended doses. Systemic effects in the studies with sodium aluminium phosphate were noted in the kidneys of both rats and dogs. Similar effects have been previously linked to high phosphate concentrations. However, in long-term studies these types of effects may also be attributable to normally occurring age-related disease (e.g. rats are particularly prone to nephropathies (2)). It is therefore likely that at the dose levels required in repeated dose toxicity study no effects would be anticipated therefore the results of the studies performed on sodium aluminium phosphate are suitable for read-across to other aluminium phosphates. (1)TOXICOLOGICAL PROFILE FOR ALUMINUM.U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, Public Health Service Agency for Toxic Substances and Disease Registry, September 2008. (2)Peter CP, D. Burek J and Van Zwieten MJ (1986) Spontaneous Nephropathies in Rats. Toxicologic Pathology. 14 (1): 91-100
Qualifier:
no guideline followed
Deviations:
not applicable
Principles of method if other than guideline:
A 90 day oral toxicity study was conducted with purebred beagle dogs fed KASAL at dietary levels of 0.3, 1.0 and 3.0%.
GLP compliance:
no
Remarks:
Study predates GLP
Limit test:
no
Species:
dog
Strain:
Beagle
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Laboratory's own IBTL colony
- Age at study initiation: See Table 1
- Weight at study initiation: See Table 1
- Fasting period before study: No data
- Housing: Animals were housed in kennels equipped with outside runs. Four dogs of the same sex and group were accommodated in a single kennel.
- Diet (e.g. ad libitum): Stock diet (Golden Choice Meals, Adolph Coors Company, Denver, Colorado) available ad libitum
- Water: available ad libitum
- Acclimation period: The dogs were observed for two weeks prior to the start of the investigation during which time they were reimmunised against rabies, distemper, infectious canine hepatitis and leptospirosis and rendered clinically free of any existing parasitic infestation.


ENVIRONMENTAL CONDITIONS
No data


IN-LIFE DATES: No data
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: No data


DIET PREPARATION
- Rate of preparation of diet (frequency): At the beginning of each week
- Mixing appropriate amounts with (Type of food): The appropriate dietary constituents for each group were thoroughly blended in a Hobart mixer. Preweighed amounts were distributed into self-feeding units and maintained in excess of the animals' consumption. One such unit was available to the dogs in each kennel on an ad libitum basis 24 hours per day.
- Storage temperature of food: No data


VEHICLE
Not applicable
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Not applicable
Duration of treatment / exposure:
90 days
Frequency of treatment:
Continuous exposure in feed
Remarks:
Doses / Concentrations:
0.3, 1.0 and 3.0%
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
Male: 94.23, 322.88 and 1107.12 mg/kg bw/day Female: 129.31, 492.77 and 1433.56 mg/kg bw/day
Basis:
other: Calculated using the mean of the weekly body weight and food consumption (Week 5 has been discounted from the 492.77 mg/kg bw/day femal group due to illegible figures in the report)
No. of animals per sex per dose:
4 animals/sex/dose
Control animals:
yes, plain diet
Details on study design:
No data
Positive control:
Not used
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily


BODY WEIGHT: Yes
- Time schedule for examinations: The body weight of each dog in every group was determined and recorded at the start of the study and weekly thereafter.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): At the end of each 7 day period, all unconsumed food was collected and weighed. Food consumption was calculated and recorded.


FOOD EFFICIENCY: No


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: Prior to inception of the study and after 42 and 84 days of testing
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all animals
- Parameters: Total leukocyte count, erythrocyte count, haemoglobin, haematocrit, differential leukocyte count


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Prior to inception of the study and after 42 and 84 days of testing
- Animals fasted: No data
- How many animals: all animals
- Parameters: Blood urea nitrogen, serum glucose, serum alkaline phosphatase, serum glutamic-oxalacetic transaminase, serum glutamic-pyruvic transaminase


URINALYSIS: Yes
- Time schedule for collection of urine: Prior to inception of the study and after 42 and 84 days of testing
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters: Albumin, glucose, pH, microscopic elements (leukocytes, erythrocytes, crystals)


NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
All major tissues and organs were examined grossly. The weights of the following organs were obtained: liver, kidneys, heart, brain, spleen, gonads, adrenal glands, thyroid gland and pituitary gland.

HISTOPATHOLOGY: Yes (see table)
Other examinations:
None
Statistics:
No data
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY: No untoward behavioural reactions were recorded during the investigation and no fatalities occurred.


BODY WEIGHT AND WEIGHT GAIN: No significant deviations from normally expected body weight gains for dogs of this age were noted (see Table 1).


FOOD CONSUMPTION AND COMPOUND INTAKE : There is no significant difference between the untreated control group and the three test groups (see Table 2).


HAEMATOLOGY: No significant abnormalities were noted at any level tested (see attached Tables 3-11).


CLINICAL CHEMISTRY: There is no significant difference between the untreated control group and the three test groups (see attached Tables 12-16).


URINALYSIS: Urinalysis revealed no significant abnormalities at any of the levels tested (see attached Tables 17-23).


ORGAN WEIGHTS: No significant abnormalities were noted among any levels tested (see attached Tables 24-32).


GROSS PATHOLOGY and HISTOPATHOLOGY: NON-NEOPLASTIC: There are no changes that can be attributed to the test material or the test procedure. All of the findings noted are attributed to spontaneous disease. (see Tables 33-36). All tissues and organs not mentioned were normal.
Dose descriptor:
NOAEL
Effect level:
322.88 mg/kg bw/day (nominal)
Based on:
other: test material, calculated based on food consumption
Sex:
male
Basis for effect level:
other: histopathology; specific to kidneys
Dose descriptor:
NOAEL
Effect level:
492.77 mg/kg bw/day (nominal)
Based on:
other: test material, calculated based on food consumption
Sex:
female
Basis for effect level:
other: histopathology; specific to kidneys
Critical effects observed:
not specified

Table 1: Mean body weight data and age for males and females

Group

Dietary level (%)

Males

Females

Mean age at inception of test (months)

Mean body weight at week 0 (kg)

Overall weight gain (kg)

Mean age at inception of test (months)

Mean body weight at week 0 (kg)

Overall weight gain (kg)

UC

None

5.9

9.5

1.9

6.0

7.3

1.7

T-I

0.3%

5.9

8.2

1.8

5.6

7.6

1.4

T-II

1.0%

5.9

9.2

2.1

5.6

5.5

1.4

T-III

3.0%

6.0

7.6

2.0

5.5

7.1

1.4

 

Table 2: Mean food consumption data

Week

-

Mean food consumed during week indicated (g/day)

Sex:

Males

Females

Group:

UC

T-I

T-II

T-III

UC

T-I

T-II

T-III

Dietary level (%):

None

0.3

1.0

3.0

None

0.3

1.0

3.0

1

-

352

375

388

401

380

451

436

385

2

-

361

381

385

430

417

407

458

418

3

-

366

362

359

392

397

378

410

386

4

-

338

371

353

342

366

382

407

375

5

-

356

358

336

363

399

359

391

369

6

-

348

335

332

366

375

352

394

351

7

-

319

347

328

364

343

369

398

352

8

-

285

305

277

323

323

331

358

346

9

-

315

335

268

325

321

361

377

363

10

-

333

303

274

328

362

370

361

356

11

-

300

336

321

317

341

332

334

330

12

-

286

268

261

287

298

302

279

288

13

-

281

338

304

346

285

344

423

350

Mean

-

326

340

322

353

354

364

387

359

 

Table 33: Gross and histological findings – Untreated control group

Dog number and sex

Organ

Gross

Grade

Histologic

Grade

1-M

Liver

-

-

Focal lymphoid infiltration

+

 

Lungs

-

-

Focal interstitial pneumonia

++

 

Prostate

-

-

Chronic focalprostatitis

++

 

Spleen

-

-

Haemosiderosis

+

2-M

Lungs

-

-

Chronic interstitial pneumonia

++

3-M

Heart

-

-

Congestion

+

 

Liver

-

-

Focal lymphoid infiltration

+

 

Lungs

-

-

Focal interstitial pneumonia

++

4-M

Liver

-

-

Congestion

+

 

Lungs

-

-

Chronic interstitial pneumonia

++

 

Spleen

-

-

Haemosiderosis

+

5-F

Liver

-

-

Congestion

++

 

 

 

 

Focal lymphoid infiltration

+

 

Lungs

-

-

Chronic interstitial pneumonia

+

 

 

-

-

Hyperemia

+

6-F

Liver

 

 

Congestion

+

 

Lungs

-

-

Chronic interstitial pneumonia

+

 

Uterus

-

-

In estrus

-

7-F

Ovaries

-

-

Proestrus

-

 

Liver

-

-

Congestion

++

8-F

Lungs

-

-

Chronic interstitial pneumonia

+

 

Table 34: Gross and histological findings – Test group I: 0.3 percent

Dog number and sex

Organ

Gross

Grade

Histologic

Grade

9-M

Liver

-

-

Congestion

+

Lungs

-

-

Hyperemia

+

10-M

Liver

-

-

Congestion

+

 

Lungs

-

-

Chronic interstitial pneumonia

+

11-M

Kidneys

-

-

Focal lymphoid infiltration

+

 

Lungs

-

-

Congestion

Focal lymphoid infiltration

+

+

12 -M

Liver

-

-

Congestion

+

 

Lung

-

-

Chronic interstitial pneumonia

++

13-F

Liver

-

-

Focal lymphoid infiltration

+

Lungs

-

-

Chronic interstitial pneumonia

+

14-F

Liver

-

-

Congestion

++

 

Lungs

-

-

Bronchopneumonia

++

15-F

Liver

-

-

Focal lymphoid infiltration

+

Lungs

-

-

Chronic interstitial pneumonia

++

 16 -F  Liver  -  -  Congestion  +
   Lungs  -  -  Chronic interstitial pneumonia ++ 

 

Table 35: Gross and histological findings – Test group II: 1.0 percent

Dog number and sex

Organ

Gross

Grade

Histologic

Grade

17-M

Lungs

-

-

Hyperemia

Chronic interstitial pneumonia

+

++

18-M

Liver

-

-

Congestion

+

 

Lungs

-

-

Chronic interstitial pneumonia

+

19 -M

-

-

-

-

-

20 -M

Lungs

-

-

Chronic interstitial pneumonia

+

21 -F

Liver

-

-

-Congestion

+

Lungs

-

-

Chronic interstitial pneumonia

Bronchopneumonia

++

++

22-F

Liver

-

-

Congestion

+

Lungs

-

-

Chronic interstitial pneumonia

+

23 -F

Liver

-

-

Congestion

+

Lungs

-

-

Chronic interstitial pneumonia

+

 

Mesenteric lymph node

-

-

Hyperemia

+

 

 Pancreas

-

-

Hyperemia

+

 24 -F

Lungs

-

-

Chronic interstitial pneumonia

+

 

Table 36: Gross and histological findings – Test group III: 3.0 percent

Dog number and sex

Organ

Gross

Grade

Histologic

Grade

25-M

Liver

-

-

Congestion

+

 

Kidney

-

-

Tubular concretions

+++

26-M

Liver

-

-

Congestion

+

 

Kidney

-

-

Tubular concretions

+++

27-M

Liver

-

-

Congestion

++

Lung

-

-

Chronic interstitial pneumonia

+

 

Prostate

-

-

Chronic focal prostatitis

+

28 -M

Kidneys

-

-

Focal lymphoid infiltration

+

Lungs

-

-

Chronic interstitial pneumonia

++

29 -F

 Liver

 -

 -

Congestion

++

Lungs

-

-

Chronic interstitial pneumonia

++

30 -F

Liver

-

-

Congestion

+

 

 Lungs

-

-

Chronic interstitial pneumonia

+

31-F

Liver

-

-

Congestion

+

 32 -F  Gonads  -  -  Calcified follicle  +
   Kidneys  -  -  Tubular concretions  +++
   Liver  -  -  Focal lymphoid infiltration  +
   Spinal cord  -  -  Calcified debris in central canal  +

 Grading system:

+ = minimal or slight

++ = mild

+++ = moderate

++++ = severe

Conclusions:
The 90-day oral administration of KASAL to purebred beagle dogs at dietary levels of 0.3, 1.0 and 3.0% revealed in three of the Group T-III animals renal concretions which were unusually large and more numerous than those normally observed in untreated dogs. The few other calcified microconcretions present in the lumen of renal tubules located at the corticomedullary junction and/or medulla of the kidney were attributed to normally occurring disease.
No significant other changes were noted. Thus the dieatry level of 1% can be considered as NOAEL (this is equivalent to 322.88 mg/kg bw/day).

This study is considered to satisfy the guideline requirements for this endpoint and also be adequate for the purposes of risk assessment. Therefore, the study is submitted as a key study and the NOAEL reported in this study is used to derive the inhalation and dermal DNELs. On consideration of all the available data, the ratio of sodium, aluminium and phosphate in the test material is not considered to be of key relevance in determining the derived no effect levels.

Read across from sodium aluminium phosphate to the following aluminium orthophosphates;

- Aluminium tris(dihydrogen phosphate)
- Aluminium orthophosphate

Can be justified on the following basis;

All members of the group are structurally similar ionic inorganic compounds consisting of aluminium cations and phosphates anions.

No members of the group are classified for acute toxicity and generally exhibited no mortalities at the classification limit. Two members of the group are classified for local effects only (i.e. skin/eye irritation) which will not have an impact on the systemic toxicity of the compounds.

An expert review of the toxicology of aluminium(1) found limited data to suggest that oral exposure to aluminium was harmful in humans. The oral toxicity of aluminium in animals is well-studied, although many of the studies are limited by a lack of reported information on aluminium content in the base diet and no specific target organs for toxicity have been identified. Further, Major sources of human oral exposure to aluminium include food (due to its use in food additives, food and beverage packaging, and cooking utensils), drinking water (due to its use in municipal water treatment), and aluminium-containing medications (particularly antacid/antiulcer and buffered aspirin formulations). Medicinal formulations containing aluminium are considered safe in healthy individuals at recommended doses.

Systemic effects in the studies with sodium aluminium phosphate were noted in the kidneys of both rats and dogs. Similar effects have been previously linked to high phosphate concentrations. However, in long-term studies these types of effects may also be attributable to normally occurring age-related disease (e.g. rats are particularly prone to nephropathies (2)).

It is therefore likely that at the dose levels required in repeated dose toxicity study no effects would be anticipated therefore the results of the studies performed on sodium aluminium phosphate are suitable for read-across to other aluminium phosphates.

(1)TOXICOLOGICAL PROFILE FOR ALUMINUM.U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, Public Health Service Agency for Toxic Substances and Disease Registry, September 2008.
(2)Peter CP, D. Burek J and Van Zwieten MJ (1986) Spontaneous Nephropathies in Rats. Toxicologic Pathology. 14 (1): 91-100
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
322.88 mg/kg bw/day
Study duration:
subchronic
Species:
dog
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 1 - 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 selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with AnnexXI, 1.5, of Regulation (EC) No. 1907/2006.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated dose 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.

 

Repeated dose 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 analogue substance sodium aluminium phosphate (CAS 7785-88-8) was conducted.

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

(1) common functional groups: sodium aluminium phosphate and aluminium dihydrogen triphosphate are both inorganic salts of aluminium (Al3+) cations and phosphate anions

(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. Chemical or biological hydrolysis of condensated phosphates into orthophosphate and dissolution of the ionic bonds, lead to the common breakdown products aluminium (Al3+) cations and phosphate (PO43-) anions.

(3) constant pattern in the changing of the potency of the properties across the category: in general, independently of the cation under consideration, the water solubility of phosphates decreases with increasing degree of phosphate condensation (orthophosphate > diphosphate > triphosphate > polyphosphate).

 

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.

 

Repeated dose toxicity

Aluminium dihydrogen triphosphate (EC 237-714-9)

Aluminium dihydrogen triphosphate was tested for repeated dose 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.

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 were 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. Due to the isolated finding in the low-dose group, the effect is not considered as adverse. 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 the low incidence of affected males in the high-dose group (1/10 animals), and the presence of a comparable effect of minor severity in the control group, a correlation of atrophy of testes in the high-dose group to test item exposure remains questionable. Furthermore, mild myocardial degeneration was seen in 1 other high-dose male in which pregnancy with a paired female was not established. 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 observed. 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. For further details on results, please refer to 7.8.1 "Reproductive toxicity".

In summary, repeated exposure to Aluminium dihydrogen triphosphate was correlated to isolated pathological findings in different organs. However, due to the sporadic occurrence of those effects, a correlation to treatment is not considered. Moreover, atrophy of testes was observed in control, mid- and high-dose males. Due to a missing dose-response and considering the fact that atrophy of testes observed in control and mid- dose males did not affect fertility, the effect on testes and associated tissues up to 300 mg/kg bw/day is considered rather spontaneous than treatment-related. In contrast, considering a rather conservative approach, the effects observed in the high-dose group, including severe atrophy of testes in 1/10 males, altered levels of calcium and total protein in females, a LOAEL of 1000 mg/kg bw/day is considered for systemic toxicity following repeated exposures based on the available data.

 

Sodium aluminium phosphate (CAS 7785 -88 -8)

Repeated dose toxicity of sodium aluminium phosphate was tested in a 90 day oral toxicity study conducted in beagle dogs (Mastalski, 1972). 4 purebred beagle dogs/sex/group received dietary levels of 0.3, 1.0 and 3.0% sodium aluminium phosphate corresponding to 94.23, 322.88 and 1107.12 mg/kg bw/day in males and 129.31, 492.77 and 1433.56 mg/kg bw/day in females. Control animals were fed with plain diet. No clinical signs indicative for toxicity were observed in any dose group. Body weight, weight gain and food consumption were unremarkable among the groups. In haematology, clinical chemistry and urinalysis, no significant abnormalities were noted at any dose level tested. Organ weights were unaffected at all dose levels tested. In pathology, renal concretions of moderate degree were observed in 2/4 males and 1/4 females of the high-dose group. The few other calcified microconcretions present in the lumen of renal tubules located at the corticomedullary junction and/or medulla of the kidney were attributed to normally occurring disease. Other findings noted in livers, lungs, gonads, prostate and lymph nodes are considered as spontaneous due to their presence in any group, including the control group, their sporadic occurrence and/or grade of severity. Based on the alterations observed in the kidney in the high-dose group, a NOAEL of 322.88 mg/kg bw/day (corresponding to 1%) is defined in the conducted study.

 

In summary, two repeated dose toxicity studies are available covering subacute and subchronic exposure to evaluate the hazardous potential of Aluminium dihydrogen triphosphate. In rats, treatment with Aluminium dihydrogen triphosphate over 46 days resulted in severe atrophy and interstitial oedema in the seminiferous tubules in the testes, severe decrease in sperm in the epididymides and intermediate intraluminal cell debris correlated to infertility observed in 1/10 males exposed to 1000 mg Aluminium dihydrogen triphosphate/kg bw/day. Further, altered calcium and total protein levels were determined in females exposed to 1000 mg/kg bw/day. Based on these results, a rather conservative NOAEL of 300 mg/kg bw/day was derived in the conducted Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test. However, due to the low incidence of affected males (1/10 animals) and restricted biological significance of the clinical parameters altered in females, robustness of the derived NOAEL of 300 mg aluminium/kg bw/day is considered limited.

Exposure to 1000 mg sodium aluminium phosphate /kg bw/day for over 90 days induced renal concretions of moderate degree in 2/4 male and 1/4 female beagle dogs, resulting in a NOAEL of 322.88 mg/kg bw/day. Based on the incidence of adversely affected animals and longer exposure duration, the effect level derived in the sub-chronic repeated dose toxicity study performed in beagle dogs is chosen for exposure assessment of repeated dose toxicity of Aluminium dihydrogen triphosphate. The selected NOAEL is considered as most adequate and reliable based on the overall assessment of incidence of adverse effects and exposure duration.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: kidneys

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

STOT-RE: not classified

GHS

STOT-RE: not classified