Registration Dossier

Administrative data

Description of key information

The key information has been provided on the analogous substance sodium aluminium phosphate. The key study (Matalski K, 1972b) has been selected as the most reliable or appropriate study for use in the derivation of DNELS. 
In addition a reliable 28 day study (OECD 422) exists for the analogous substance dipotassium hydrogenorthophosphate (Shim, 2005), however as the study is only a 28-day study and in accordance with Annex XI, Section 3.2 (a.ii) of Regulation (EC) N0. 1907/2006 (REACH) the data are not considered to be suitable for derivation of a DNEL as subchronic data are available. Furthermore, full access to the data has not been granted to all registrants.
Additional supporting data provided on sodium dihydrogenorthophosphate are not considered to fulfil the guideline requirements for repeated dose toxicity (sub-chronic or chronic). Full justification for the choice of data and the rationale for read-across can be found below.
A reliable 28 day study (OECD 422) exists for the analogous substance dipotassium hydrogenorthophosphate (Shim, 2005), however as the study is only a 28-day study and in accordance with Annex XI, Section 3.2 (a. ii) of Regulation (EC) N0. 1907/2006 (REACH) the data are not considered to be suitable for derivation of a DNEL as subchronic data are availableand as such the data are only supplied as supporting information.
Additional supporting data are not considered to fulfil the guideline requirements for repeated dose toxicity (sub-chronic or chronic).

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:
experimental study
Adequacy of study:
key study
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
See read-across justification report under Section 13 ‘Assessment Reports’.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
In accordance with REACH Annex XI, Section 1.5, of Regulation (EC) No. 1907/2006 (REACH) the standard testing regime may be adapted in cases where a grouping or read-across approach has been applied.

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 or 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

Sodium aluminium phosphate is essentially a sodium orthophosphate that also contains an aluminium ion. Although aluminium is known to have toxic effects, the only systemic toxicity observed in the tests performed on sodium aluminium phosphate are not indicative of aluminium toxicity. The addition of aluminium in the phosphate compound is unlikely to have an impact on the use of this data for the sodium and potassium phosphates as any toxicity observed is due to the phosphate content of the test material.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report under Section 13 ‘Assessment Reports’.

3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report under Section 13 ‘Assessment Reports’.

4. DATA MATRIX
See read-across justification report under Section 13 ‘Assessment Reports’.
Reason / purpose:
read-across: supporting information
Qualifier:
no guideline followed
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 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 histologicfindings – 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 histologic 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 histologic 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 histologicfindings – 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 substance to be registered is justified on the following basis: Sodium aluminium phosphate is essentially a sodium orthophosphate that also contains an aluminium ion. Although aluminium is known to have toxic effects, the only systemic toxicity observed in the tests performed on sodium aluminium phosphate are not indicative of aluminium toxicity. The addition of aluminium in the phosphate compound is unlikely to have an impact on the use of this data for the sodium and potassium phosphates as any toxicity observed is due to the phosphate content of the test material. Therefore the results of the tests performed with sodium aluminium phosphate can reliably be read across to the phosphates detailed above (more detailed rationale is provided in the endpoint summary).
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
322.88 mg/kg bw/day
Study duration:
subchronic
Species:
dog
Quality of whole database:
11 reliability 2 repeated dose studies were available on sodium aluminium phosphate. These studies ranged in duration from 28 days to 6 months. The available toxicity studies have been predominantly been performed on variants of sodium aluminium phosphate referred to in the reports as KASAL, LEVN-LITE and LEVAIR. The ratios of sodium aluminium and phosphate in these materials is reported in the discussion.

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
Quality of whole database:
Workplace exposure data suggests that tripotassium orthophosphate is irritating to the respiratory tract. To this end, the appropriate STOT classification for the respiratory tract has been applied to tripotassium orthophosphate.

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

Read across from sodium aluminium phosphate to sodium and potassium orthophosphates:Derivation of the long term DNELs is proposed based on a series of tests performed with sodium aluminium phosphate.

This read-across argument applies to the following substances;

-          Sodium dihydrogenorthophosphate

-          Disodium hydrogenorthophosphate

-          Trisodium orthophosphate

-          Potassium dihydrogenorthophosphate

-          Dipotassium hydrogenorthophosphate

-          Tripotassium orthophosphate

-          Potassium pentahydrogen bis(phosphate)

 

In accordance with REACH Annex XI, Section 1.5, of Regulation (EC) No. 1907/2006 (REACH) the standard testing regime may be adapted in cases where a grouping or read-across approach has been applied.

 

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 or 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

 

Read-across from sodium and potassium orthophosphates is considered appropriate for the repeated-dose endpoint based on the following similarities between substances:

 

(1)  All substances are ionic and share the PO43-anion as a common functional groups.

(2)  All members of the group will ultimately dissociate into the common breakdown products of the Na+ or K+ cations (for sodium and potassium orthophosphates respectively) and the PO43-anion (all).

Progression through the group sees an increase in cation number from one to three followed by a change in cation from sodium to potassium and again an increase in number from one to three. Both cations are group 1 alkali metals with the same ionic charge, similar chemical behaviour and both sodium and calcium are essential biological elements.

 

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.

 

Sodium aluminium phosphate is essentially a sodium orthophosphate that also contains an aluminium ion. Although aluminium is known to have toxic effects, the only systemic toxicity observed in the tests performed on sodium aluminium phosphate are not indicative of aluminium toxicity. The addition of aluminium in the phosphate compound is unlikely to have an impact on the use of this data for the sodium and potassium phosphates as any toxicity observed is due to the phosphate content of the test material. Therefore the results of the tests performed with sodium aluminium phosphate can reliably be read across to the phosphates detailed above.

Choice of data:

The available studies are performed on sodium aluminium phosphate variants. These are referred to as KASAL, LEVN-LITE and LEVAIR are believed to have the following ratios (Kasal has been reported as having two different ratios and as such it is unclear as to which ratio is correct):

Test material name

Sodium

Aluminium

Phosphate

KASAL

15

3

8

KASAL

8

2

4

LEVAIR

1

3

8

LEVN-LITE

3

2

8

 

All available studies report the doses administered to the animals as either ppm or % in feed. As such and where the relevant information (e.g. bodyweights and food consumption) is available this has been converted to mg/kg bw/day.

11 reliability 2 repeated dose oral toxicity studies are available on sodium aluminium phosphate. One of these appears to be a literature paper based on a full report also presented in the dossier (Hicks JS et al, Food Chem Toxicol. 1987 Jul;25(7):533-8. PMID: 3623343. Sprague GL, T-12644) and two lacked data to convert the dose from % in feed to consumed dose (Reyna M, BTL-71-49D and Smith PS, BTL-71-49A). The latter study was a range finding study for a 90-day study also presented in the dossier.

All the available study reports list the doses administered to the animals in either ppm or % in feed. Where the information is available in the report (i.e. body weights and food consumption) this has been converted to mg/kg bw.



Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Choice of endpoint
The following issues are taken into account when deciding on which endpoint to base the Derived No Effect Level.
1. Nephrocalcinosis (in the form of microconcretions) were observed in the renal tubes of animals investigated in some of the tests. Rats generally and particularly female rats are known to be susceptible to nephrocalcinosis when administered high doses of phosphates (typically starting at about 0.5 – 1.0 % in the diet). Occupational exposure is unlikely to reach this level and Humans are likely to be less sensitive to calcium phosphate precipitation when compared to laboratory rats.
2. Nephrocalcinosis and/or reduced body weight gain were the only toxic effects observed in any of the available studies.
3. The ratio of sodium, aluminium and phosphate in the test material appears to be less relevant to the toxicity endpoint (N(L)OAEL) than the feed consumption, body weight and dosing levels used in the tests (see appendix 1). In all the studies on the rat, the N(L)OAEL is the lowest dose level and is based on Nephrocalcinosis. Two of the studies performed on the dog have a N(L)OAEL at the highest dose level and two studies observed minimal nephrocalcinosis and reduced body weight at the highest dose leading to a NOAEL level at the mid dose level.

As Nephrocalcinosis is only assumed to be relevant for dietary exposure, the endpoints derived from this effect have not been taken into account for the dermal and inhalation routes of exposure. The studies where nephrocalcinosis was observed exhibited no other forms of toxicity and therefore the lowest NOAEL for deriving the an inhalation No Effect Level is taken from the ninety day and six month studies in the dog (Mastalski K, IBT J749 - key study and Pettersen JC et al T-12969 - supporting data as non-standard time-frame observed). The NOAEL used is 323 mg/kg bw/day based on reduced body weight gain at the higher dose level.

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

Justification for classification or non-classification

The only indication of systemic toxicity observed in the tests performed on sodium aluminium phosphate was nephrocalcinosis observed in the renal tubes. Rats generally and particularly female rats are known to be susceptible to nephrocalcinosis when administered high doses of phosphates (typically starting at about 0.5 – 1.0 % in the diet).The effects are only seen in high dose animals (well above the recommended classification limits for STOT RE as defined in the Guidance on the Application of Regulation (EC) No 1272/2008) and therefore classification for STOT RE is not justified and no classification is proposed.