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Toxicological information

Repeated dose toxicity: oral

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Administrative data

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). JUSTIFICATION FOR READ-ACROSS AND CHOICE OF DATA (applicable to worker and general population DNELs): A Maximum tolerable daily intake (MTDI) value of 70 mg/kg bw /day of phosphorus as calculated by the Joint FAO/WHO Expert Committee on Food Additives (JEFCA) is available. This can be applied to all the substances discussed as any toxicity effects noted via the oral route are not attributable to the cation but are as a result of high doses of phosphates. This value was based on data generated on a large number of different inorganic phosphates. On this basis a number of sodium, sodium aluminium, potassium, calcium and magnesium orthophosphates (those used as food additives and their analogues) are considered as suitable for read-across for the repeated-dose toxicity endpoint for the following reasons: - All substances are similar inorganic ionic compounds. In aqueous solutions they will dissociate to their cationic and anionic forms and therefore these can be viewed as separate moieties with regards to toxicity. - The Na+, K+, Ca2+and Mg2+cations are naturally occurring essential minerals that are highly regulated by homeostatic mechanisms. As such recommended intake values for all exist and are about the key NOAEL taken from the data and therefore no further assessment of their contribution to the toxicity of the materials is necessary. - The Al3+is present in the substance tested in the studies from which the values for risk assessment are derived and therefore no further consideration of the toxicity of the aluminium cation is required as this is already taken into account. - The phosphate moiety is not considered to differ to that from any other inorganic orthophosphate from a toxicological point of view for the purpose of risk assessment and the derivation of appropriate DNELs it is considered to be appropriate to use the most reliable data available for orthophosphates (see endpoint records and summary) and no further data was generated on calcium or magnesium orthophosphates - The main toxicological finding in repeated dose studies with most inorganic phosphates is nephrocalcinosis (calcification of the kidneys). It is noted by JEFCA that rats are particularly susceptible to these effects and these effects were taken into account when deriving the MTDI value. Please see the endpoint summary provided under ‘Toxicological Information’ for a full detailed justification.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1972
Report date:
1972

Materials and methods

Test guideline
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

Test material

Constituent 1
Reference substance name:
Phosphoric acid, aluminium sodium salt
EC Number:
232-090-4
EC Name:
Phosphoric acid, aluminium sodium salt
Cas Number:
7785-88-8
Constituent 2
Reference substance name:
sodium aluminium phosphate (15:3:8)
IUPAC Name:
sodium aluminium phosphate (15:3:8)
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): KASAL

Test animals

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

Administration / exposure

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
Doses / concentrationsopen allclose all
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

Examinations

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

Results and discussion

Results of examinations

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.

Effect levels

open allclose all
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

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

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

Applicant's summary and conclusion

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 dietary 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. A Maximum tolerable daily intake (MTDI) value of 70 mg/kg bw /day of phosphorus as calculated by the Joint FAO/WHO Expert Committee on Food Additives (JEFCA) is available. This can be applied to all the substances discussed as any toxicity effects noted via the oral route are not attributable to the cation but are as a result of high doses of phosphates. This value was based on data generated on a large number of different inorganic phosphates.
On this basis a number of sodium, sodium aluminium, potassium, calcium and magnesium orthophosphates (those used as food additives and their analogues) are considered as suitable for read-across for the repeated-dose toxicity endpoint for the following reasons:
- All substances are similar inorganic ionic compounds. In aqueous solutions they will dissociate to their cationic and anionic forms and therefore these can be viewed as separate moieties with regards to toxicity.
- The Na+, K+, Ca2+and Mg2+cations are naturally occurring essential minerals that are highly regulated by homeostatic mechanisms. As such recommended intake values for all exist and are about the key NOAEL taken from the data and therefore no further assessment of their contribution to the toxicity of the materials is necessary.
- The Al3+is present in the substance tested in the studies from which the values for risk assessment are derived and therefore no further consideration of the toxicity of the aluminium cation is required as this is already taken into account.
- The phosphate moiety is not considered to differ to that from any other inorganic orthophosphate from a toxicological point of view for the purpose of risk assessment and the derivation of appropriate DNELs it is considered to be appropriate to use the most reliable data available for orthophosphates (see endpoint records and summary) and no further data was generated on calcium or magnesium orthophosphates
- The main toxicological finding in repeated dose studies with most inorganic phosphates is nephrocalcinosis (calcification of the kidneys). It is noted by JEFCA that rats are particularly susceptible to these effects and these effects were taken into account when deriving the MTDIvalue.

Please see the endpoint summary provided under ‘Toxicological Information’ for a full detailed justification.

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