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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
a short-term toxicity study does not need to be conducted because a reliable sub-chronic (90 days) or chronic toxicity study is available, conducted with an appropriate species, dosage, solvent and route of administration
Cross-reference
Reason / purpose:
data waiving: supporting information
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

The source substance and the target substance are considered to be similar enough to facilitate read-across for the following reasons:
1. Both 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
2. Both substances will ultimately dissociate into the common breakdown products of the Na+ cations and the PO43- anion. 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
3. The Na+ 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 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/

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.

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).

Data source

Materials and methods

Results and discussion

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion