Registration Dossier

Diss Factsheets

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 for cross-reference:
data waiving: supporting information
Reference
Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
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

1. Both substances are inorganic salts of a monovalent cation from Group 1A of the periodic table, and triphosphoric acid. Thus, they share the Na+ or K+ cation and P3O105- anion.
2. Both the Na+ and the K+ cation have a similar biological function and therefore triphosphate salts of these types are not considered to differ in their systemic toxicity profile; differences arise in their local effects profile due to the increasing or decreasing acidity/alkalinity and buffering capacities of the substances. This has been shown not to have an effect on systemic toxicity.
3. In addition, both salts have been shown to be of similar low toxicity in acute oral studies and therefore comparisons can be drawn to allow read-across. Therefore it is not considered to be scientifically justified to perform any further in vivo studies.

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 for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
See attached expert statement.
GLP compliance:
no
Remarks:
Predates GLP
Limit test:
no
Species:
rat
Strain:
other: albino
Sex:
male/female
Details on test animals or test system and environmental conditions:
Groups of 5 animals/cage; cages had bottoms with wood shavings, tap water from local water supply and Purina Fox Chow ad libitum, diets prepared weekly and stored in covered containers. Standard diet is considered to meet the nutritional requirements of the test animals. Information on homogeneity and stability of test material in diet is not included. Frequency of changes in cage bedding and cage cleaning are not documented. Since standard diet and tap water were used; fresh diets were prepared weekly and phosphates are stable in food, this aspect of the study can be considered acceptable.
Route of administration:
oral: feed
Vehicle:
not specified
Details on oral exposure:
no data.
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Not applicable.
Duration of treatment / exposure:
2 years
Frequency of treatment:
ad libitum and daily in diet.
Remarks:
Doses / Concentrations:
0.05%, 0.5% and 5%
Basis:
nominal in diet
No. of animals per sex per dose:
50
Control animals:
yes, concurrent no treatment
Details on study design:
no data.
Positive control:
No data.
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data
- Assessments: appetite, condition of coat, feces and evidence of illness or tumor

BODY WEIGHT: Yes
- Time schedule for examinations: weekly during the first 3 months and every 2 weeks thereafter

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: pre-experimentally and at monthly intervals for the first 6 months, every 2 months of the first year, and every 3 months during second year.
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 5 male and 5 female
- Parameters examined: Hemoglobin, red blood cell counts, white blood cell counts and differential counts

CLINICAL CHEMISTRY: No

HISTOPATHOLOGY: Yes
- Animals: 10 males and 10 females
- Organs examined: brain, lungs, heart, liver, spleen, kidneys, adrenals, gonads, stomach, large and small intestine, urinary bladder, bone marrow and muscle

URINALYSIS: Yes
- Time schedule for collection of urine: At least three times a year
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters examined: sugar and protein

NEUROBEHAVIOURAL EXAMINATION: No

OTHER:
BONE ANALYSIS
-Samples of bone removed at time of autopsy for examination to detect any gross abnormalities in morphology or calcification. Femurs of left leg radiographed and lengths measured. Wet weights, dry weights and ash weights recorded.

ORGAN WEIGHTS: Yes
- Organs: liver, kidneys, lungs, brain, stomach, heart, spleen


Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table in attachments)
HISTOPATHOLOGY: Yes (see table in attachments)
Statistics:
No data.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
Mortalities were high as a result of intercurrent epidemics of infections. The highest mortality (80%) over the 2 year period was observed in females in the 5% dose group. Respiratory infection and pericarditis-peritonitis were the most prominent causes of death.

BODY WEIGHT AND WEIGHT GAIN
Femur lengths and body weights in males and females in the 5% TPP group were smaller than those of control animals, indicating a true reduction in growth.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Food consumption measurements made after 1 month and again after 3 months on the experimental regimen showed that there was some effect responsible for the growth retardation in the rats given 5% TPP diet.

HAEMATOLOGY
At 1 year there was evidence of anaemia in male rats of the 5% dose group. The red blood cells counts, haemoglobin values and haematocrits were somewhat lower than those observed in the other groups. Otherwise the haematological indices were within normal limits.

URINALYSIS
Urine analyses for sugar and protein were normal.

ORGAN WEIGHTS
Organ weights, recorded at the time of sacrifice were mostly in the normal ranges but revealed increased kidney weight-body weight ratios on the average in both male and female rats given the diet containing 5% TPP. There were also slight increase in the weights of liver, testes, brain, stomach and heart possibly attributable to the smaller body weight. In some instances increases in liver and kidney weights relative to body weights were observed in female rats in the 5% dose group.

HISTOPATHOLOGY: NON-NEOPLASTIC
A thorough histological study of the tissues in the rats with increased kidney weight showed the presence of a definable 'chronic tubular nephropathy' (a kidney lesion) in all the rats, male and female given the 5% TPP diet. Rats given 0.5% TPP and 0.05% TPP did not exhibit changes that could be identified as chronic tubular nephropathy. There was no indication that TPP is carcinogenic. The tumors observed were of the types usually found in old rats, and their incidence was the same in all groups.

BONE ANALYSIS
The femurs in both sexes in the 5% group contained slightly more water and slightly less organic matter as compared with controls. The ash content and ratios of calcium to phosphorous were normal for both sexes. Radiographically the bones of rats appeared normal for all dose groups.
Dose descriptor:
NOEL
Effect level:
0.5 other: % in diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
gross pathology
organ weights and organ / body weight ratios
other: At the next dosing tier effects observed included: Growth depression, increased kidney weight, chronic tubular nephropathy in the kidney
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 250 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
gross pathology
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
5 other: % in diet
System:
urinary
Organ:
kidney
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified

- See the attached expert statement for further discussion and mortality tables.

- See attached tables.

Summary of results.

1. Growth depression was noted for the male rats given the diet containing 5% TPP during the entire period. Diets containing 0.5% TPP or less did not retard growth.

 

2. Mortalities were high; higher in the female group given the diet containing 5% TPP than in the other groups.

 

3. Food consumption measurements made after 1 month and again after 3 months on the diets indicated that there was some specific toxic effect of 5% TPP in the diet responsible for the growth reduction.

 

4. Urine analyses gave normal values for sugar and protein.

 

5. Repeated blood samples gave, for the most part, normal haematological values. Some evidence of anemia was found, particularly in the male rats given the 5% TPP diet.

 

6. Organ weights were normal except for increased kidney weightbody weight ratios in both male and female rats given the 5% TPP diet. Liver weight-body weight ratios were increased in the female rats on this high level diet.

 

7. A thorough histological study revealed a characterized, "chronic tubular nephropathy" in the kidneys of all rats, male and female, given the 5% TPP diet. No histological changes were found in the tissues of the rats given 0.05% or 0.5% TPP diets that were attributed to the administration of the tripolyphosphate.

Conclusions:
According to the discussion presented in the attached expert statement this study satisfies the regulatory requirements for this endpoint and has therefore been considered suitable as a key study.
At a dose of ca. 250mg/kg bw/day (0.5% in diet), the test material did not demonstrate any adverse effect and is therefore considered not be classified in accordance with Regulation (EC) no 127/2008 (EU CLP).
At the highest dose tested, (5.0% in diet), the major findings were limited to; growth retardation, increased kidney weights and chronic tubular nephropathy.

Data source

Materials and methods

Results and discussion

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion