Registration Dossier

Administrative data

Endpoint:
chronic toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented study report which meets basic scientific principles
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1978
Report Date:
1978

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
(limited parameters examined)
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test substance (as cited in study report): Blankophor P (acidic sodiumsalt)
- Analytical purity: 81%
- Physical state: solid

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Winkelmann, Borchen, Germany
- Age at study initiation: 28 - 32 days old
- Weight at study initiation: mean: 48 g
- Housing: single
- Diet: Altromin R-Pulverfutter (Altromin GmbH, Lage/Lippe, Germany), ad libitum
- Water: tap water; ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 1

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
24 months
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
males: 5.23, 52.29, and 520.78 mg/kg bw/day; females: 7.02, 69.33, and 709.25 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
100, 1000 and 10000 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
- test groups: 50
- control group: 100
Control animals:
yes, plain diet

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: first 6 months weekly, after that every two weeks

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

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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at 1, 3, 6, 12 and 24 months
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 10/sex at 24 months otherwise 5/sex
- Parameters checked: haemoglobin, haematocrit, erythrocytes, leucocytes, MCV, MCH, reticulocyte, thromocytes

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at 1, 3, 6, 12 and 24 months
- Animals fasted: No data
- How many animals: 10/sex at 24 months otherwise 5/sex
- Parameters checked: ALP, GOT, GTP, bilirubin, protein, blood glucose, cholesterol

URINALYSIS: Yes
- Time schedule for collection of urine: at 1, 3, 6, 12 and 24 months (urine from 16 o'clock)
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked: glucose, protein, blood, pH, ketone bodies, bile pigments, sediments, urea, creatinine

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (aorta, eyes, duodenum, jejunum, urinary bladder, heart, testes, pituitary, liver, lung, lymph nodes, stomach, spleen, epididymis, adrenals, kidneys, os femoris, oesophagus, ovaries, pancreas, prostate, seminal vesicle, thymus, skeletal muscle, sternum, trachea, and uterus)
Statistics:
U-test (Mann); Whitney wilcoxon

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:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: No differences compared to negative controls were observed.
- after one year: 2 male and 0 female of 100 animals died in the control group; at 100 ppm 1/50 males and 1/50 females died; at 1000ppm 3/50 males and 0/50 females and at 10000ppm 0/50 males and 0/50 females died
- after two years: in the control group 37/100 males and 25/100 females died; at 100 ppm 23/50 males and 17/50 females died; at 1000ppm 25/50 males and 14/50 females died and at 10000ppm 16/50 males and 17/50 females died

BODY WEIGHT AND WEIGHT GAIN: comparable in all groups

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): normal in all groups

HAEMATOLOGY: No substance-related changes in any parameter were observed.

CLINICAL CHEMISTRY: after 1 month: increase in GOT and GPT at 10000 ppm (males), increase in GPT at 1000 and 10000 ppm (females); no dose-dependent changes in any parameter after 3, 6, 12 and 24 months treatment.

URINALYSIS: normal in all groups

ORGAN WEIGHTS: significant increase of kidey weight in males and females at 10000 ppm, as the difference is < 10%, it is not considered toxicologically relevant; the other changes in organ weight (liver, lung, heart, and testes) were considered not to be treatment-related as no dose-relationship was observed.

GROSS PATHOLOGY: no abnormalities detected

HISTOPATHOLOGY: no abnormalities detected; only findings that are age-related and common for this strain were observed

OTHER: From type, localisation and frequency of observed tumors there is no indication for cancerogenic effect of the test substance

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
10 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects, highest dose tested
Dose descriptor:
NOAEL
Effect level:
709 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: overall effects, highest dose tested
Dose descriptor:
NOAEL
Effect level:
521 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: overall effects, highest dose tested

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Food and active ingredient intake:

Dosis [ppm]

mean food intake

mean active ingredient intake

 

kg/animal

g/animal/day

g/kg bw

mg/kg bw /day

 

male

0

16.48

22.43

-

-

100

16.49

22.44

3.84

5.23

1000

16.44

22.36

38.4

52.24

10000

16.61

22.6

382.77

520.78

 

female

0

12.5

17.01

-

-

100

12.54

17.06

5.16

7.02

1000

12.79

17.4

50.96

69.33

10000

12.86

17.52

521.3

709.25

Mean absolute organ weights (mg)

Dosis (ppm)

Body weight (g)

Thymus

Heart

Lungs

Liver

Spleen

Kidneys

Adrenals

Testes/

ovary

Males

0

396

25

1246

2036

14364

742

2792

54

3331

100

372

26

1303

2716**

13036

665

2782

57

2908*

1000

368*

23

1184

2235

12755**

697

2740

51

3171

10000

390

27

1353**

1809

15524

790

3037**

55

3554

Females

0

264

21

959

1529

9507

530

1978

72

114

100

244*

19

947

1508

8854

551

1921

71

117

1000

267

19

971

1436

9600

608

2009

69

106

10000

265

20

973

1210*

9938

595

2108**

70

114

* significant different from control; p < 0.05

** significant different from control; p < 0.01

 

Applicant's summary and conclusion

Conclusions:
In this Combined Chronic Toxicity / Carcinogenicity Studies performed to a protocol similar to the OECD Guideline 453 no specific adverse effect was observed by treatment of rats with the test substance for 2 years.