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Carcinogenicity

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Description of key information

In the rat and mouse, the test substance applied in the diet at concentrations of up to 10,000 ppm and 500 ppm, respectively did not induce an increase in tumour incidence in either species. 

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Survival in all but one group < 50% at termination
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Deviations:
yes
Remarks:
(photoperiod (hrs dark / hrs light): 14 dark/10 light)
GLP compliance:
no
Specific details on test material used for the study:
Code number : TK 10048
Batch number : EN 26590/74
Physical state: solid
Species:
mouse
Strain:
other: Tif: MAGf (SPF)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Animal Production Stein, Ciba Geigy Ltd.
- Age at study initiation: approx. 4 weeks old
- Weight at study initiation: 24.0 - 24.5 g (male); 21.5 - 21.7 g (female)
- Housing: Groups of 5 in Macrolon cages type 3
- Diet: Nafag No. 890; ad libitum
- Water: as libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 10
- Air changes (per hr): 15 - 17
- Photoperiod (hrs dark / hrs light): 14 dark/10 light


IN-LIFE DATES: From October 1st, 1978: To: Oct 1st, 1980
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): not stated
- Mixing appropriate amounts with (Type of food): TK 10048 was weighed on a calibrated balance. The pulverised food was then homogenously mixed with the appropriate concentrations of the compound and 30 % water was added before pelleting to ensure the necessary pellet quality. The pellets were subsequently air-dried.
- Storage temperature of food: not stated

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Prior to the initiation of the study, pretest feed samples were analysed for concentration and stability of the test material. The same was undertaken with the food batches applied during the test. These analyses were carried out in the Analytical Laboratories of the Plastics and Additives Division of Ciba-Geigy Ltd, Basle/Switzerland. The results of these analyses revealed a concentration of 74 - 134% of the nominal value.
Duration of treatment / exposure:
24 months
Frequency of treatment:
Daily
Post exposure period:
None
Dose / conc.:
0.66 mg/kg bw/day (actual dose received)
Remarks:
males (dose equivalent to 5 mg/kg feed nominal concentration. Calculated by food consumption and body weight)
Dose / conc.:
6.33 mg/kg bw/day (actual dose received)
Remarks:
males (dose equivalent to 50 mg/kg feed nominal concentration. Calculated by food consumption and body weight)
Dose / conc.:
61.72 mg/kg bw/day (actual dose received)
Remarks:
males (dose equivalent to 500 mg/kg feed nominal concentration. Calculated by food consumption and body weight)
Dose / conc.:
0.65 mg/kg bw/day (actual dose received)
Remarks:
females (dose equivalent to 5 mg/kg feed nominal concentration. Calculated by food consumption and body weight)
Dose / conc.:
5.95 mg/kg bw/day (actual dose received)
Remarks:
females (dose equivalent to 50 mg/kg feed nominal concentration. Calculated by food consumption and body weight)
Dose / conc.:
58.94 mg/kg bw/day (actual dose received)
Remarks:
females (dose equivalent to 500 mg/kg feed nominal concentration. Calculated by food consumption and body weight)
No. of animals per sex per dose:
50
Control animals:
yes, plain diet
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: weekly, after 3 months monthly

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- 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

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER:
ORGAN WEIGHTS: Liver, adrenals, brain, heart, kidneys and gonads were weighed.
FOOD CONVERSION: Measured as g food consumed/kg body weight/day
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see Table 1)
HISTOPATHOLOGY: Yes (see Table 1)
Statistics:
For each time point and parameter, a uni-variate statistical analysis was conducted. Due to the routine manner of the analysis system, parameter free methods were applied. Each treated group was compared to the control group in respect of dispersion and displacement. In addition a trend test was applied considering all groups.
Survival analysis was performed by the generalised Wilcoxon Test (Breslow 1970) and the generalised Savage Test (Mantel-Cox 1966). The Mantel-Cox and Breslow Tests differ in the way they weight observations. The Breslow Test gives greater weight to early observations, and is less sensitive to late events which occur when few animals on the study remain alive. Both tests are valid in large samples whether the censoring patterns (moribund sacrifice or interim sacrifice) are equal or unequal.
Statistical analysis is performed to draw attention to distinct values. A statistically significant difference between two values does not necessarily imply biological relevance of that deviation and is not conclusive for a treatment related effect.
Details on results:
CLINICAL SIGNS AND MORTALITY
No clinical signs and no signs of local and/or systemic toxicity were observed. Statistical analysis showed significant intergroup and intragroup differences in survival time. These differences were not dose dependent and therefore attributed to spontaneous variation rather than to the treatment (see Table 2, 3 & 4). The intermediate dose group of treated males (50 mg/kg feed) showed a significantly shorter survival time than the control whilst for females the low and high dose group (5 and 500 mg/kg feed) have significantly longer survival times than the respective control. Since the effect is not dose related it can be inferred that the observed effects are not related to treatment.
Mortalities: male (out of 50 animals at initiation): 33, 36, 40 and 34; females (out of 50 animals at initiation): 36, 24, 27 and 19 in the control, 5, 50 and 500 ppm dose groups.

BODY WEIGHT AND WEIGHT GAIN
The mean body weight gain of both males and females of the treated groups was similar to the controls.

FOOD CONSUMPTION AND COMPOUND INTAKE
Food intake of both males and females of the treated groups was similar to the controls. Based on feed intake, the mean daily intake of test substance was calculated to be 0, 0.7, 6 or 62 mg/kg bw/day in males and 0, 0.7, 6 or 59 mg/kg bw/day in females.
FOOD CONVERSION
Statistical analysis of food conversion data was not performed. Specific food consumption in relation to body weight of all treated groups was similar to that of controls.

ORGAN WEIGHTS
Organ weights and ratios showed marked inter- and intra-group differences. These variations are common in aged animals. The analysis of organ weights and ratios revealed a slight increase in brain, heart, kidney and adrenal weights in males, and a slight increase in heart, adrenal and ovary weights in females in both the intermediate and high dosage groups (50 and 500 mg/kg feed). However, as such weight variations are not unusual in aged mice, and since the histopathological findings in these organs did not indicate any difference between the controls and the treated animals, no experimental significance is attributed to these fluctuations. Moreover the histopathological findings in these organs did not indicate any difference between the controls and the treated animals.

GROSS PATHOLOGY
The macroscopical appearances of the treated animals were comparable to those of the controls. All gross changes seen in some treated and control mice are regarded as incidental in nature.

HISTOPATHOLOGY: NON-NEOPLASTIC
Microscopical lesions and changes found in some control and test animals and described as congenital, degenerative or inflammatory in nature are attributed to naturally occurring diseases which are common in aged mice of this breeding colony.

HISTOPATHOLOGY: NEOPLASTIC
Numerous benign and malignant tumours were observed in both control and treated mice. Frequency and type of the neoplasms occurring in this study were not influenced by the treatment.
Dose descriptor:
NOAEL
Effect level:
> 60.3 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: The top dose level did not produce inflammatory, degenerative, proliferative or neoplastic lesions on examination at the end of the 24 month dosing period. Therefore the NOAEL can be assigned as greater than the top dose.
Critical effects observed:
no

Table 2: Survival time data

Test group

Sex

Survival time

75th quantile

Breslow

P-value

Mantel-Cox

P-value

1. Control

M

497 days

2. 5 ppm

M

553 days

0.0629

0.0891

3. 50 ppm

M

427 days

4. 500 ppm

M

516 days

1. Control

F

500 days

2. 5 ppm

F

622 days

0.0225

0.0330

3. 50 ppm

F

568 days

4. 500 ppm

F

720 days

Table 3: Median survival times and parameters of the proportional hazards model

Group

Median Survival Time (Days)

Parameter Estimates (Beta)

Standard Error of Estimate

Z

Probability of Greater Absolute Value

Males:

Control

725

-

-

-

-

Low Dose

671

0.138

0.284

0.486

0.627

Intermediate Dose

609

0.610

0.272

2.241

0.025

High Dose

682

0.203

0.281

0.721

0.471

Females:

Control

728

-

-

-

-

Low Dose

>725

-0.539

0.293

-1.837

0.066

Intermediate Dose

>725

-0.282

0.278

-1.011

0.312

High Dose

>725

-0.907

0.321

-2.825

0.005

Overall test: Males - X2 = 6.19, p=0.103; Females - X2=9.21, p=0.027

Table 4: General occurrence of tumours

 

0 ppm

5 ppm

50 ppm

500 ppm

 

M

F

M

F

M

F

M

F

Examined microscopically

50

50

50

50

50

50

50

50

Mortality

33

36

36

24

40

27

34

19

Terminal sacrifice

17

14

14

26

10

23

16

31

Without tumours

20

16

18

16

26

21

19

17

With 1 tumour

26

29

29

20

21

21

24

24

With 2 tumours

4

5

2

10

2

8

6

8

With 3 tumours

 

 

1

4

1

 

1

1

With ≥4 tumours

0

0

0

0

0

0

0

0

Number of tumour bearing animals

30

34

32

34

24

29

31

33

 

Conclusions:
It can be inferred from the study that the test substance when administered to mice daily in the diet over a period of 24 months at dietary levels of 5, 50 and 500 mg/kg feed corresponding to a mean daily intake of 0.7, 6 and 62 mg/kg bw in male and 0.7, 6 and 59 mg/kg bw in female animals respectively did not produce inflammatory, degenerative, proliferative or neoplastic lesions.
Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Survival < 50% at termination
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
GLP compliance:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): TK 10048
- Lot/batch No.: 26580
- Appearance: yellow
- Physical state: solid (powder)
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Anglia Laboratory Animals, Alconbury, UK
- Age at study initiation: 28 ± 1 day
- Weight at study initiation: 70 - 90g; weights of the rats per group differed by no more than -2.5 g.
- Housing: 5 animals/cage (wire mesh floors)
- Diet: ad libitum; Spratt's Laboratory Diet 2
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2
- Humidity (%): 50 ± 5
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with Spratt's Laboratory Diet 2
- Storage temperature of food: in heat sealed, opaque polythene bags
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Performed every 13 weeks. Samples were extracted with distilled chloroform and determined spectrophometrically.

Recovery
- 1000 ppm: 95 - 105%
- 3000 ppm: 98.3 - 101.6%
- 10000 ppm: 90 -103%
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
Daily
Post exposure period:
No
Dose / conc.:
37.7 mg/kg bw/day (actual dose received)
Remarks:
males (dose equivalent to 1000 ppm nominal concentration. Calculated by food consumption and body weight)
Dose / conc.:
113.2 mg/kg bw/day (actual dose received)
Remarks:
males (dose equivalent to 3000 ppm nominal concentration. Calculated by food consumption and body weight)
Dose / conc.:
382.6 mg/kg bw/day (actual dose received)
Remarks:
males (dose equivalent to 10,000 ppm nominal concentration. Calculated by food consumption and body weight)
Dose / conc.:
50.4 mg/kg bw/day (actual dose received)
Remarks:
females (dose equivalent to 1000 ppm nominal concentration. Calculated by food consumption and body weight)
Dose / conc.:
147.7 mg/kg bw/day (actual dose received)
Remarks:
females (dose equivalent to 3000 ppm nominal concentration. Calculated by food consumption and body weight)
Dose / conc.:
501.9 mg/kg bw/day (actual dose received)
Remarks:
females (dose equivalent to 10,000 ppm nominal concentration. Calculated by food consumption and body weight)
No. of animals per sex per dose:
50
Control animals:
yes, plain diet
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: weekly for the first eight weeks then fortnightly

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined: Yes
- Mean daily diet consumption calculated as g food/rat/week: Yes
- 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: Yes

WATER CONSUMPTION: Yes
- Time schedule for examinations: During weeks 6, 12 and 26
- Dose groups: control and 10000 ppm groups

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: weeks 0, 12, 26, 52, 78 and 103
- Dose groups that were examined: control and 10000 ppm groups

HAEMATOLOGY: Yes
- Time schedule for collection of blood: weeks 0, 6, 12, 25, 77 and 104
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes, overnight
- How many animals: 10/sex control and 10000 ppm group. The investigations were extended at week 25 to 10 females from the mid dose group (3000 ppm), at week 52 to 10 males and 10 females of the low and mid dose groups, at week 79 to 10 males of the low and mid dose groups and at week 102 to 10 males and 10 females fr the low and mid dose groups for packed cell volume, haemoglobin and red cell count.
- Parameters in table 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: weeks 6, 12, 25, 52, 77 and 102
- Animals fasted: Yes, overnight
- How many animals: 10/sex control and 10000 ppm group. The investigations were extended at weeks 52 to the 1000 and 3000 ppm groups for measurement of plasma glucose only and at week 85 for total serum protein and serum protein electrophoresis.
- Parameters in table 2 were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: weeks 6, 12, 26, 52, 78 and 103
- Metabolism cages used for collection of urine: No data
- How many animals: 10/sex control and 10000 ppm group
- Animals fasted: Yes, overnight
- Parameters checked in table 3 were examined.

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table 4)
HISTOPATHOLOGY: Yes (see table 5)
Statistics:
Although it is clear that statistics were used in this study, there is no description of the actual methods.
Details on results:
CLINICAL SIGNS AND MORTALITY
There were no visible signs of reaction to treatments. No marked differences between the distribution of mortalities in control and treated groups were observed.
Mortalities: males (out of 50 animals at initiation): 41, 41, 36 in 1000, 3000 and 10000 ppm dose groups, respectively, and 32 in the control; female (out of 50 animals at initiation): 28, 38, 29 in 1000, 3000 and 10000 ppm dose groups, respectively, and 28 in the control.


BODY WEIGHT AND WEIGHT GAIN
A marginally lower rate of bodyweight gain was recorded during the first 52 weeks of the study among males receiving 10000 ppm. Thereafter, body weight change was comparable to that of control animals.

FOOD CONSUMPTION
A transient reduction of food intake was recorded between weeks 6 and 78 for males receiving 10000 ppm. From week 79 till the study end, food intake was similar to that of controls.

COMPOUND INTAKE:
1000 ppm: 37.7 mg/kg bw (male); 50.4 mg/kg bw (female)
3000 ppm: 113.2 mg/kg bw (male); 147.7 mg/kg bw (female)
10000 ppm 382.6 mg/kg bw (male); 501.9 mg/kg bw (female)

WATER CONSUMPTION
Water consumption was not influenced as recorded in the controls and high dose animals during weeks 6, 12 and 26.

FOOD EFFICIENCY
Food efficiency was unimpaired

OPHTHALMOSCOPIC EXAMINATION
No abnormalities of the eyes were detected that were considered to be treatment related

HAEMATOLOGY
Minimally lower values for the red cell parameters were consistently recorded at weeks 6, 12, 25 and 52 for animals receiving 10000 ppm. At week 25, lower values were also recorded in females receiving 3000 ppm.
During week 77 a more marked reduction in red cell parameters was recorded in males receiving 10000 ppm although this could be accounted for by the low values recorded in 3 out of 10 of the rats examined.
Other small differences between values for control and treated rats, although in some cases attaining a level of statistical significance were considered to be of no toxicological significance, as all values were within the accepted range for rats of the age and strain employed.

CLINICAL CHEMISTRY
A marginally higher SAP (Serum alkaline phosphatase) value was recorded in week 12 for males receiving 10000 ppm and in week 102 for females of the same dose group. As this finding was not seen consistently in either males or females, it was considered to be of doubtful toxicological significance.
Higher glucose values were recorded during week 52 in some rats (particularly males) receiving 10000 ppm. This was however not considered a finding of toxicological significance since no dose dependent relationship could be seen when rats of the low and mid dose groups were subjected to examination. In addition, subsequent recordings of the glucose levels indicated no difference to control animals.
During week 77, a marked reduction in albumin levels was recorded in all male rats receiving 10000 ppm. Because later examinations (week 85) in all males of treated groups did not indicate any differences from controls, this abnormal finding at week 77 were considered to be of no toxicological significance.
All other parameters measured revealed similar values for controls and rats receiving 10000 ppm.

URINALYSIS
There were no differences in urinary parameters among controls or treatment groups.

ORGAN WEIGHTS
A slight but significant increase in relative liver weight was recorded in males receiving 1000 or 10000 ppm and in females receiving 3000 ppm. These changes were not dosage related and no significant increase in absolute liver weight was recorded. In adddition, in the absence of any histopathological changes, these findings were considered unrelated to treatment

GROSS PATHOLOGY
No treatment related changes were observed.

HISTOPATHOLOGY (NON-NEOPLASTIC):
There was no evidence that treatment with test substance induced any adverse effects.

HISTOPATHOLOGY (NEOPLASTIC):
There was no evidence to suggest that the administration of the substance was associated with the disturbance of the spontaneous tumour profile in the strain of rat employed.

A summary of the effects seen follows:

Endocrine glands:
The largest incidence of tumours in this category occurred in the pituitary gland, and this tumour was seen in rats from both control and treated groups. Pituitary gland tumours are commonly seen in laboratory rats of this age, and there was no evidence of a treatment-related change. The majority of tumours seen were pituitary gland adenomata. The incidence of tumours in other endocrine glands showed no evidence of a treatment-related change.

Cutaneous and subcutaneous tissue:
There was no evidence of a treatment-related effect in the incidence of tumours in cutaneous and subcutaneous locations.

Lymphoreticular system:
The low incidence of tumours of lymphoreticular origin showed no evidence to suggest a treatment-related effect.

Liver:
One malignant and five benign liver cell tumours were recorded. This was within the expected range.

Reproductive system:
The only neoplasms recorded in male rats were testicular interstitial cell tumours in three control rats and in one treated rat. Among female rats, the tumours recorded were four ovarian adenomas, one luteinoma, one uterine adenocarcinoma and one uterine fibrosarcoma. These tumours of the reproductive system are not uncommon in the laboratory rat and were considered to be of no toxicological significance.

Mammary tissue:
No treatment-related effect was seen in the incidence of the fibroadenomas, adenomas and adenocarcinomas recorded in this study.

Miscellaneous tumours:
The individual tumour types and the incidence of these neoplasms were within the normal range for this strain of rats as seen in the historical controls.

Total tumour incidence:
The total number of rats bearing neoplasms was similar in treated and control groups.
Dose descriptor:
NOAEL
Effect level:
> 10 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: corresponding to 382.6 mg/kg bw (male); 501.9 mg/kg bw (female)
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
NOEL
Remarks:
(systemic)
Effect level:
3 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: clinical signs; body weight; clinical chemistry; haematology / corresponding to 113.2 mg/kg bw (male); 147.7 mg/kg bw (female)
Remarks on result:
other: Effect type: toxicity (migrated information)
Critical effects observed:
no
Conclusions:
The NOEL (systemic toxicity) in this study is 3000 ppm, equivalent to 113.2 mg/kg bw/day (male) and 147.7 mg/kg bw/day (female). The individual tumour types and the incidence of these neoplasms were within the normal range for this strain of rats. The total number of rats bearing neoplasms was similar in treated and control groups.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. No carcinogenic effects were observed at dose levels exceeding the limit dose in life-long feeding studies in rats and mice. As a result, the substance is not classified for repeated dose toxicity under Regulation (EC) No. 1272/2008, as amended for the thirteenth time in Regulation (EC) No. 2018/1480.

Additional information

In a combined chronic / carcinogenicity study, the test substance (no data on purity) wasadministered to50 Sprague-Dawley rats per sex per dose indietat dose levels of 0,1000, 3000 or 10000 ppm (mg/kg feed) for 104 weeks. Calculated from feed intake and presented relative to body weights, compound intake amounted to 37.7, 113.2, 382.6 mg/kg bw/d for male animals and 50.4, 147.7 and 501.9 mg/kg bw/d for female animals.

There were no compound related effects in mortality, clinical signs,ophthalmoscopic evaluations, water consumption, urinalysis, organ weights as well as gross and histopathology parameters.

Body weights gain were marginally lower during the first 52 weeks of the study among males receiving 10000 ppm. Thereafter, body weight change was comparable to that of control animals. The reduced body weights were associated with reduced food consumption which dropped between weeks 6 and 78 in males. Thereafter, food consumption normalised and was comparable with that of control animals. Haematology evaluations revealed consistently lower red cell parameters in males of the highest dose group between week 6 and 77. In females, red cell parameters were reduced only in the intermediate group and only during the 25thweek appraisal.A marginally higher SAP (Serum alkaline phosphatase) value was recorded in week 12 for males receiving 10000 ppm and in week 102 for females of the same dose group. As this finding was not seen consistently in either males or females, it was considered to be of doubtful toxicological significance.Higher glucose values were recorded during week 52 in some rats (particularly males) receiving 10000 ppm.This was however not considered a finding of toxicological significance since no dose dependent relationship could be seen when rats of the low and mid dose groups were subjected to examination. In addition, subsequent recordings of the glucose levels indicated no difference to control animals.Amarked reduction in albumin levelswas recorded duringweek 77in all male rats receiving 10000 ppm.However, because later examinations (week 85) in all males of treated groups did not indicate any differences from controls,this abnormal findingat week 77 were considered to be of no toxicologicalsignificance.The NOEL is 3000 ppm

At the doses tested, there wasnotreatment related increase in tumour incidence when compared to controls (Ciba Geigy Ltd. 1978).

This chronic/carcinogenicity study in theratis acceptable and satisfies the guideline requirement for a chronic/carcinogenicity studyOECD 453 inrats.

In a carcinogenicity study in mouse, the test substance was administered to50Tif: MAGf (SPF)mice per sex per dose indietat dose levels of 0, 5, 50 or 500 ppm (= mg/kg feed)for 2 years. This amounted to a compound intake of0.66, 6.33 and 61.72 mg/kg bw, respectivelyfor males and0.65, 5.95 and 58.94 mg/kg bw, respectively forfemales.

There were no compound related effects in mortality, clinical signs, body weight, food consumption, organ weights, or gross and histologic pathology. The NOAEL is> 500 ppm.

At the doses tested, there was no treatment related increase in tumour incidence when compared to controls (Ciba Geigy Ltd. 1981).

This carcinogenicity study in themouse is acceptable and satisfies theguideline requirement for a carcinogenicity study OECD 451 in mice.