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In a combined chronic and oncogenicity study, Wistar rats were exposed for 130 weeks at dose levels of 40, 140 and 500 ppm. 10 animals/sex/dose were sacrificed after 52 weeks of treatment and 20/sex/dose after 104 weeks. The remaining 50/sex/dose were assigned to the oncogenicity phase of the study and designated for sacrifice at 130 weeks for evaluation of carcinogenicity following lifetime exposure to the test substance. No treatment-related clinical signs of toxicity were observed in any dose group. Statistically significant increased bw gain was noted for males of the 2 highest dosage groups from the chronic toxicity phase of the study, and for females of the 40 and 500 ppm dosage groups from the oncogenicity phase of the study. Transient increased food consumption values were noted during the treatment period in all treated groups of the oncogenicity animals, and in treated groups of chronic toxicity males. Ophthalmologic examinations and hearing tests did not show treatment-related findings. Urinalysis data revealed no changes considered to be related to the compound administration. Hematological investigations showed statistically significant decreased hemoglobin (HB) concentration and hematocrit (HCT) values in both sexes of the highest dosage group after 52 weeks only. In addition, statistically significant decreased erythrocyte count (RBC) was noted for females of the highest dosage group after 52 weeks. Mean corpuscular haemoglobin concentration (MCHC) was statistically significant decreased for these female animals after 52, 78 and 104 weeks of treatment. The assessment of biochemical data indicated no changes of toxicological significance for standard biochemical parameters. No treatment-related macroscopic changes were noted. There were no signs of oncogenic potential of GA in this study. No NOEL for female rats was determined in this study. Changes in biochemical parameters (increased kidney GS activity) were noted for all treated females. In addition, changes in hematological parameters (decreased hemoglobin concentration, decreased hematocrit values, decreased erythrocyte count, decreased mean corpuscular hemoglobin concentrations) (500 ppm group), changes in biochemical parameters (inhibition of liver GS activity (140 and 500 ppm)), inhibition of brain GS activity (500 ppm), decreased concentrations of glutathione in the liver (140 and 500 ppm), decreased concentrations of GSH in blood (140 and 500 ppm), increased ammonia levels in urine and brain (500 ppm), and increased kidney weights (500 ppm) were noted for female rats. NOEL for male rats was 40 ppm (approximately 2 mg/kg bw/d) based on changes in biochemical parameters (inhibition of liver GS activity (140 and 500 ppm), increased kidney GS activity (140 and 500 ppm), decreased GSSG levels in the liver (140 and 500 ppm), decreased GSH levels in blood (500 ppm), increased GSSG concentrations in blood (500 ppm), changes in hematological parameters (decreased hemoglobin concentration, decreased hematocrit values) (500 ppm group), and increased kidney weights (140 and 500 ppm) noted for males rats. In the absence of clinical signs or correlative pathological changes, observed hematological and biochemical effects, and increased kidney weights were not considered to be adverse.

The NOAEL for male and female rats was considered to be > 500 ppm (24.4 and 28.7 mg/kg bw/d for males and females, respectively). The choice of the highest dose level in this study was too low with regard to the requirements of the guideline. However, there is a second oncogenicity study in rats available where higher dose levels have been used.

In the abovementioned oncogenicity study, Glufosinate-ammonium (GA) was administered by admixture with the diet to Wistar rats (60/sex/dose level) at concentrations of 1000, 5000 or 10000 ppm for 104 weeks. The concentrations corresponded to a dose rate of 0, 45.4, 228.9 and 466.3 mg/kg bw/d for males, and 0, 57.1, 281.5 and 579.3 mg/kg bw/d for females.

No treatment related mortalities or clinical signs of toxicity were observed. Statistically significant decreased bw was noted for males and females of the 5000 and 10 000 ppm groups during the first weeks of treatment. Relative food consumption was decreased in animals of the 1000, 5000 and 10 000 ppm groups during the first weeks of treatment. When compared to controls

higher relative food consumption was noted for males of the 5000 and 10 000 ppm groups during weeks 3 and 4 of study, and for females of the 10 000 ppm group during weeks 3 and 4 of study. Higher relative food consumption was also noted for males of the 10 000 ppm groups from week 21 until the end of the study. Hematological investigations revealed no treatment-related effects on differential white cell count. Statistically significant increased weight of the kidneys was noted for all treated male and female animals. Gross pathology showed lower incidence of pituitary nodules for males in the treated groups when compared to the controls. This finding was confirmed microscopically by a statistically significant negative trend with respect to dose for pituitary adenoma of the pars distalis in males of the 5000 and 10 000 ppm. However, these values were within the limits of the historical control data. Microscopic evaluations showed no increase in any type of neoplasm in any dose group. Statistically significant increase in retinal atrophy characterised by partial or complete loss of the outer nuclear layer of one or both eyes was noted for males and females of the 10 000 ppm group and for females of the 5000 ppm group. In kidneys, a statistically significant decrease of multifocal corticomedullary mineralisation was noted for all treated females, and there was a statistically significant decrease in caliceal mineralisation in females of the 5000 and 10 000 ppm groups. The etiology of the effects is not known. Whether it means an improved kidney function has not been investigated. No indications of any oncogenic potential of GA were observed at doses up to 10000 ppm (equivalent to 466 and 579 mg/kg bw/d for males and females, respectively). No NOEL for male and female rats was determined in this study. Increased kidney weights were noted for all treated animals. In addition statistically significant increase in retinal atrophy was noted for females of the 5000 and 10 000 ppm groups and for males of the 10000 ppm group. Reduced bw was also noted for animals of the 5000 and 10 000 ppm groups. Two commonly occurring age-related changes in rats appear to have been reduced by treatment: the incidence of pituitary adenoma in males (5000 and 10000 ppm groups) and mineralisation of the kidneys in females at all doses. The etiology of these effects is not known. The NOAEL was considered to be 5000 ppm (228.9 mg/kg bw/d) and 1000 ppm (57.1 mg/kg bw/d) for males and females, respectively based on the effects on the retina.

In a 2-year oncogenicity study in mice, Glufosinate-ammonium was administered by admixture with the diet to NMRI mice (60/sex/dose) at concentrations of 0 (controls), 20, 80 or 160 (males only) or 320 (females only) ppm. 10/sex/dose were designed for interim sacrifice after 52 weeks of treatment (chronic toxicity groups); 50/sex/dose were designed for terminal sacrifice after 104 weeks (2 years) of treatment (oncogenicity groups). For the oncogenicity groups the concentrations corresponded to a dose rate of 0, 2.8, 10.8 and 22.6 mg/kg bw/d for males, and 0, 4.2, 16.2 or 64 mg/kg bw/d for females. For the chronic toxicity groups the concentrations corresponded to a dose rate of 0, 3.2, 13 or 25 mg/kg bw/d for males, and 0, 4.4, 17.9 or 69.2 mg/kg bw/d for females. Special investigations were carried out on glutathione levels in whole blood and liver tissue after 104 weeks of treatment. The mortality rate of males of the highest dosage group was statistically significant increased after 104 weeks of treatment when compared with that of control animals (this effect was considered to be treatment-related, but the cause of the higher mortality could not be established based on the findings observed). No treatment-related clinical signs of toxicity were noted. Statistically significant reduced mean bw gain was noted for animals of the highest dosage group in the oncogenicity study and for males of the highest dosage group in the chronical toxicity study when compared with the control mice. The mean food consumption of all mice was comparable. Ophthalmologic examinations and hearing tests did not show treatment-related findings. Haematological investigations revealed no changes considered to be related to the compound administration. The assessment of biochemical data indicated the following substance-related effects: slightly increased glucose level for male and female mice of group 4 at 52 weeks of treatment; slightly increased aspartate aminotransferase (ASAT) activity for female mice of group 4 at 52 weeks of treatment; slightly decreased glutathione level in whole blood for male mice of group 4 at 104 weeks of treatment. No organ weight changes were considered to be treatment-related although statistically significant reduced absolute and relative liver weights were noted for treated females in the oncogenicity study. No treatment-related macroscopic or microscopic changes were observed. No increase in any type of neoplasm in any dose group was noted.

No indications of any oncogenic potential of GA were observed for female mice at doses up to 320 ppm (highest dose level tested, equivalent to 64 mg/kg bw/d) or for male mice at doses up to 160 ppm (highest dose level tested, equivalent to 22.6 mg/kg bw/d). NOEL/NOAEL for male and NOEL for female mice was 80 ppm (equivalent to 11 and 16 mg/kg bw/d for males and females, respectively) based on increased mortality rate (males only), reduced bw gain and changes in biochemical parameters (increased glucose level, increased aspartate aminotransferase (ASAT) activity (females only), decreased glutathione level in blood (males only) noted for animals of the highest dosage level. The NOAEL was 320 ppm (64 mg/kg bw/d) for female animals.

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
Study period:
Apr 1994 - Mar 1998
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Version / remarks:
May 1981
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.32 (Carcinogenicity Test)
Version / remarks:
Jul 1996
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPP 83-2 (Carcinogenicity)
Version / remarks:
Nov 1984
Deviations:
no
GLP compliance:
yes
Species:
rat
Strain:
Wistar
Remarks:
HanIbm:WIST, SPF quality
Details on species / strain selection:
Recognized by the international guidelines as the recommended test system.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: BRL, Biological Research Laboratories Ltd., CH-4414 Fullinsdorf/Switzerland
- Total of animals: 240 males and females each
- Age at delivery: 4 weeks
- Body weight and range (at acclimatization): males: 61-101 grams (mean: 76 grams); females: 46-70 grams (mean: 58 grams)
- Fasting period before study: not specified
- Housing: groups of 5
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 14 days

DETAILS OF FOOD AND WATER QUALITY:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/- 3
- Humidity (%): 40-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12 with music

IN-LIFE DATES: From: April 12, 1994 (delivery) To: April 24, 1996 (first day of necropsy)
Route of administration:
oral: feed
Vehicle:
other: feed (pelleted standard Kliba 343 rat/mouse maintenance diet)
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): Every two weeks
- Mixing appropriate amounts with (Type of food): pelleted standard Kliba 343 rat/mouse maintenance diet
- Storage temperature of food: At room temperature in disposable paper bags
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test substance was found to be homogeneously distributed in the prepared pellets, and the mean concentrations were close to the nominal concentrations.
Duration of treatment / exposure:
at least 104 weeks
Frequency of treatment:
continuous
Dose / conc.:
1 000 ppm
Dose / conc.:
5 000 ppm
Dose / conc.:
10 000 ppm
No. of animals per sex per dose:
60
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: The high dose of 10,000 ppm was chosen based on overt toxicity and lethality at 20,000 ppm in a previous 13-week feeding study. A NOAEL was considered to be 40 ppm upon increases in absolute and relative kidney weights in males at 140 and 500 ppm in a chronic toxicity study. In a new 90-day feeding study in Wistar rats recently performed, glufosinate ammonium was applied at dietary concentrations of 0 - 7,500 - 10,000 - 20,000 mg/kg (ppm). The study resulted in signs of overt toxicity in both sexes at 20,000 ppm and in lethality in the top dosed females (2/10). Based upon all relevant data, a dose regime of 0 - 1,000 - 5,000 - 10,000 ppm was chosen for the conduct of this oncogenicity study in rats. The high dose is equivalent to 50% of a dose causing overt toxicity and lethality, and therefore was expected to meet the criteria for achieving the maximum tolerated dose (MTD).
- Rationale for animal assignment (if not random): random
- Rationale for selecting administration route: Simulates the possible route of human exposure
Positive control:
not included
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily. In addition, each rat had a weekly detailed clinical examination which included palpation for tissue masses

BODY WEIGHT: Yes
- Time schedule for examinations: weekly until week 13, every two 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: Yes

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

OPHTHALMOSCOPIC EXAMINATION: Yes / No / No data
- Time schedule for examinations:
- Dose groups that were examined:

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At 52, 78, and after 104 weeks (between 6 and 9.15 am)
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: No
- How many animals: All animals
- Parameters checked: differential leukocyte count (Diff. WBC count)

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, after 104 weeks, all animals
- Samples of the following tissues and organs were collected from all animals at necropsy and fixed in neutral phosphate buffered 4% formaldehyde solution:
Adrenal glands, Aorta, Auricles, Brain - including sections of medulla/pons, cerebral and cerebellar cortex, Cecum, Colon, Duodenum, Epididymides, Esophagus, Eyes - with optic nerve and Harderian gland, Femur - including joint, Heart, Ileum, Jejunum, Kidneys, Larynx, Lacrimal gland exorbital, Liver, Lungs infused with formalin,Lymph nodes - mandibular mesenteric, Mammary gland area, Nasopharynx, Ovaries, Pancreas, Pituitary gland, Prostate gland, Rectum, Salivary gland - mandibular sublingual, Sciatic nerve, Seminal vesicles, Skeletal muscle, Skin, Spinal cord - cervical midthoracic lumbar, Spleen, Sternum with bone marrow, Stomach, Testes, Thymus - if present, Thyroid gland / parathyroid, Tongue, Trachea, Urinary bladder infused with formalin, Uterus, Vagina, All gross lesions and tissue masses.
- Organ weights: The following organ weights were recorded: Brain, kidneys, liver, spleen, testes, adrenals, heart, pituitary, ovaries, thyroid


HISTOPATHOLOGY: Yes
Sections of the following organs/tissues were examined microscopically (number of sections per organ) from all animals:
Adrenal glands (2), aorta (1), brain [medulla/pons, cerebrum, cerebellum] (4), bone (femur) (1), bone marrow (sternum) (1), epididymides (2), esophagus (1),
exorbital lacrymal glands (2), eyes (2), Harderian glands (2), heart (1), joint (knee) (1), kidneys (2), large intestine [cecum, colon, rectum] (3), larynx (1),
liver (2), lungs (2), lymph nodes [mandibular, mesenteric] (2), mammary gland area (1), optic nerves (2), ovaries (2), pancreas (1), parathyroid glands (2),
pituitary gland (l), prostate (1), salivary glands [sublingual, mandibular] (4), sciatic nerve (1), skeletal muscle (l), skin (1), small intestine [duodenum, jejunum, ileum] (3), spinal cord (cervical, midthoracic, lumbar) (3), spleen (1), stomach (1), testes (2), thymus (1), thyroid gland (2), tongue (1), trachea (1), urinary bladder (1), uterus (3), vagina (1) and all gross lesions.
Statistics:
- ANOVA, Dunnett's test, Dunnett's test, Steel test: body weights, food consumption, organ weights, clinical laboratory data
- Fisher's test: spontaneous mortality
- Statistical evaluation of neoplastic lesions was performed according to Peto et al., 1980, using the test for positive trend with respect to dose rates.
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
- control: 16 males, 17 females
- 1000 ppm: 11 males, 14 females
- 5000 ppm: 9 males, 16 females
- 10,000 ppm: 12 males, 17 females
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
- 10,000 ppm: In males, mean body weight was up to 12% lower than in controls in weeks 2 to 4. In females, it was up to 11% lower in weeks 1 to 5.
- 5,000 ppm: In females, 3-5% decrease and 9% decrease in males in weeks 2 and 3
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
- 10,000 ppm: In both sexes, food consumption was temporarily depressed for 2 weeks. Following this initial effect there were no treatment-related effects until food consumption in males at 10,000 ppm became generally higher than in controls (by 3-11%) from weeks 21/22 to weeks 73/74 (except for weeks 37/38), after which there was no difference from control in that sex group. Relative food consumption was lower by 29% in males and 20% in females
- 5,000 ppm: In both sexes, food consumption was temporarily depressed for 2 weeks. Following the initial depression of food intake, food consumption remained generally statistically significantly lower than in controls from weeks 6/7 to weeks 19/20 in males (by 4-10%) and weeks 3/4 to weeks 19/20 in females (by 3-12%). In the absence of a similar effect at the higher dose, this is not considered to be treatment-related. Relative food consumption was lower by 29% in males and 24% in females.
- 1,000 ppm: In both sexes, food consumption was temporarily depressed for 1 weeks. Relative food consumption was lower by 15% in males and 11% in females
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
Treatment had no effect on differential white cell count.
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
In both sexes and at all doses there was a slight but approximately dose-related increase in weight of the kidneys, which was shown in absolute weight, organ/body weight ratio and organ/brain weight ratio. At 10,000 ppm absolute kidney weight in males was 27%, and in females 22%, higher than in controls.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
The type, incidence and severity of macroscopic findings did not indicate any toxic or oncogenic effect.
In males, the incidence of pituitary nodules was significantly lower at 18, 8, 9, and 9 (control, 1000 ppm, 5000 ppm, 10000 ppm, respectively)
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
A statistically significant decrease of multifocal corticomedullary mineralisation was noted in females at all doses.
- 10,000 ppm: A statistically significant increase in retinal atrophy, characterised by partial or complete loss of the outer nuclear layer of one or both eyes, was noted in males and females; There was a statistically significant decrease in caliceal mineralisation in females. In males, the caliceal mineralisation was not statistically significant.
- 5,000 ppm: A statistically significant increase in retinal atrophy, characterised by partial or complete loss of the outer nuclear layer of one or both eyes, was noted in males and females; There was a statistically significant decrease in caliceal mineralisation in females. In males, the caliceal mineralisation was not statistically significant.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
No indications of any oncogenic potential of the test substance were observed at doses up to 10,000 ppm, equivalent to approximately 500 mg/kg/day.
Details on results:
Test article intake reflects relative food consumption and in this study the highest test article intakes were seen in weeks 2/3.
Over the whole study, test article intake was approximately in direct proportion to the concentration of the test substance in the food:
- Males (mg/kg bw/day): 45.4 (1000 ppm), 228.9 (5000 ppm), 466.3 (10,000 ppm)
- Females (mg/kg bw/day): 57.1 (1000 ppm), 281.5 (5000 ppm), 579.3 (10,000 ppm)
Relevance of carcinogenic effects / potential:
Pituitary gland
There was a statistically significant negative trend with respect to dose for pituitary adenoma of the pars distal is in males at 5,000 ppm and 10,000 ppm: 24, 20, 13*, 13* for control, 1000 ppm, 5000 ppm, and 10000 ppm, respectively (*=one-sided Exact Fisher test, p<0.05). However, findings were still within the limits of the historical control data.

There were no treatment-related effects in relation to neoplastic findings, the incidence and organ distribution of all other findings being considered comparable with controls.
Dose descriptor:
NOAEL
Remarks:
chronic toxicity
Effect level:
5 000 ppm
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Effects on retina
Dose descriptor:
NOAEL
Remarks:
chronic toxicity
Effect level:
1 000 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: effects on retina
Dose descriptor:
NOEL
Remarks:
carcinogenicity
Effect level:
10 000 ppm
Based on:
test mat.
Sex:
male/female

Table 1: Organ weights

Kidney weight in the test substance-related groups as % of control

 

1,000 ppm

5,000 ppm

10,000 ppm

 

M

F

M

F

M

F

Absolute weight

118**

118**

113*

115**

127**

122**

Kidney to body weight ratio

128**

113*

126**

124**

135**

118**

Kidney to brain weight ratio

118

116**

124*

115**

125*

122**

* = statistically significantly different from control (<0.05)

** = statistically significantly different from control (<0.01)

Table 2: Histopathological results

 

Number of animals with microscopic findings treatment-related changes

Sex

Males

Females

Dose (ppm)

0

1000

5000

10000

0

1000

5000

10000

No. examined

60

60

60

60

60

60

60

60

Kidneys

 

 

No. examined

No with findings

 

60

58

 

60

53

 

60

53

 

60

56

 

59

50

 

60

53

 

60

45

 

60

45

Caliceal mineralization

10

10

5

5

26

23

16*

14*

Corticomedullary

mineralization

-

-

-

-

34

22*

16**

17**

Pituitary gland

No. examined

No with findings

60

41

60

36

60

21

60

35

59

45

60

43

60

37

60

44

Adenoma of

pars distalis

24

20

13*

13*

38

36

25*

35

Eyes

No. examined

No with findings

60

5

60

6

60

7

60

14

58

7

60

4

59

19

59

32

Retinal atrophy

4

3

4

12*

3

2

19**

29**

* = One-sided Exact Fisher test (<0.05)

** = One-sided Exact Fisher test (<0.01)

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
Aug 1983 - Sep 1985
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
GLP compliance:
yes
Species:
mouse
Strain:
NMRI
Remarks:
SPF quality
Details on species / strain selection:
The test system is recognized by the guidelines of the international regulatory agencies as a suitable rodent mammalian species for studies of this type.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: KFM, Kleintierfarm Madoerin AG, CH 4414 Fuellinsdorf / Switzerland
- Age at study initiation: 4 weeks
- Weight at study initiation:18 - 27 g (males), 15 - 24 g (females)
- Housing: individually
- Diet (e.g. ad libitum): pelleted standard Kliba No. 343 rat / mouse maintenance diet, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 10 days under test conditions, after veterinary examination

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2 °C
- Humidity (%): 55 +/- 10 %
- Air changes (per hr):10 - 15
- Photoperiod (hrs dark / hrs light): 12 h / 12 h
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): at least twice monthly
- Mixing appropriate amounts with (Type of food): standard Kliba No. 343 rat / mouse maintenance diet
- Storage temperature of food: room temperature
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyses of the test article were performed every 6 months.
Stability and homogeneity of the test article in the feed was determined before test initiation. Intercurrent sampling for analyses for concentration and homogeneity was performed at three-month intervals. Analyses were performed in the RCC Analytical Chemistry Laboratory, according to a method supplied by the sponsor.
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
daily
Dose / conc.:
0 ppm
Remarks:
Group 1, males and females
Dose / conc.:
20 ppm
Remarks:
Group 2, males and females
Dose / conc.:
80 ppm
Remarks:
Group 3, males and females
Dose / conc.:
160 ppm
Remarks:
Group 4, males
Dose / conc.:
320 ppm
Remarks:
Group 4, females
No. of animals per sex per dose:
60
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: Based on a preliminary 13-week feeding study in mice.
Observations and examinations performed and frequency:
MORTALITY: Yes
- Time schedule: twice daily

CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

DERMAL IRRITATION (if dermal study): No

BODY WEIGHT: Yes
- Time schedule for examinations: weekly during months 1 - 3 and twice monthly thereafter

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Time schedule: The food consumption was recorded for a 7-day period and the mean daily food consumption calculated. These data were recorded weekly during months 1 - 3 and twice monthly thereafter.
- The food nominal dosage level was calculated for each cage. Group means were calculated thereafter.

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

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: at pretest and at 6, 12, 18 and 24 months of treatment
- Dose groups that were examined: 10 animals per sex and group

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 52 and 104 weeks
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: No
- How many animals: five animals of each sex and group
- Parameters examined: erythrocyte count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, reticulocyte count, nucleated erythrocytes - normoblasts, heinz bodies, methemoglobin, total leukocyte count, differential leukocyte count, red cell morphology

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after 52 and 104 weeks
- Animals fasted: Yes (18 hour fasting period)
- How many animals: five animals of each sex and group
- Parameters examined: glucose, urea, creatinine, total bilirubin, total cholesterol, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, gamma-glutamyl-transferase, sodium, potassium, chloride, albumin, total protein, reduced glutathione, oxidized glutathione, total glutathione

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER:
- Hearing Tests: at pretest, and at 6, 12, 18 and 24 months of treatment.
- Examination of teeth and mucous membranes: weekly during the first three months and twice monthly thereafter.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes
Statistics:
The following statistical methods were used to analyze the body weights, food consumption, organ weights and clinical laboratory data:
- Univariate one-way analysis of variance was used to assess the significance of intergroup differences.
- If the variables could be assumed to follow a normal distribution, the Dunnett-test (many to one t-test) based on a pooled variance estimate was applied for the comparison between the treated groups and the control groups.
- The Steel-test (many-one rank test) was applied when the data could not be assumed to follow a normal distribution.
For the overall spontaneous mortality data, the Fisher's exact test for 2 x 2 tables was applied.
Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables.
Individual values, means, standard deviations and statistics were rounded off before printing. For example, test statistics were calculated using exact values for means and pooled vairances and then rounded off to two decimal places. Therefore, two groups may display the same printed means for a given parameter, yet display different test statistics values.
Clinical signs:
no effects observed
Description (incidence and severity):
No treatment-related clinical symptom or sign of toxicity was noted.
Mortality:
mortality observed, treatment-related
Description (incidence):
The mortality rate of the group 4 males was significantly increased after 104 weeks when compared with that of the other treated and control animals. This effect is considered to be treatment-related, but the cause of the higher mortality could not be established based on the findings observed.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Animals for the one-year interim sacrifice:
The group 4 males displayed mostly significantly reduced body weight gain between weeks 3 and 33 when compared with the other treated and control mice.

Oncogenicity animals (two years):
Isolated, significantly reduced body weight gain was observed in the group 4 males. The group 4 females displayed significantly reduced body weight gain between weeks 7 and 31.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
The mean food consumption of all mice was comparable, no treatment-related effect was noted.

Test article consumption:
- Animals for the one-year interim sacrifice: The mean daily test article consumption was 3.2, 13 and 25 mg/kg bw for males and 4.4, 17.9 and 69.2 mg/kg bw for females of groups 2, 3 and 4, respectively.
- Oncogenicity animals: The mean daily test article consumption was 2.8, 10.8 and 22.6 mg/kg bw for males and 4.2, 16.2 and 64 mg/kg bw for females of groups 2, 3 and 4, respectively.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No treatment-related effect was noted.
Haematological findings:
no effects observed
Description (incidence and severity):
The assessment of hematological data (including differential blood counts) indicated no changes of toxicological significance at 52 and 104 weeks of treatment.
Treatment-unrelated: All statistical differences in the results of the hematological parameters were considered to be incidental and of normal biological variation.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
The assessment of biochemical data indicated the following substance-related effects at 52 and 104 weeks of treatment:
- slightly increased glucose level for male and female mice of group 4 at 52 weeks of treatment;
- slightly increased aspartate aminotransferase (ASAT) activity for female mice of group 4 at 52 weeks of treatment;
- slightly decreased glutathione level in whole blood for male mice of group 4 at 104 weeks of treatment.
These changes are indicative of a toxic effect related to the treatment.
Furthermore, a slightly decreased albumin and total protein level was noted for female mice of group 4 at 52 weeks of treatment; however, the decrease seems to be accidental and not treatment-related.
All other statistical differences in the results of the biochemical parameters were considered to be incidental and of normal biological variation.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
After 52 weeks of treatment, the absolute and relative spleen weights of the group 4 females were slightly but not significantly higher than those of the other treated and control mice.
After 104 weeks of treatment, no organ weight changes which are considered to be treatment-related could be detected because of wide variations in individual organ weights, although the absolute and relative liver weights of the groups 2 and 4 females were significantly lower than those of the controls.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Numerous gross findings were observed in the mice that died during the course of the study or that were sacrificed on schedule. The type and incidence of these gross findings do not indicate any toxic or oncogenic effects of the test article.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Numerous non-neoplastic lesions were noted. The type, incidence, and severity of these lesions are considered to be similar in both the treated and the control mice.
These non-neoplastic lesions mainly affected the large parenchymatous organs as well as the endocrine and reproductive organs.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
In the mice scheduled for the interim kill and for the mice scheduled for the terminal kill, a number of neoplastic lesions were observed. Their type and incidence, as well as the organ distribution were considered to be similar in both the treated and the control mice. The same applied with respect to the number of mice bearing one or more neoplasms, the number of benign and malignant neoplasms per group, and the number of mice with metastases.
In the mice scheduled for interim kill, neoplasms were encountered mainly in the hemolymphoreticular system and the lungs.
Other effects:
no effects observed
Description (incidence and severity):
- Hearing tests: No treatment-related effect was noted.
- Examination of teeth and mucous membranes: No treatment-related effect was noted in any animal of any group.
Dose descriptor:
NOEL
Remarks:
also NOAEL for male mice
Effect level:
80 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: absence of adverse effects
Remarks on result:
other: about 11 mg/kg bw/d for males and about 16 mg/kg bw/d for females
Dose descriptor:
NOAEL
Effect level:
320 ppm
Sex:
female
Remarks on result:
other: corresponding to 64 mg/kg bw/d
Critical effects observed:
no

Table 1: Food Consumption (g/animal/day) Oncogenicity Males

 

Group 1

0 ppm

Group 2

20 ppm

Group 3

80 ppm

Group 4

160 ppm

Days 1 - 8

Weeks 1/2

6.9

7.0

6.5

6.7

Days 8 - 15

Week 2/3

7.3

7.0

6.3

7.5

Days 15 - 22

Week 3/4

7.1

5.7

5.6

5.7

Days 22 - 29

Week 4/5

6.9

6.0

6.0

6.0

Days 29 - 36

Week 5/6

6.5

6.7

6.5

6.3

Days 36 - 43

Week 6/7

6.6

6.6

6.6

6.5

Days 43 - 50

Week 7/8

6.7

6.6

6.4

6.3

Days 50 - 57

Week 8/9

6.4

6.3

6.0

6.0

Days 57 - 64

Week 9/10

6.3

6.9

6.9

6.9

Days 64 - 71

Week 10/11

6.2

6.3

6.0

5.8

Days 71 - 78

Week 11/12

6.9

6.8

6.8

6.5

Days 78 - 85

Week 12/13

6.8

7.0

6.9

7.2

Days 85 - 92

Week 13/14

6.1

6.1

6.0

5.9

Days 99 - 106

Week 15/16

6.3

6.5

6.4

6.1

Days 113 – 120

Week 17/18

5.9

6.1

6.1

5.8

Days 127 - 134

Week 19/20

6.5

6.5

6.2

6.1

Days 141 - 148

Week 21/22

5.7

5.6

5.7

5.6

Days 155 - 162

Week 23/24

5.9

6.8

6.6

6.7

Days 169 - 176

Week 25/26

5.8

5.9

5.7

5.7

Days 183 - 190

Week 27/28

6.3

5.9

5.9

5.7

Days 197 - 204

Week 29/30

6.3

6.7

6.2

7.0

Days 211 - 218

Week 31/32

7.1

6.9

5.6

6.4

Days 225 - 232

Week 33/34

6.3

6.6

6.3

6.1

Days 239 - 246

Week 35/36

6.8

7.5

6.3

6.6

Days 253 - 260

Week 37/38

6.2

6.7

6.2

6.1

Days 267 - 274

Week 39/40

5.8

5.8

5.8

6.1

Days 281 - 288

Week 41/42

6.1

6.1

6.1

6.0

Days 295 - 302

Week 43/44

5.7

6.3

6.1

5.9

Days 309 - 316

Week 45/46

5.7

5.9

5.9

5.7

Days 323 - 330

Week 47/48

6.2

5.9

5.8

5.6

Days 337 - 344

Week 49/50

6.1

6.6

6.1

6.1

Days 351 - 358

Week 51/52

6.5

6.0

5.8

6.0

Days 365 - 372

Week 53/54

6.5

6.5

6.3

6.5

Days 379 - 386

Week 55/56

6.2

6.2

5.9

5.9

Days 393 - 400

Week 57/58

6.3

6.6

7.3

6.0

Days 407 - 414

Week 59/60

6.4

6.2

5.9

5.9

Days 421 - 428

Week 61/62

6.2

5.9

6.1

6.4

Days 435 - 442

Week 63/64

6.1

6.2

6.5

6.3

Days 449 - 456

Week 65/66

5.6

5.8

5.8

5.7

Days 463 - 470

Week 67/68

5.9

5.9

5.9

5.8

Days 477 - 484

Week 69/70

6.3

6.4

6.8

6.6

Days 491 - 498

Week 71/72

6.4

6.1

6.5

6.0

Days 505 -- 512

Week 73/74

6.0

6.3

6.3

6.1

Days 519 - 526

Week 75/76

5.8

6.0

5.9

5.6

Days 533 - 540

Week 77/78

6.5

6.5

6.4

6.3

Days 547 - 554

Week 79/80

5.6

6.1

6.4

6.6

Days 561 - 568

Week 81/82

6.4

6.3

6.6

6.2

Days 575 - 582

Week 83/84

5.5

6.1

6.4

5.9

Days 589 - 596

Week 85/86

5.9

6.8

7.1

5.9

Days 603 - 610

Week 87/88

5.4

5.8

5.9

5.7

Days 617 - 624

Week 89/90

5.7

5.8

5.7

5.8

Days 631 - 638

Week 91/92

5.5

6.4

6.1

5.9

Days 645 - 652

Week 93/94

6.5

6.8

6.6

7.0

Days 659 - 666

Weeks 95/96

6.6

7.2

6.7

6.2

Days 673 - 680

Weeks 97/98

6.1

6.9

6.4

6.2

Days 687 - 694

Weeks 99/100

6.2

7.5

6.2

5.2

Days 701 - 708

Weeks 101/102

6.8

7.3

6.7

6.5

Days 715 - 722

Weeks 103/104

6.4

6.7

6.1

6.9

Days 722 - 728

Week 104

6.8

6.3

6.1

6.8

Mean

6.3

6.4

6.2

6.2

Table 2: Food Consumption (g/animal/day) Oncogenicity Females

 

Group 1

0 ppm

Group 2

20 ppm

Group 3

80 ppm

Group 4

160 ppm

Days 1 - 8

Weeks 1/2

5.6

5.9

5.9

5.7

Days 8 - 15

Week 2/3

6.4

6.0

6.4

6.3

Days 15 - 22

Week 3/4

5.9

5.0

5.2

5.1

Days 22 - 29

Week 4/5

6.1

5.8

6.0

5.5

Days 29 - 36

Week 5/6

6.3

6.2

6.5

5.9

Days 36 - 43

Week 6/7

6.3

6.6

6.6

6.2

Days 43 - 50

Week 7/8

6.4

6.6

6.0

5.8

Days 50 - 57

Week 8/9

6.4

6.7

6.1

6.0

Days 57 - 64

Week 9/10

6.2

7.1

6.9

6.9

Days 64 - 71

Week 10/11

6.4

6.7

6.4

6.4

Days 71 - 78

Week 11/12

7.4

7.3

6.9

6.9

Days 78 - 85

Week 12/13

7.1

7.9

7.2

7.9

Days 85 - 92

Week 13/14

6.5

7.0

6.7

6.3

Days 99 - 106

Week 15/16

6.7

7.0

6.7

6.4

Days 113 – 120

Week 17/18

6.3

6.7

6.4

6.1

Days 127 - 134

Week 19/20

6.7

6.6

6.4

6.5

Days 141 - 148

Week 21/22

6.2

6.2

5.7

5.7

Days 155 - 162

Week 23/24

6.4

7.3

6.7

7.3

Days 169 - 176

Week 25/26

6.2

6.3

5.9

5.8

Days 183 - 190

Week 27/28

6.6

6.5

6.0

5.8

Days 197 - 204

Week 29/30

7.0

7.9

7.6

7.9

Days 211 - 218

Week 31/32

7.2

7.5

7.3

6.6

Days 225 - 232

Week 33/34

6.5

7.2

6.3

6.4

Days 239 - 246

Week 35/36

7.1

9.4

7.6

7.0

Days 253 - 260

Week 37/38

6.6

7.4

6.8

6.6

Days 267 - 274

Week 39/40

6.2

6.6

6.4

6.3

Days 281 - 288

Week 41/42

6.3

6.5

6.1

6.1

Days 295 - 302

Week 43/44

5.5

7.2

7.0

6.2

Days 309 - 316

Week 45/46

5.8

6.9

6.5

6.1

Days 323 - 330

Week 47/48

6.2

6.9

6.6

5.7

Days 337 - 344

Week 49/50

6.4

7.3

6.9

6.5

Days 351 - 358

Week 51/52

6.5

6.6

6.5

5.8

Days 365 - 372

Week 53/54

7.1

7.4

7.7

6.8

Days 379 - 386

Week 55/56

6.6

6.9

6.9

6.1

Days 393 - 400

Week 57/58

6.9

7.1

7.1

6.3

Days 407 - 414

Week 59/60

6.9

6.7

7.1

6.2

Days 421 - 428

Week 61/62

6.5

7.0

7.1

6.3

Days 435 - 442

Week 63/64

6.9

7.1

7.3

7.3

Days 449 - 456

Week 65/66

6.4

6.7

6.5

6.1

Days 463 - 470

Week 67/68

6.8

7.0

7.3

6.3

Days 477 - 484

Week 69/70

7.0

7.4

7.7

7.4

Days 491 - 498

Week 71/72

6.9

7.2

7.0

6.6

Days 505 -- 512

Week 73/74

6.9

7.7

7.5

6.8

Days 519 - 526

Week 75/76

6.3

6.7

6.7

6.2

Days 533 - 540

Week 77/78

8.1

8.5

8.4

7.5

Days 547 - 554

Week 79/80

6.9

8.0

7.4

8.2

Days 561 - 568

Week 81/82

8.0

7.1

8.0

6.3

Days 575 - 582

Week 83/84

6.3

7.6

7.8

6.9

Days 589 - 596

Week 85/86

7.2

8.5

8.3

7.4

Days 603 - 610

Week 87/88

7.3

6.8

6.7

5.6

Days 617 - 624

Week 89/90

6.9

7.3

7.7

6.3

Days 631 - 638

Week 91/92

6.6

8.4

8.1

6.5

Days 645 - 652

Week 93/94

8.1

9.6

9.4

7.5

Days 659 - 666

Weeks 95/96

8.5

10.0

10.2

7.1

Days 673 - 680

Weeks 97/98

7.7

9.0

9.3

7.5

Days 687 - 694

Weeks 99/100

8.1

10.3

9.0

8.3

Days 701 - 708

Weeks 101/102

7.8

9.4

9.4

8.1

Days 715 - 722

Weeks 103/104

8.0

8.1

8.0

5.9

Days 722 - 728

Week 104

6.3

8.4

8.0

5.5

Mean

6.6

7.1

7.0

6.4

Table 3: Body Weights (grams) Oncogenicity Males

 

Group 1

0 ppm

Group 2

20 ppm

Group 3

80 ppm

Group 4

160 ppm

Day 3

Week 1

30

29

29

28

Day 10

Week 2

33

32

33

32

Day 17

Week 3

35

34

35

33

Day 25

Week 4

36

36

37

35

Day 31

Week 5

36

36

38

36

Day 38

Week 6

38

37

38

36

Day 45

Week 7

40

39

40

38

Day 52

Week 8

40

39

41

39

Day 59

Week 9

41

41

43

40

Day 66

Week 10

41

41

42

40

Day 73

Week 11

42

42

44

41

Day 80

Week 12

43

43

45

42

Day 87

Week 13

44

43

45

43

Day 101

Week 15

45

44

46

44

Day 115

Week 17

46

45

47

45

Day 129

Week 19

47

46

48

45

Day 143

Week 21

48

47

49

46

Day 157

Week 23

49

48

50

47

Day 171

Week 25

50

49

50

48

Day 185

Week 27

49

47

50

46

Day 199

Week 29

51

49

51

48

Day 213

Week 31

51

50

51

48

Day 227

Week 33

51

50

51

48

Day 241

Week 35

52

51

52

49

Day 255

Week 37

52

51

52

49

Day 268

Week 39

52

51

52

49

Day 283

Week 41

53

51

52

50

Day 297

Week 43

53

52

52

50

Day 311

Week 45

53

52

53

51

Day 325

Week 47

53

52

53

50

Day 339

Week 49

53

52

53

50

Day 353

Week 51

52

51

52

50

Day 367

Week 53

52

51

52

50

Day 381

Week 55

53

52

52

50

Day 395

Week 57

53

51

52

50

Day 409

Week 59

53

52

52

49

Day 423

Week 61

53

51

52

49

Day 437

Week 63

53

51

52

49

Day 451

Week 65

52

50

51

49

Day 465

Week 67

52

51

51

49

Day 479

Week 69

52

50

51

49

Day 493

Week 71

52

50

51

48

Day 507

Week 73

52

49

50

49

Day 521

Week 75

51

49

50

49

Day 535

Week 77

52

49

51

49

Day 549

Week 79

52

49

51

49

Day 563

Week 81

52

49

50

49

Day 577

Week 83

52

49

50

48

Day 591

Week 85

51

49

49

47

Day 605

Week 87

51

48

48

47

Day 619

Week 89

50

48

48

47

Day 633

Week 91

50

48

48

47

Day 647

Week 93

50

48

48

46

Day 661

Week 95

49

46

48

47

Day 675

Week 97

49

47

48

48

Day 689

Week 99

48

47

47

46

Day 703

Week 101

49

46

47

46

Day 717

Week 103

47

45

46

47

Day 724

Week 104

47

45

45

45

Table 4: Body Weights (grams) Oncogenicity Females

 

Group 1

0 ppm

Group 2

20 ppm

Group 3

80 ppm

Group 4

160 ppm

Day 3

Week 1

24

23

23

22

Day 10

Week 2

25

25

25

25

Day 17

Week 3

26

26

26

25

Day 25

Week 4

27

27

27

26

Day 31

Week 5

27

27

27

27

Day 38

Week 6

28

27

28

27

Day 45

Week 7

29

28

28

27

Day 52

Week 8

29

28

29

27

Day 59

Week 9

30

29

29

28

Day 66

Week 10

30

28

29

28

Day 73

Week 11

31

30

30

29

Day 80

Week 12

31

30

31

30

Day 87

Week 13

31

30

31

29

Day 101

Week 15

32

30

31

30

Day 115

Week 17

33

31

32

31

Day 129

Week 19

33

32

32

30

Day 143

Week 21

34

32

33

31

Day 157

Week 23

34

33

34

32

Day 171

Week 25

35

33

34

32

Day 185

Week 27

35

34

34

33

Day 199

Week 29

35

34

35

33

Day 213

Week 31

36

34

35

33

Day 227

Week 33

36

35

36

34

Day 241

Week 35

36

36

36

35

Day 255

Week 37

36

35

36

34

Day 268

Week 39

36

36

37

35

Day 283

Week 41

37

36

37

35

Day 297

Week 43

36

36

37

36

Day 311

Week 45

37

37

37

36

Day 325

Week 47

37

36

37

36

Day 339

Week 49

37

37

38

36

Day 353

Week 51

38

38

38

36

Day 367

Week 53

38

38

38

36

Day 381

Week 55

38

37

38

37

Day 395

Week 57

38

38

39

36

Day 409

Week 59

38

38

39

37

Day 423

Week 61

39

39

39

37

Day 437

Week 63

40

39

40

38

Day 451

Week 65

39

40

39

37

Day 465

Week 67

39

40

40

38

Day 479

Week 69

39

39

39

39

Day 493

Week 71

39

39

39

39

Day 507

Week 73

39

39

39

38

Day 521

Week 75

39

40

40

38

Day 535

Week 77

40

40

40

38

Day 549

Week 79

40

40

40

39

Day 563

Week 81

40

40

41

38

Day 577

Week 83

40

40

41

38

Day 591

Week 85

40

39

43

38

Day 605

Week 87

40

39

42

38

Day 619

Week 89

40

40

43

39

Day 633

Week 91

39

40

42

40

Day 647

Week 93

39

39

42

41

Day 661

Week 95

40

40

41

38

Day 675

Week 97

41

41

41

38

Day 689

Week 99

40

39

42

39

Day 703

Week 101

40

37

40

41

Day 717

Week 103

40

38

40

41

Day 724

Week 104

40

38

41

40

Table 5: Organ weights (gram) after 104 weeks Males

 

Group 1

0 ppm

Group 2

20 ppm

Group 3

80 ppm

Group 4

160 ppm

Body weight

42.5

41.4

40.3

42.0

Brain

0.493

0.504

0.487

0.484

Heart

0.258

0.230

0.264

0.235

Liver

2.26

1.86

2.87

2.43

Thyroids

0.009

0.009

0.010

0.008

Thymus

0.020

0.029

0.050

0.020

Kidneys

0.792

0.709

0.732

0.732

Adrenals

0.014

0.020

0.239

0.029

Spleen

0.302

0.186

0.117

0.263

Testes

0.202

0.189

0.191

0.189

Table 6: Organ weights (gram) after 104 weeks Females

 

Group 1

0 ppm

Group 2

20 ppm

Group 3

80 ppm

Group 4

320 ppm

Body weight

35.0

36.1

39.0

36.4

Brain

0.537

0.507

0.510

0.499

Heart

0.213

0.212

0.208

0.175

Liver

2.96

2.01

2.14

1.94

Thyroids

0.008

0.012

0.012

0.009

Thymus

0.030

0.021

0.040

0.035

Kidneys

0.638

0.677

0.550

0.568

Adrenals

0.015

0.014

0.019

0.020

Spleen

0.536

0.178

0.326

0.209

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Justification for classification or non-classification

None of the three available oncogenicity studies showed any indication of an oncogenic potential of Glufosinate-ammonium. Classification according to Regulation (EC) 1272/2008 is therefore not warranted.

Additional information