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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable study but with restrictions (only 3 animals per dose and sex, animals were 8 to 9 month old instead of guideline recommended 4 to 6 months, no data on test substance purity, no GLP)

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1970
Report Date:
1970
Reference Type:
publication
Title:
Unnamed
Year:
2001
Reference Type:
publication
Title:
Unnamed
Year:
2010
Report Date:
2010

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity in Non-Rodents)
Deviations:
yes
Remarks:
(only 3 animals per dose and sex, animals were 8 to 9 month old instead of guideline recommended 4 to 6 months, no data on test substance purity)
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder

Test animals

Species:
dog
Strain:
Beagle
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Animals, Inc., Cumberland, Va. (USA)
- Age at study initiation: Mean age: male dogs 35 weeks, female dogs 32 weeks
- Weight at study initiation: Mean weight: male dogs 11.5 kg, female dogs 8.1 kg
- Housing: Singly in metal boxes on perforated plates in a closed building
- Diet (ad libitum): Test groups: Powdered diet mixed with the test substance, control group: Plain diet
- Water (ad libitum): Tap water, offered in automatic waterinq devices ad libitum
- Allocation in a random manner
- Immunization: all dogs
- Vaccination: Vaccinations by breeder against distemper, hepatitis, leptospirosis and rabies; Revaccinations after arrival in Inbifo kennel against distemper, hepatitis, and leptospirosis (1 ml/dog CANDUR SHL, Behringwerke)
- Anthelmintic treatment by breeder: After positive fecal findings
- Acclimation period: Five weeks (control dogs four weeks)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): room temperature about 20°C
- Humidity (%): relative humiditv about 70 %

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Pulp, blended by mixing 1,5 parts by weight of a powdered dog diet and 3 parts by weight of tap water, offered in earthen crocks ad libitum (ALTROMIN H, powdered; manufacturer: Altrorain GmbH, Lage/Lippe)

no further details
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
three months
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
15, 30, 60, 120, 240 mg/kg bw / d
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
approx. 15, 30, 60, 120, 240 mg/kg bw / d
Basis:
other: actual ingested (actual doses were approx. 100 % of nominal doses)
No. of animals per sex per dose:
3 male, 3 female, control: 5 animals each sex
Control animals:
yes, plain diet
Details on study design:
- Post-exposure recovery period in satellite groups: No
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked: Behaviour, state of health, toxic symptoms, food consumption

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: 3 times per week

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/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: No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Before starting, following monthly
- Dose groups that were examined: All animals

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Before starting, following monthly
- Anaesthetic used for blood collection: No data
- Animals fasted: No
- How many animals: All animals
- Parameters checked: Erythrocytes, reticulocytes, HEINZ' bodies, packed cell volume (PCV), haemoglobin concentration in blood, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), Leucocyte count, differentiatial leucocyte count, thrombocyte count, sedimentation rate of erythrocytes

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Before starting, following monthly
- Animals fasted: No data
- How many animals: All animals
- Parameters checked: Glucose concentration in blood, prothrombin time, blood clotting time, in serum: glutamate pyruvate transaminase (GPT) activity, glutamic oxaloacetic transaminase (GOT) activity, Alkaline phosphatase activit, total protein concentration, concentration of serum fractions (electrophoresis), bilirubin concentration, urea-nitrogen concentration, sodium and potassium concentration

URINALYSIS: Yes
- Time schedule for collection of urine: Before starting, following monthly
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No data
- Parameters checked: Urine volume, specific weight and osmolality of urine, colour of urine, hydrogen-ion concentration in urine, albumin, glucose, ketone body, occult blood and bilirubin concentration in urine, organized and unorganized sediments in urine

NEUROBEHAVIOURAL EXAMINATION: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

ORGAN WEIGHTS: Yes (related to body weight, but not to brain weight)

HISTOPATHOLOGY: Yes
- Organs checked: brain, spinal cord, nerve, hypophysis, eye, tongue, glandula submandibularis, thyroid, thymus, mamma, aorta, heart, trachea, lung, oesophagus, liver, gall bladder, pancreas, stomach, duodenum, jejunum, ileum, colon, cecum, lymph node, spleen, kidney, adrenals, urinary bladder, testis, ovaries, epididymis, prostate, uterus, bone, skin, skeletal muscle, bone marrow

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
One male dog of the 240 mg/kg bw dose-group died in the 8th week of test material administration on the 55th day of the administration period after it had lost 2.8 kg of its initial weight of 8.4 kg (= 33 % weight loss). A few days before the dog died the faeces contained red blood.
With the exception of those dogs which ate considerably less than normal over several weeks, the behaviour and the general state of health was not influenced. No test material related salivation or vomiting occurred. No abnormalities in colour and/or consistency of faeces. The heavily starving dogs became meagre, sleepy and weak. The dog that died showed a strongly decreased food consumption; the test material dose of this dog was therefore distinctly below the nominal dose.

BODY WEIGHT AND WEIGHT GAIN (Tab. 1)
In the male dogs the mean body weight per group decreased in the 60 mg/kg bw dose-group (-0.9 kg), 120 mg/kg bw dose-group (-2.9 kg) and 240 mg/kg bw dose-group (-0.9 kg) over the whole study period. The decrease was most pronounced in the 120 mg/kg bw dose-group (Tab. 1). The most pronounced individual decrease (absolute decrease) happened in a male dog of the 120 mg/kg bw dose group, which lost 4.0 kg (=33 % of initial weight). In the 60 mg/kg bw dose-group only one male dog showed a marked weight loss (about - 2.1 kg). The weight loss of the two remaining male dogs of the 240 mg/kg bw dose group was not pronounced. Only 2 female dogs showed a remarkable weight loss over the whole study period: -0.5 kg in the 120 mg/kg bw dose group and -0.8 kg in the 240 mg/kg bw dose group.

FOOD CONSUMPTION AND COMPOUND INTAKE
The individual food consumption scattered considerably from week to week. In the male dogs the food consumption was considerably depressed in the 120 mg/kg bw dose-group and in the 240 mg/kg bw dose-group. In the 60 mg/kg bw dose-group the food consumption was higher in the first three weeks and in the last three weeks of the administration period than in the time between. The female dogs of the 240 mg/kg bw dose-group showed the lowest food consumption; considering the body weight of the female dogs in the 240 mg/kg bw dose-group, the food consumption does not appear to be influenced by the test material. On a few days some dogs, which did not eat a sufficient amount of the standard diet, were offered small amounts of a pet diet (trade name CHAPPI, consisting of tinned meat); the dog that died premature rejected this supplementary food.

FOOD EFFICIENCY
no data

WATER CONSUMPTION AND COMPOUND INTAKE
no data

OPHTHALMOSCOPIC EXAMINATION
The conjunctivae, sclera and cornea did not show any remarkable changes. The opthalmoscopy did not reveal noteworthy findings. The tonometric data give no hint for remarkable changes.

HAEMATOLOGY
Erythrocytes: The male dogs of the 120 mg/kg bw dose-group showed a remarkable decrease (about 30%) in the erythrocyte count after three months; this depression was most pronounced in dog one dog of the 120 mg/kg bw dose group (about 50%). One female dog of the 240 mg/kg bw dose group showed a remarkable decrease in the erythrocyte count with a minimum after 2 months. After one month one normoblast was seen when differentiating 100 white blood cells in blood film of one female dog of the 15 mg/kg bw dose group, four normoblasts were seen in one female dog of the 240 mg/kg bw dose group. After three months one normoblast each was seen in one female dog of the 120 mg/kg bw dose group and one male dog of the 240 mg/kg bw dose group, two each were seen in one male dog of the 120 mg/kg bw dose group and one female dog of the 240 mg/kg bw dose group. Shrivelled erythrocytes appeared in the blood films of the 30, 60, 120, and 240 mg/kg bw dose-group; this phenomenon was more pronounced in the 120 and 240 mg/kg bw dose-group than in the forementioned lower dose groups and more pronounced in the male dogs than in the female dogs, in the female dogs slight anisocytosis was observed in two dogs.
Reticulocytes: No remarkable changes in male dogs. In the female dogs the highest reticulocyte count was found in one dog of the 240 mg/kg bw dose group after two months.
HEINZ' bodies: No HEINZ' bodies.
PCV: The male dogs of the 120 mg/kg bw dose-group showed remarkable decrease in the PCV, which was most pronounced in one dog of the 120 mg/kg bw dose group after three months (37% vs. 47% in the control group). Female dogs showed a pronounced decrease after one and two months and a less pronounced decrease after three months (51, 28, 29, 40% at beginning, first, second, and third month).
Haemoglobin concentration in blood: The male dogs of the 120 mg/kg bw dose-group showed a remarkable decrease in the haemoglobin concentration in blood after three months (about 30%). One female dog of the 240 mg/kg bw dose group showed a remarkable decrease after one and two months and a less pronounced decrease after three months (17.3, 8.9, 7.7, 10.4 g/10 ml at beginning, first, second, and third month).
MCV: In the male dogs the MCV was remarkably increased in the 120 mg/kg bw dose-group after three months (+ 17%). From the female dogs one of the 240 mg/kg bw dose group showed the highest MCV (about + 23%) of all dogs after two months.
MCHC: The male dogs showed a remarkable decrease after three months (about - 17% in the 120 mg/kg bw dose group). One female dog of the 240 mg/kg bw dose group showed the lowest MCHC figures of all female dogs after two and three months (- 22%).
Leucocyte count (total): In the male dogs the leucocyte number was slightly increased in the 120 mg/kg bw dose-group after three months. In the female dogs one animal showed an increased leucocyte number after two and three months.
Differential leucocyte count: The juveniles showed a slight tendency to higher relative figures with increasing doses. A similar tendency seemed to exist with respect to the band cells. The highest relative number of mature neutrophils in female dogs was found in one female animal of the 240 mg/kg bw dose group after two months.
Sedimentation rate of erythrocytes: In the male dogs only one dog showed a remarkably increased sedimentation rate immediately before death. In female dogs no remarkable changes.

CLINICAL CHEMISTRY
Glucose concentration in blood: The dog of the 240 mg/kg bw dose group that died showed a distinctly decreased glucose concentration immediately before death. In female dogs no remarkable findings.
GPT activity in serum: In the male dogs increased figures were shown in the 30 mg/kg bw dose-group and higher dose groups already after one month. After three months also one male dog of the 15 mg/kg bw dose group showed a very high activity. In the female dogs a remarkably increased activity after one and two months is limited to the 120 and 240 mg/kg bw dose-group. After three months also the 30 mg/kg bw dose-group and 60 mg/kg bw dose-group showed at least in some dogs an increased activity (Tab. 2).
GOT activity in serum: In the male dogs an increased activity was seen in some dogs of the 30, 60, and 120 mg/kg bw dose-group after one month. The same was true in the 60, 120, and 240 mg/kg bw dose-group after two months. After three months increased figures were seen in all dose groups; the two surviving dogs of the 240 mg/kg bw dose-group showed only slightly increased activity. In the female dogs increased activity was seen in the 240 mg/kg bw dose-group after one, two and three months. Two female dogs showed slightly or moderately increased activity after three months (Tab. 2).
Alkaline phosphatase activity in serum: In the male dogs distinctly increased activity was seen in all dogs of the 60, 120, and 240 mg/kg bw dose-group after one, two and three months. In the 30 mg/kg bw dose-group not all figures were increased and in the 15 mg/kg bw dose-group only a tendency to higher figures could be seen; an exception is the high activity shown by one male dog after three months. In the female dogs distinctly increased activity was seen in all dogs of the 120 and 240 mg/kg bw dose-group after one, two and three months. In the 30 and 60 mg/kg bw dose-group not all figures were distinctly increased. The 15 mg/kg bw dose-group indicated an evident tendency to an increased activity (Tab. 2).
Total protein concentration in serum: In the male dogs a slight tendency to lower protein concentration existed depending on time and dose. In the female dogs a similar slight trend existed. The lowest mean figures appeared in the 120 mg/kg bw dose-group after two and three months.
Concentration of serum fractions (electrophoresis): Albumin: The albumin portion of the serum proteins showed the same general trend as the total protein. In the male dogs the decrease was most pronounced in the 120 mg/kg bw dose-group after three months. In the female dogs a similar trend existed. Low mean and individual figures appeared in the 240 mg/kg bw dose-group already after one month.
α1-globulin: In the male and female dogs the a1-globulin figures showed after one, two and three months higher values in the dose groups than in the control group. The highest mean values appeared in the 120 mg/kg bw dose-group.
α2-globulin: In the male and female dogs the α2-globulin figures showed after one, two and three months a tendency to lower values in the 30, 60, 120, and 240 mg/kg bw dose-group.
β1- and β 2-globulin: After one, two and three months all dose groups showed several figures which were higher than the figures in the control-group and the initial values.
γ-globulin: The dogs of all dose groups showed a tendency to higher y-globulin values.
Bilirubin concentration in serum: After three months the bilirubin figures were slightly increased in the male dogs in the 15, 30, 60, and 120 mg/kg bw dose-group. The dog that died showed a very strong increase whereas the other two male dogs of the 240 mg/kg bw dose-group showed normal figures. The figures of the female dogs were not remarkable.

URINALYSIS
Colour of urine: The urine of two male dogs of the 120 mg/kg bw dose groups and two female dogs (60 and 240 mg/kg bw dose group) had a red shade after three months, the urine of one female dog of the highest dose group (240 mg/kg bw) and of the dog that died had a brown shade one month earlier.
Bilirubin concentration in urine: The bilirubin test showed some remarkable changes. Bilirubin was detected in one male dog of the 120 mg/kg bw dose group after two and three months and in one female dog of the highest dose group (240 mg/kg bw) and of the dog that died after one and two months.

NEUROBEHAVIOUR no data

ORGAN WEIGHTS
In the male dogs the evaluation of the organ weights was complicated because of the body weight losses observed in the 60, 120, and 240 mg/kg bw dose-group. 2 and 1 male dogs of the 120 and 240 mg/kg bw dose groups showed low liver weights which were relative to body weight within normal limits, whereas the relative weights of a number of other organs of these dogs, e.g. brain lung, kidneys and adrenals, were larger than those of all other dogs. The forementioned three dogs were also remarkable because of their low testes and epididymes weights. All male dogs of the 120 mg/kg bw dose group and the dog that died showed the lowest thymus weights. One female dog of the 240 mg/kg bw dose group had a remarkably small heart weight. The relative liver weights showed slight trend to higher figures in the dose groups especially in the 60 and 120 mg/kg bw dose-group. The uterus showed a dose weight relationship from 30 to 240 mg/kg bw dose-group with decreasing weight. The lowest mean weights of thymus in the females were found in the 240 mg/kg bw dose-group.

GROSS PATHOLOGY
The autopsy revealed only few remarkable findings. The dog that died and one male dog of the 120 mg/kg bw dose group showed an icterus universalis, one female dog of the 240 mg/kg bw dose group showed a slighter degree of icterus. In the dog that died, the liver had a brown-yellowish shade, in the male dog of the 240 mg/kg bw dose group a yellow-greenish shade was remarkable. In the dog that died, the spleen had a mottled appearance on the outer surface and on the cutting surface; the same was true for the liver of one female dog of the 240 mg/kg bw dose group.

HISTOPATHOLOGY: NON-NEOPLASTIC
Tongue: Except small mononuclear foci in the stroma below the mucosa of upper side - especially around blood vessels - and signs of slight terminal hemostasis in the dog that died no remarkable changes.
Thymus: One male control dog showed signs of slight interstitial lipomatosis. Two female control dogs showed only small amount of interstitial tissue with only small number of fat cells. One male dog of the 30 mg/kg bw dose group showed a slight interstitial lipomatosis, female dog of the 60 mg/kg bw dose group a slight atrophy with slight lipomatosis. One female each of the 15 and 240 mg/kg bw dose group and all male animals of the 120 mg/kg bw dose group showed atrophy, with distinct increase of connective tissue; furthermore in these dogs a hyperplasia of the epithelial components which appeared partly as solid cell gatherings or cysts were visible. The atrophy in the dogs of the 120 mg/kg bw dose-group and in the female dog of the 240 mg/kg bw dose group can be considered as test material related.
Liver: The liver tissues showed many pronounced changes in all dose groups. Several of these changes appeared already in the 15 mg/kg bw dose-group. These changes were found in the following dogs:
Fatty changes in KUPFFER' cells: One male dog of the 15 mg/kg bw dose group, all male animals of the 30 mg/kg bw dose group and one female of the 120 mg/kg bw dose group.
Fatty degeneration of hepatocytes: All male animals of the of the 60 mg/kg bw dose group and all females of the 240 mg/kg bw dose group (monocellular fatty changes), two females of the 60 mg/kg bw dose group and two males each of the 120 and 240 mg/kg bw dose groups (focal fatty degeneration, partly central and peurtly peripheral) and the dog that died (diffuse).
Protein globules in cytoplasm: Two males of the 15 mg/kg bw dose group, one male and all female animals of the 30 mg/kg bw dose group, all males of the 60 mg/kg bw dose group and all males and two females of the 120 mg/kg bw dose group.
Hepatocytes with 4 nuclei per cell: One male of the 30 mg/kg bw dose group.
Centrolobular cholestasis: One male each of the 60, 120, and 240 mg/kg bw dose group and one female of the 240 mg/kg bw dose group.
Brownish pigmentation of hepatocytes: One male of the 30 mg/kg bw dose group.
Yellow pigmentation of KUPFFER' cells: One male of the 15 mg/kg bw dose group and one male and one female of the 120 mg/kg bw dose group.
KUPFFER'cell hyperplasia: One female control animal, all females of the 15 mg/kg bw dose group, one male and one female of the 30 mg/kg bw dose group, two males and all females of the 60 mg/kg bw dose group, two male and two female animals of the 120 mg/kg bw dose group and two female and all male dogs of the 240 mg/kg bw dose group.
Monocellular necrosis: One male and one female dog of the 30 mg/kg bw dose group and one female of the 240 mg/kg bw dose group.
Fibrosis: One male animal of the 60 mg/kg bw dose group.
Inflammation: One male each of the 60 and 240 mg/kg bw dose group. The liver tissue of the dog that died showed an indistinct structure. The slides did not indicate a clear relationship between dose and the strength of the changes of the liver. Even in the 15 mg/kg bw dose-group distinct changes could be observed. The described changes were test material related.
Gall bladder: Several dogs including dogs of control group showed mononuclear cell infiltration of the stroma in varying degree and occasionally thickening of folds; one male dog of the 15 mg/kg bw dose group, and one female animal each of the 60 and 240 mg/kg bw dose group showed an oedema of the stroma. An increased number of submucous glands could be seen in dogs two female control dogs. The mucosa of the dog that died showed autolytic changes. No dose related changes.
Stomach: The mucosa appeared slightly thin in one dog of the control group. No dose related changes.
Duodenum, Jejunum and Ileum: The stroma of the villi appeared fibrous and showed increased cellularity in several dogs including dogs of control-group. The lymphatic tissue of the ileum was well developed. The section of one male dog of the 30 mg/kg bw dose group showed parts of the choledochus which appeared regular. In one female dog of the 30 mg/kg bw dose group and one male animal of the 60 mg/kg bw dose group parasites were visible in the lumen. No dose related changes.
Lymph node: The dog that died showed broadened medullary sinus and a slight atrophy of the cortex; follicles exist only in the cortex. No further pathological changes.
Spleen: Several changes only in the red pulp of the dogs of all dose groups could be seen. In two male dogs of the 120 mg/kg bw dose group, the dog that died, and one female dog of the 240 mg/kg bw dose group several foci of extramedullary hematopoiesis were visible. Signs of a distinct fresh haemostasis were shown in dogs one female animal of the 30 mg/kg bw dose group, two males of the 60 mg/kg bw dose group, one male and one female of the 120 mg/kg bw dose group and the dog that died. In one male dog of the 120 mg/kg bw dose group a subacute hemostasis with fibrination was visible. One female dog of the 30 mg/kg bw dose group showed an increased number of macrophages containing pigment. Test material related changes.
Kidney: In most groups including control group granulomas consisting of fibroblasts and histiocytes were visible. In two male dogs of the 30 mg/kg bw dose group and one male dog each of the 60 and 240 mg/kg bw dose groups slight changes of the glomeruli were visible; they showed adhesions as well as homogeneous inclusions. The glomeruli vary in size and were partially slightly enlarged. There was no indication for increased protein permeability. The afferent arterioles did not show changes. One male and female of the 30 mg/kg bw dose group and one male each of the 60 and 120 mg/kg bw dose groups showed fatty changes of glomeruli. The dog that died furthermore showed strong inflammatory changes as well as pigmentation and bile cylinders; the interstitial tissue was rich in fibres. Remarkable changes of glomeruli were detected in the 30 mg/kg bw dose-group and higher dose groups.
Adrenals: In one female dog of the 15 mg/kg bw dose group cortical tissue was found in the fibrous capsule. One male dog of the 60 mg/kg bw dose group and two female dogs of the 240 mg/kg bw dose group showed an infiltration of longish cells with hyperchromatic nuclei (possibly indicating haematopoiesis) in the medulla. The dog that died showed lipoid depletion of cortex. Questionable relation of changes to test material administration in one male dog of the 60 mg/kg bw dose group and two female dogs of the 240 mg/kg bw dose group; test material related changes in the dog that died.
Testis: One male control dog showed several tubules which consist only of SERTOLI' cells. One male dog of the 30 mg/kg bw dose group showed several giant spermatogonia and multinucleated giant cells in tubules and one male dog of the 60 mg/kg bw dose group showed several multinucleated giant cells in tubules and a slight chronic inflammation in the capsule. Another male dog of the 60 mg/kg bw dose group showed a strong defect in spermiogenesis, a distinct atrophy of the tubules, hyperchromia and hyperplasia of the spermatogonia and multinucleated giant cells. One dog of the 120 mg/kg bw dose group showed a moderate atrophy, another dog of the same dose group disturbances of spermiogenesis and progressing atrophy, the last dog of this dose group disturbances of spermiogenesis, round cell infiltration of interstitial tissue with hyperplasia of LEYDIG' cells and nearly no spermatocytes in the lumina of tubules. Two of the male dog treated with 240 mg/kg bw showed disturbances of spermiogenesis, slight atrophy of tubular epithelium and multinucleated giant cells. Test material related changes.
Prostate: One male dog of the 30 mg/kg bw dose group showed a slight atrophy of the glands and a slight increase of stroma. In one male dog of the 60 mg/kg bw dose group the glandular epithelium was slightly flattened. Another male dog of this dose group showed the same changes like the dog of the 30 mg/kg bw dose group but in a more pronounced form. One dog of the 120 mg/kg bw dose group showed a slight atrophy. Another dog of the 120 mg/kg bw dose group and two animals of the 240 mg/kg bw dose group showed very strong atrophy and sclerosis of the stroma. These results were considered as test material related changes.
Uterus: Slight atrophy of all layers of the uterus wall in one dog of the 60 mg/kg bw dose group and all dogs of the 240 mg/kg bw dose group; in one of the latter group this change more pronounced than in the others of this group. These results were considered as test material related changes.
Bone, skin, skeletal muscle, bone marrow, brain, spinal cord, nerve, hypophysis, eye, gland. sumbmandib., thyroid, mamma, aorta, trachea, lung, esophagus, pancreas, colon, cecum, urinary bladder, ovaries, epididymis: No test material related changes were observed.

HISTORICAL CONTROL DATA: no data

Effect levels

open allclose all
Dose descriptor:
other: no no-effect-level defined
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Remarks on result:
not measured/tested
Remarks:
Effect level not specified (migrated information)
Dose descriptor:
NOEL
Effect level:
< 15 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Data assessment by HPV program 2001 on Phenolic Benzotriazols.
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: EPA assessment 2010 (CFR Vol. 75). LOAEL = 60 mg/kg/d

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Tab. 1: Body weight development and food consumption over the whole study period (1st - 15th week) in both male and female dogs. Given is the mean over all 3 dogs (control group 5 dogs). In the 240 mg/kg bw dose group one male dog died and therefore its body weight change is given from 1st - 8th week.

 

body weight changes (kg)

food consumption (g/d dry weight)

dose-group

male dogs

female dogs

male dogs

female dogs

control

0.6

0.7

418

305

15 mg/kg bw

1.1

0.2

428

281

30 mg/kg bw

0.0

1.0

368

366

60 mg/kg bw

-0.9

0.9

448

313

120 mg/kg bw

-2.9

0.3

240

337

240 mg/kg bw

(-0.9)

-0.2

(305)

255

Tab. 2: Clinical Chemistry: enzymatic activity of GPT, GOT and alkaline phosphatase in the serum of both male and female dogs at the end of the study. Given is the mean over all 3 dogs (control group 5 dogs). In the 240 mg/kg bw dose group one male dog died and therefore the data refers only to the two surviving dogs.

 

GPT activity in serum (mU/ml)

GOT activity in serum (mU/ml)

Alkaline phosphatase activity in serum

(mU/ml)

dose-group

male dogs

female dogs

male dogs

female dogs

male dogs

female dogs

control

7.8

10.6

13.4

16.8

22

39

15 mg/kg bw

70.9

13.1

41.1

13.1

96

84

30 mg/kg bw

52.3

48.5

22.4

21.5

253

206

60 mg/kg bw

119.9

28.9

42.9

19.6

236

373

120 mg/kg bw

98.9

59.7

56.7

27.5

290

207

240 mg/kg bw

85.4

96.1

30.8

66.7

245

498

Applicant's summary and conclusion