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Description of key information

Repeated dose toxicity of the test item was examined in several subchronic and chronic studies in rats and dogs (most of them prior GLP, equivalent to OECD guideline 408, 452 or 409). In addition, a study on delayed neurotoxicity was performed (OECD guideline 418). In the majority of the studies all animals survived, adverse effects or signs of toxicity were not observed. In one dog study, myelin lesions and behavioural changes were observed. However, the test on neurotoxicity as well as the outcome of the other studies in rats and dogs gave no hint for a neurotoxic potential. The NOAEL after repeated dose administration is therefore considered to be 78 mg/kg bw in males and 91 mg/kg bw in females.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1978 - 1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
no analytical verification of test material, age of animals not mentioned, no description of environmental conditions and diet, no analysis of platlet count and quick time, no measurement of albumin and protein, no measurement of electrolytes
GLP compliance:
no
Remarks:
prior inition of GLP-guidelines
Limit test:
no
Specific details on test material used for the study:
- test item: Weston XR-1532
- hand written note: contains 1% xxxpropanolamine
Species:
rat
Strain:
other: Charles River CD@ rats
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, Michigan
- Age at study initiation: /
- Weight at study initiation: male 80 - 107g, females 77 - 98g
- Housing: singly
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: /

ENVIRONMENTAL CONDITIONS
animals were housed individually in hanging wire-mesh cages and maintained in a temperature-, humidity- and light-controlled room

IN-LIFE DATES
07.11.1978 - 5./6.02.1979
Route of administration:
oral: feed
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): daily
- Mixing appropriate amounts with (Type of food): first making a p remix of appropriate amounts of the test material and Rodent Laboratory Chow, premix was then added to additional amounts of Rodent Laboratory Chow@ and mixed
- Storage temperature of food: - 200°C liquid nitrogen (prevent hydrolysis)

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Recovery determinations, Homeogeneitiy determinations, test diet analysis,
Duration of treatment / exposure:
90d
Frequency of treatment:
daily
Dose / conc.:
100 ppm
Remarks:
corresponding to 7.6 mg/kg bw in males and 8.7 mg/kg bw in females
Dose / conc.:
300 ppm
Remarks:
corresponding to 22 mg/kg bw in males and 26 mg/kg bw in females
Dose / conc.:
1 000 ppm
Remarks:
corresponding to 78 mg/kg bw in males and 91 mg/kg bw in females
No. of animals per sex per dose:
20
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: not given
- Rationale for animal assignment (if not random): on the basis of general good health
- Rationale for selecting satellite groups: no satellite group
- Post-exposure recovery period in satellite groups: no post observation period
Positive control:
no
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- daily

OPHTHALMOSCOPIC EXAMINATION: Yes
- Dose groups that were examined: all

HAEMATOLOGY: Yes
- Time schedule for collection of blood: month 1 and 3 of the study
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 10/group
- Parameters checked: hematocrit, hemoglobin concentration, erythrocyte count and total and differential leucocyte counts

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: month 1 and 3 of the study
- Animals fasted: Yes
- How many animals: 10/group
- Parameters checked: blood glucose levels, blood urea nitrogen levels, serum alkaline phosphatase, serum glutamic oxalacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), Cholinesterase activities in plasma, red blood cells and brain (termination only), Brain cholinesterase was determined at termination only

URINALYSIS: Yes
- Time schedule for collection of urine: month 1 and 3 of the study
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked: appearance, pH, volume and specific gravity; qualitative measurements for albmin,glucose, bilirubin, occult blood, microscopic examination of the spun deposit

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
At the termination of the study period all the rats were sacrificed using carbon dioxide gas and necropsied. Select organ weights were from all rats were recorded.

HISTOPATHOLOGY: Yes
The following tissues from 10 male and 10 female rats from the control group and the 1000-ppm group were paraffin embedded, sectioned, stained with hematoxylin and eosin and examined microscopically: adrenals, aorta, eye and optic nerve, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, liver, trachea, spleen, pancreas, urinary bladder, bone marrow (sternum), prostateluterus, seminal vesicles, testes/ovaries, brain, heart, lung and bronchi, sciatic nerve, pituitary, thyroid and parathyroid, mesenteric lymph node, mandibular lymph node, spinal cord, salivary gland, (submaxillary), skeletal muscle (thigh), skin, mammary gland, thymus, kidneys, any other tissue with gross lesions
Additionally livers and spleens from 10 male and 10 female rats from the 100-ppm and 300-ppm groups were similarly processed and examined.
Other examinations:
Bone marrow smears from all rats were made at the time of necropsy, fixed in methyl alcohol, stained by Giemsa's method and examined microscopically.
Statistics:
All statistical analyses compared the treatment groups with the control group by sex. Body weights (week 13 ), food consumption (weeks 1-13), absolute and relative organ weights (terminal sacrifice), and hematology, biochemistry and urinalysis parameters (1 and 3 months) were compared by analysis of variance (one-way classification), Bartlett's test for homogeneity of variances and the appropriate t-test (for equal or unequal variances) as described by Steel and Torrie using Dunnett's multiple comparison tables to judge significance of differences.
Clinical signs:
no effects observed
Description (incidence and severity):
No signs of overt toxicity were observed among the treated rats. Incidental signs observed for a few control and/or treated rats included hair loss, missing or malalinged upper incisor, excessive lacrimation, red material around eyes, leaning to left, red or swollen eyes, rales, corneal opacity, swollen ventral neck, swollen conjunctiva and dilated pupil.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
All animals survived until scheduled day of necropsy with exeption of one female animal of the high dose group. It is not documented whether this female died by accident or not.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The group mean body weights of both the low- and mid-dose male and female rats were greater than control values, and both groups of high-dose males and females had group mean body weights lower than
controls.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Low- and mid-dose male rats consumed slightly more food than did controls, while high-dose males ate slightly less than control. All of the groups of female consumed approximately equivalent amounts of food.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Description (incidence and severity):
There were no compound-related effects noted during the 3-month ophthalmic examinations.
Haematological findings:
no effects observed
Description (incidence and severity):
No compound-related effects on the results of the hematologic tests.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No compound-related effects on the results of the biochemical tests.
Urinalysis findings:
no effects observed
Description (incidence and severity):
No compound-related effects on the results of the urinalysis tests.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No compound-related organ weight variations were seen in any of the rats fron treatment groups.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No compound-related gross lesions were seen in any of the rats fron treatment groups.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Microscopic lesions considered probably compound-related were seen in livers and spleens of the female rats from the 1000-ppm group. This consisted of very slight to slight extramedullary hematopoiesis in these organs. This lesion was not present in rats from the control and the 300-ppm groups, but was seen in one rat from the 100-ppm group. However, in as much as a mild degree of extramedullary hematopoiesis in liver and spleen could occasionally occur in normal young rats, occurrence of this lesion in one rat from the 100-ppm group, was not considered in any way related to the compound administration.
Histopathological findings: neoplastic:
not examined
Dose descriptor:
NOAEL
Effect level:
1 000 ppm
Sex:
male/female
Remarks on result:
other: corresponding to 78 mg/kg bw in males and 91 mg/kg bw in females
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
55 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Several studies (prior GLP, similar to concurrent OECD guideline) were conducted to examine toxicity after repeated dose application to rats. The test material was administered in diet to male and female rats at dose levels from 100 - 3000 ppm for 90 days, 6 months or 2 years, respectively. Treatment related death were not recorded. In the key study, one female animal was found dead with an unknown cause of death. Except for the key study, clinical signs of toxicity, changes in hematology clinical chemistry or urinalysis as well as changes in body weight and food consumption were not observed in any of the studies. In the course of the key study, slightly lower body weight and slight extramedullary hematopoisis in animals of the high dose group were recorded. The 90d rat study performed by IBT was disregarded considering the history of IBT of falsifying study reports.

In the 4-month study performed with dogs, the test item was applied unchanged in capsules to beagle dogs (4/sex/dose) at concentrations of 4, 12 and 40 mg/kg bw. One female was sacrificed in moribund due to strong decrease in food consumption and subsequent body weight loss starting from week 9. At this female, signs of uncoordinated behaviour were observed; histopathology revealed abnormalities of axonal fibers and myelin. Moreover, 7/8 high dose animals showed degenerative myelin lesions. Beside this finding, animals from all treatment groups suffered from an eosinophilic pneumonia. This effect is not regarded as treatment related but may origin from parasite infestation. A second study with dogs is available by IBT. Similar to the rat study mentioned above, this study report was also disregarded.

To further investigate the neurotoxicity findings a test on delayed neurotoxicity in hens was performed. The animals (4 female hens/dose) received a single dose of 800, 1200, 1800, 2700, 4050 or 6080 mg/kg bw of the substance by gavage. The hens were observed for 14 days, group 1 and 2 was then necropsied. Animals of the other groups were redosed and observed for further 21 days. Check for neurotoxicity was performed three times a week. None of the hens died; sings of (neuro)toxicity or any changes in histopathology were not observed.

Discussion:

Subchronic or chronic administration of the test material did not induce mortalities (except for the dog study) or any sign of toxicity in rats and dogs. Also behaviour and reactions were considered to be normal. At the end of the dog study degenerative myelin lesions were observed in the top dose group. A test on delayed neurotoxicity performed in hens was also without findings. All animals appeared to be normal referring to gait, motoractivity, balance or leg weakness. Histhopathological examination of the nervous system gave no hint on myelin lesions. Thus, it is questionable if the effects observed in the second dog study result from the test item or from an impurity. On the other hand, test substance purity was given as 100%. Another finding of the dog study was pneumonia in animals of all treatment groups. With regard to this health status, an additional disease, i.e. virus infection, leading to neurotoxicity is thinkable.

In conclusion, the substance is not considered to be neurotoxic and the NOAEL after repeated dose administration is 1000 ppm or 78 mg/kg bw in males and 91 mg/kg bw in females.

Justification for classification or non-classification

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

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified for repeated dose toxicity under Regulation (EC) No. 1272/2008.