Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report Date:
1999

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Test substance: 69.57 % Quab 188 in 28.44 % water

Test animals

Species:
rat
Strain:
other: Bor:WISW(SPFCpb)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Asta Pharma AG, Artur-Ladebeck-Str. 128-152, D-4800 Bielefeld 14, GERMANY
- Age at study initiation: 7 wk
- Weight at study initiation: 146-165 g (m); 130-147 g (f)
- Fasting period before study:
- Housing: 1/Macrolon type II cage
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: 2 wk

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.5-23.5
- Humidity (%): 40-65
- Photoperiod (hrs dark / hrs light): 12 h/12 h

IN-LIFE DATES: From: 1988-07-12 To: 1988-08-9

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
TS administered as supplied.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
28 days, 7 days/week
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
1 085 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
5
Control animals:
other: tap water
Details on study design:
- Dose selection rationale: range finding test (864810)
- Rationale for animal assignment (if not random): random considering the homogeneity of body weight means'
- Rationale for selecting satellite groups: no satellite groups
Positive control:
none

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily for mortality, daily for behaviour, general condition and clinical symptoms

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: see above

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption : weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pre and post test using focussed cisual light beam

HAEMATOLOGY: Yes
- Time schedule for collection of blood: wk 4
- Anaesthetic used for blood collection: Yes (CO2)
- How many animals: all
- Parameters checked: see table

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
- Animals fasted: Yes / No / No data
- How many animals: all
- Parameters checked: see table

URINALYSIS: Yes
- Time schedule for collection of urine: wk 4
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked: see table

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes all animals. Organ weights: see table
HISTOPATHOLOGY: Yes (see table)
Statistics:
Body weights, food consumption' and organ weights of each sex were compared with the corresponding control values using the Dunnett-test.
The clinical pathology parameters were evaluated using the Dunnett-test or Steel-test

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
In group 2, which was the only treated group, clinical symptoms included slightly red discoloured salivation, alopecia in the fore legs or neck. One female performed strenuous respiration, tremor and piloerection on day 20.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Two females died 10 minutes after the second administration and were replaced by spare animals. However, the authors did not consider this substance related.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Description (incidence and severity):
Haematological parameters of the treated group had no statistically significant changes when compared to the control group.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Clinical chemistry showed a slightly but statistically significantly decreased (-26 %) glucose value to control group. The female rats had a decreased creatinine concentration while the creatinine kinase (202 %) and aspartate aminotransferase (ASAT) values were slightly increased but were within the normal range of this strain of rats. The change in ASAT was only slight (22 %) but significant. The creatine kinase values, which are known to vary over a wide range, were within the historical controls. No morphological changes were found to correlate with the increased creatine kinase values.
Urinalysis findings:
no effects observed
Description (incidence and severity):
Urinalysis did not produce any substance-related findings.
Behaviour (functional findings):
not examined
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
The only statistically significant, although slight, change in organ weights was a decrease of absolute (-16 %) and relative body weight (-14 %) heart weight in males and a 20 % increase of relative kidney weight in males. Females had no statistically significant changes in their organ weights.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
In the macroscopical examination of the necropsy, focal alopecia of the forepaws (1 male) and neck (1 female) and reddening of the proximal parts of the small intestine or the glandular stomach was seen. The latter finding was only observed in the animals that died on day 2 of the study for non-substance related reasons.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Microscopically, slight or moderate vacuolisation of proximal tubule cells of the inner cortical and outer medullar region of the kidney were seen in 5/10 male animals but not in females. This was not observed in control animals. In addition, this region had minimal tubular hyperplasia (4/5 males, 2/5 females) and minimal or slight hypertrophy (5/5 males 0/5 females). Control animals had no hyperplasia or hypertrophy. The female rat with alopecia was diagnosed to have moderate atrophy of hair glands and sebaceous glands in the affected skin areas. The causes of the two deaths of the female rats in the group 2 were unresolved by the necropsy examination.
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
In group 2, which was the only treated group, clinical symptoms included slightly red discoloured salivation, alopecia in the fore legs or neck. One female performed strenuous respiration, tremor and piloerection on day 20. Two females died 10 minutes after the second administration and were replaced by spare animals. However, the authors did not consider this substance related.


BODY WEIGHT AND WEIGHT GAIN
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Neither the food consumption nor the bodyweight development was affected significantly by the treatment.


OPHTHALMOSCOPIC EXAMINATION
NEUROBEHAVIOUR
The reflexes, eyes, hearing and teeth had no abnormalities.
No effects in limited examination.

HAEMATOLOGY
Haematological parameters of the treated group had no statistically significant changes when compared to the control group.

CLINICAL CHEMISTRY
Clinical chemistry showed a slightly but statistically significantly decreased (-26 %) glucose value to control group. The female rats had a decreased creatinine concentration while the creatinine kinase (202 %) and aspartate aminotransferase (ASAT) values were slightly increased but were within the normal range of this strain of rats. The change in ASAT was only slight (22 %) but significant. The creatine kinase values, which are known to vary over a wide range, were within the historical controls. No morphological changes were found to correlate with the increased creatine kinase values.

URINALYSIS
Urinalysis did not produce any substance-related findings.

ORGAN WEIGHTS
The only statistically significant, although slight, change in organ weights was a decrease of absolute (-16 %) and relative body weight (-14 %) heart weight in males and a 20 % increase of relative kidney weight in males. Females had no statistically significant changes in their organ weights.

GROSS PATHOLOGY
In the macroscopical examination of the necropsy, focal alopecia of the forepaws (1 male) and neck (1 female) and reddening of the proximal parts of the small intestine or the glandular stomach was seen. The latter finding was only observed in the animals that died on day 2 of the study for non-substance related reasons.

HISTOPATHOLOGY: NON-NEOPLASTIC
Microscopically, slight or moderate vacuolisation of proximal tubule cells of the inner cortical and outer medullar region of the kidney were seen in 5/10 male animals but not in females. This was not observed in control animals. In addition, this region had minimal tubular hyperplasia (4/5 males, 2/5 females) and minimal or slight hypertrophy (5/5 males 0/5 females). Control animals had no hyperplasia or hypertrophy. The female rat with alopecia was diagnosed to have moderate atrophy of hair glands and sebaceous glands in the affected skin areas. The causes of the two deaths of the female rats in the group 2 were unresolved by the necropsy examination.


HISTORICAL CONTROL DATA (if applicable)


Effect levels

open allclose all
Dose descriptor:
NOAEL
Sex:
male/female
Remarks on result:
not determinable due to adverse toxic effects at highest dose / concentration tested
Dose descriptor:
LOAEL
Effect level:
1 085 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: kidney effects

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

From EU RA, 2008

In group 2, which was the only treated group, clinical symptoms included slightly red discoloured salivation, alopecia in the fore legs or neck. One female performed strenuous respiration, tremor and piloerection on day 20. Two females died 10 minutes after the second administration and were replaced by spare animals. However, the authors did not consider this substance related. Neither the food consumption nor the bodyweight development was affected significantly by the treatment. The reflexes, eyes, hearing and teeth had no abnormalities. Haematological parameters of the treated group had no statistically significant changes when compared to the control group. Clinical chemistry showed a slightly but statistically significantly decreased (-26 %) glucose value to control group. The female rats had a decreased creatinine concentration while the creatinine kinase (202 %) and aspartate aminotransferase (ASAT) values were slightly increased but were within the normal range of this strain of rats. The change in ASAT was only slight (22 %) but significant. The creatine kinase values, which are known to vary over a wide range, were within the historical controls. No morphological changes were found to correlate with the increased creatine kinase values. Urinalysis did not produce any substance-related findings. The only statistically significant, although slight, change in organ weights was a decrease of absolute (-16 %) and relative body weight (-14 %) heart weight in males and a 20 % increase of relative kidney weight in males. Females had no statistically significant changes in their organ weights. In the macroscopical examination of the necropsy, focal alopecia of the forepaws (1 male) and neck (1 female) and reddening of the proximal parts of the small intestine or the glandular stomach was seen. The latter finding was only observed in the animals that died on day 2 of the study for non-substance related reasons. Microscopically, slight or moderate vacuolisation of proximal tubule cells of the inner cortical and outer medullar region of the kidney were seen in 5/10 male animals but not in females. This was not observed in control animals. In addition, this region had minimal tubular hyperplasia (4/5 males, 2/5 females) and minimal or slight hypertrophy (5/5 males 0/5 females). Control animals had no hyperplasia or hypertrophy. The female rat with alopecia was diagnosed to have moderate atrophy of hair glands and sebaceous glands in the affected skin areas. The causes of the two deaths of the female rats in the group 2 were unresolved by the necropsy examination.

Applicant's summary and conclusion

Conclusions:
Slight morphological findings in the kidney (fine, diffuse vacuolisation of tubular cells, slight tubular cell hyper- plasia and hypertrophy). The findings were more pronounced in males than in females. Based on these kidney changes, the LOAEL for CHPTAC after oral administration is 1085 mg/kg bw/day.
Executive summary:

In a short-term repeated toxicity study, the test item CHPTAC was applied by gavage to young adult Bor:WISW rats (5/sex/dose) at dose levels of 0 and 1085 mg/kg bw. Slight morphological findings in the kidney (fine, diffuse vacuolisation of tubular cells, slight tubular cell hyperplasia and hypertrophy) were observed. The findings were more pronounced in males than in females. Based on these kidney changes, the LOAEL for CHPTAC after oral administration is 1085 mg/kg bw/day.