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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets national standard method, basic data given, acceptable for assessment (Engl. translation with key data, 6 data tables and 2 figures included)

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1973
Report Date:
1973
Reference Type:
other company data
Title:
Unnamed
Year:
1974
Report Date:
1974

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: national standard (Japan)
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Diisopropylnaphthalene (DIPN) (R-300)
- DIPN isomer mixture
- clear liquid
- not further specified

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Tokyo Experimental Animals, Inc.
- Age at study initiation:
- Weight at study initiation:
- Fasting period before study:
- Housing: 1 / cage (steel cage)
- Diet: ad libitum
- Water: ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Photoperiod (hrs dark / hrs light): 12 / 12


Administration / exposure

Route of administration:
oral: feed
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:


Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
6 months
Frequency of treatment:
continuous
Doses / concentrations
Remarks:
Doses / Concentrations:
0.25, 0.5, and 1 % in the diet = ca. 170, 340, and 670 mg/(kg bw*d)
Basis:
nominal in diet
No. of animals per sex per dose:
10
Control animals:
yes, plain diet
Details on study design:
Post-exposure period: none

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Time schedule for examinations: weekly
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

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

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 6 mon (termination)
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: No
- How many animals: all
- Parameters checked in table [No.?] were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after 6 mon (termination)
- Animals fasted: No
- How many animals: all
- Parameters checked in table [No.?] were examined.

URINALYSIS: Yes
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes / No / No data
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:

OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (not documented)
HISTOPATHOLOGY: Yes (see table 6)
Statistics:
done (Methods not stated)

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
No mortality occurred at any dose level. In the high dose group, reduced activity, diarrhea, and rough fur were observed.

BODY WEIGHT AND WEIGHT GAIN
Body weight gain was reduced in a dose-related manner at the 0.5- and 1-% dietary level in both male and female animals (Tab. 2),
with a mean weight gain of 90 and 80 % of control at 0.5 % and with 62 and 57 % of control at 1 % (males and females, resp.).

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Significant depression in the 1%-group (p <0.05): approx. 22 % (m), approx. 19 % (f) vs. control (Report, Tab. 1 and Fig 2).
There is a dose-related declining trend in food consumption, but not statistically significant at the 0.25 and 0.5% dosage level.

HAEMATOLOGY
Significant decreases in erythrocyte count (EryC) (at 0.5- and 1-% level, male/female) and in white blood cells (at 1-% level, females), in haemoglobin and haematocrit (Ht) (>0.5-% level, males; and 1-% level, females).
The mean EryC was reduced at about 14 and 16 % in males and at 9 % in females, the leukoC at about 23 % in females; the mean Ht was reduced at 5.5 and 7 % in males and at about 8 % in females vs. respective controls (significance level p <0.05).

CLINICAL CHEMISTRY
Only the highest dose group of males showed significant changes in SGOT (mean increase: +45%) and sugar (mean decrease: -27%),
a negative trend was seen for the blood-glucose level noticeable in high-dose females (significance level: p <0.05%).

URINALYSIS
No differences were observed between control and treated groups for pH, protein, occult blood and glucose.

ORGAN WEIGHTS
At the high doses, hepatic and renal enlargement as well as spleen enlargement was seen (some 20 %, related to relative organ weights).

GROSS PATHOLOGY
Hypertrophy in the liver was observed for the males and females of the 0.5- and 1-% level group.
Effects in kidneys (at 0.5- and 1-% level, males and females) were specified as "cell infiltration into stroma" and "cylinder in renal tubule cavity". There was no evidence of nephropathy and degenerations.
In the spleen (1-% level, males and females), "congestions" were observed.
In the thymus, "abnormalities of the medulla" and "congestion or bleeding" are reported in the high-dosed groups (males and females), but these effects were also present in the controls (males) and low-dose group (females) and are considered not to be treatment related.

HISTOPATHOLOGY: NON-NEOPLASTIC
Overall, histopathology revealed no morphological abnormalities but extremely slight changes at the highest dose level in both sexes
and in males at the 0.5-% level. Thus very slight anomalies in the liver at the two highest dose levels were assigned as " irregularity
of liver cells" and "congestion and bleeding". There was no evidence of fatty degeneration or necrosis in the liver.

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
(= 0.25% dietary level)
Effect level:
ca. 170 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: body weight; haematology; gross pathology; organ weights
Dose descriptor:
LOAEL
Remarks:
(= 0.5% dietary level)
Effect level:
ca. 340 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: body weight; haematology; gross pathology; organ weights

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion