Bis(isopropyl)naphthalene

Endpoint summary

Description of key information

One key study concerning repeated dose toxicity was identified (Kawai, 1973; rat, oral, 6 months). In this study a NOAEL of 170 mg/kg/day was determined.

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

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)

Qualifier:

according to guideline

Guideline:

other: national standard (Japan)

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system 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

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

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

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)

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.

Dose descriptor:

NOAEL

Remarks:

(= 0.25% dietary level)

Effect level:

ca. 170 mg/kg bw/day (nominal)

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)

Sex:

male/female

Basis for effect level:

other: body weight; haematology; gross pathology; organ weights

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

170 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

Repeated dose toxicity: oral

Four study reports were identified. But only one oral study is assessed to be valid. In Kawai 1973, bis(isopropyl)naphthalene (DIPN) was orally administered in diet for 6 months. Observations and evaluations correspond to test guideline requirements. Kawai reports a NOAEL of 170 mg/kg bw/day for DIPN.

The oral 24 months study of Kawai (1977) is a combined carcinogenicity/chronic toxicity study. But there were only a few animals set up as satellites for treatment/observation periods shorter than 24 months. Thus the endpoint chronic toxicity (treatment period shorter than 24 months) is not adequately covered. Observations at 24 months are largely influenced by age involution. Furthermore, mortality was substantially increased at later time points (starting from month 18) due to high incidence of pneumonia in all animals. The derived NOAEL of 12 mg/kg bw/day is considered to be confounded by secondary factors and, hence, not suitable to express the inherent chronic toxicity potential of the test substance.

Repeated dose toxicity: dermal

No valid information is available. The study record of Kureha 1979 only stands for a short abstract/summary authored by Kureha Chemicals Industry Co. which does not provide sufficient details for assessment.

Repeated dose toxicity: inhalation

No information could be located. With respect to the low vapour pressure of diisopropylnaphthalene, inhalation is considered to be a potential exposure route of minor practical relevance. Moreover, given the low toxicity found after acute inhalation as well as after repeated oral exposure it is concluded that adverse effects following prolonged inhalation exposure will be low grade, too.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

The NOAEL determined for repeated dose toxicity of diisopropylnaphthalene exceeds guidance values for Danger of serious damage to health by prolonged exposure according to Directive 67/548/EEC and for specific target organ toxicity - repeated exposure according to regulation (EC) No. 1271/2008. Classification is not required.