Bis(isopropyl)naphthalene

Endpoint summary

Description of key information

The oral LD50 of bis(isopropyl)naphthalene (DIPN) was determined to be 4130 mg/kg bw in male rats and 4320 mg/kg bw in female rats (MITES, 1982).
In a limit test, no mortality was observed for rats exposed to an analytically verified DIPN aerosol concentration of 5.64 mg/L for 4 hours (RCC, 1988).
In a limit test, no mortality was observed for rats following dermal administration of 9250 mg/kg (IBR, 1986).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: Crjh : CD

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Japan Inc.
- Age at study initiation: no data
- Weight at study initiation: males 115 - 166 g, females 102 - 127 g
- Fasting period before study: yes
- Housing: 5 per cage in polycarbonate cages
- Diet (e.g. ad libitum): pelletized rat diet (rat.MF, Oriental Yeast Co.), ad libitum
- Water (e.g. ad libitum): tap water through polycarbonate bottles, ad libitum
- Acclimation period: more than a week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 - 24
- Humidity (%): 50 - 60
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

Route of administration:

oral: gavage

Vehicle:

olive oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 0.18 - 0.7 mL TS/mL olive oil according to dose
- Amount of vehicle (if gavage): 1 mL/100 g bw
- Justification for choice of vehicle: no data

MAXIMUM DOSE VOLUME APPLIED: 1 mL/100 g bw

Doses:

males: 1.73, 2.21, 2.78, 3.46, 4.32, 5.38, and 6.72 g/kg bw (1.8, 2.3, 2.9, 3.6, 4.5, 5.6, 7.0 mL/kg)
females: 2.78, 3.46, 4.32, 5.38, 6.72 (2.9, 3.6, 4.5, 5.6, 7.0 mL/kg)

No. of animals per sex per dose:

10

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: several times at day of administration, once or more times daily thereafter until 14 days
(time of sacrifice). Body weights were measured shortly before, 7 and 14 days after administration.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

LD50 values were determined using the method of Litchfield and Wilcoxon.

Sex:

male

Dose descriptor:

LD50

Effect level:

4 130 mg/kg bw

95% CL:

3 550 - 4 800

Remarks on result:

other: LD50 is reported as 4.3 mL/kg bw

Sex:

female

Dose descriptor:

LD50

Effect level:

4 320 mg/kg bw

95% CL:

3 650 - 5 090

Remarks on result:

other: LD50 is reported as 4.5 mL/kg bw

Mortality:

1.58 g/kg group:  0/10
2.20 g/kg group: 1/10 (day 2)
2.78 g/kg group:   1/20 (day 3)
3.46 g/kg group:   6/20 (days 2-4)
4.32 g/kg group:  11/20 (days 1-5)
5.38 g/kg group:  14/20 (days 1-5)
6.72 g/kg group:  20/20 (days 1-6)

Clinical signs:

other: Reduced activity, reduced muscle tonus, toe walking, diarrhea, incontinence, haemic nasal discharge, emaciation

Gross pathology:

Dead animals
Dose-related discolored liver, discolored and atrophic spleen and kidneys, reddish purple appearance of the adrenal glands, hypertrophy of the adrenal glands, scattered reddish spots in and reddish appearance of the lungs, hemorrhage in the thymus gland
Surviving animals
Occasionally in male, but not in female animals, scattered reddish spots in the lung, atrophy of spleen and hypertrophy of mesentery lymph nodes.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

In a valid acute oral toxicity study according to OECD test guideline 401, LD50 values of 4130 and 4320 mg/kg bw were determined for male and female rats respectively.

Endpoint conclusion

Dose descriptor:

LD50

Value:

4 130 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

adopted 1981

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Kleintierfarm Madoerin AG, Fuellinsdorf, Switzerland
- Age at study initiation: males 11 weeks, females 13 weeks
- Weight at study initiation: males 237.5 - 255.6 g, females 218.3 - 239.7 g
- Housing: 5 per cage in makrolon cages, type IV, with standard softwood bedding
- Diet (e.g. ad libitum): pelleted standard Kliba 343 rat maintenance diet (Klingenthalmuehle AG. Kaiseraugst, Switzerland), ad libitum
- Water (e.g. ad libitum): community tap water from Geneva, ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 40 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 09.11.1987 To: 01.12.1987

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: exposure chamber according to Sachsse et al (1973, 1976): Breathing atmosphere (aerosol) is passed through a central
cylindrical tube vertically positioned to which animal confinement chambers are radially attached. From the internal active exposure chamber,
small tubes lead to the breathing zone of the attached confinement chambers. Surplus breathing air and exhaled air are discharged through
an outer cylindrical tube positioned around the internal active chamber.
- Exposure chamber volume: volume of the internal active chamber: 1 L
- Method of holding animals in test chamber: Macrolon restraint tubes of suitable size and shape vertically attached to the exposure chamber
- System of generating particulates/aerosols: The test atmosphere was generated by a constant volume reservoir feeding a Hospitak No. 950
nebulizer following dissolution with water. Following the nebulizer, a dilution system was used to dilute the test article output of the nebulizer
with clean air to the concentration required for the study. The aerosol generating system was designed to create an aerosol with a mass median
diameter of 3 µm or less. Following aerosolization, the test article was discharged into the exposure chamber.
- Method of particle size determination: separation of particles using a Mercer 7 stage cascade impactor. The sampling air flow was 1.0 L/min
and the mass content of the different stages of the impactor was assessed gravimetrically.
- Temperature, humidity, pressure in air chamber: 21°C, 12% (relative humidity), slight positive pressure in inner chamber and slight negative
pressure in outer chamber.

TEST ATMOSPHERE
- Brief description of analytical method used: Test substance was sampled by passing test atmosphere through three in line gas washing bottles
containing ice-cold acetonitrile as solvent. Aliquots of this solution were analyzed by HPLC (solvent acetonitrile/water 70/30, column RP-18).
KMC was used as external standard for calibration (see Appendix D).
- Samples taken from breathing zone: yes

VEHICLE
- no

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: 36.3% ≤4.6 and >3.0 µm, 23.3% ≤3.0 and >2.13 µm, 40.4% ≤2.13 µm
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): no data

Analytical verification of test atmosphere concentrations:

yes

Remarks:

see above

Duration of exposure:

4 h

Concentrations:

5.64 mg/l (Limit test; mean analytical exposure concentration)

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: once per hour during exposure, once after exposure on test day 1 and twice daily thereafter,
body weight measurements at days 1 (day of exposure), 8, and 15 of test
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight; lungs from all animals were collected at necropsy and
fixed in a neutral phosphate buffered 4% formaldehyde solution.

Statistics:

No statistics

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.64 mg/L air

Based on:

test mat.

Remarks:

(aerosol)

Exp. duration:

4 h

Mortality:

2/5 females died at day 14 post exposure; no deaths among males.

Clinical signs:

other: During exposure: slight to moderate nose bleeding (epistaxis), no other significant signs. After exposure: slight to moderate signs of discomfort and physiological distress: hunched posture, piloerection, distended abdomen, tremor, impaired breathing, sa

Body weight:

Males: Mean body weight decreased from test day 1 to day 8. Until test day 15, mean body weight increased again,
but the starting value was not reached.
Females: Mean body weight decreased continuously over day 8 up to day 15 (only 3 animals at day 15).

Gross pathology:

red spots in the lung

Conclusions:

In an acute inhalation toxicity test using only one concentration (5.64 mg/L, limit test), 5 rats/sex were exposed to KCM (diisopropylnaphthalene) as aerosol for 4 hours.Two of the female rats died at day 14 (mortality 2/10 total). The LC50 for acute inhalation toxicity can be assessed to be >5.64 mg/L based on the mortality observed.

Endpoint conclusion

Dose descriptor:

LC50

Value:

5 640 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga GmbH, Sulzfeld, Germany
- Age at study initiation: four to seven weeks
- Weight at study initiation: males 245 - 255 g, females 205 - 225 g
- Fasting period before study: no data
- Housing: singly in Makrolon-cages with bedding
- Diet (e.g. ad libitum): R 4 complete rat diet (Ssniff Versuchstier-Diäten GmbH, Soest, Germany), ad libitum
- Water (e.g. ad libitum): drinking water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 23
- Humidity (%): 40 - 70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 /12

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: ca 34 cm²
- % coverage: ca. 10% of body surface
- Type of wrap if used: occlusive wrap (Leukoplast)

REMOVAL OF TEST SUBSTANCE
- Washing (if done): test substance residues were washed off with water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 4500 mg/kg
- Concentration (if solution): pure test substance

Duration of exposure:

24 hours

Doses:

4500 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations: 0.25, 0.5, 1, 2, and 4 hours after TS administration, daily thereafter;
weighing: at days -1, 0 (day of administration), 7, and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

no calculations

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 4 500 mg/kg bw

Remarks on result:

other: only one dose administered (limit test); no mortality

Mortality:

No mortality

Clinical signs:

other: No clinical signs

Gross pathology:

No macroscopic findings

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

In an acute dermal toxicity test using only one dose (4500 mg/kg bw, limit test), 5 rats/sex were exposed to KMC 113/1 (diisopropylnaphthalene) for 24 hours. No mortality and no clinical or gross pathological findings were observed. The LD50 for acute dermal toxicity can be assessed to be >4500 mg/kg bw under the conditions of this test.

Endpoint conclusion

Dose descriptor:

LD50

Value:

4 500 mg/kg bw

Additional information

Acute toxicity: oral

For assessment of the acute oral toxicity of bis(isopropyl)naphthalene (DIPN), two valid studies are available. The study with the lower LD50 is chosen as representative for the inherent potential of acute oral toxicity of DIPN.

MITES 1982

In this valid acute oral toxicity study according to OECD test guideline 401, LD50 values of 4130 and 4320 mg/kg bw were determined for male and female rats, respectively.

IBR 1986

In this valid acute oral toxicity study according to OECD test guideline 401, a LD50 value of 15,180 mg/kg bw was determined in rats.

The much higher LD50 value in this study compared to the study of MITES 1982 is regarded to be caused by the use of olive oil as vehicle in the MITES study resulting in better intestinal absorption of the test substance. Thus, comparable internal doses are achieved by greatly varying doses administered.

Classification will be based on the lower values.

 

Acute toxicity: inhalation

For assessment of the acute inhalation toxicity of DIPN, one valid study is available.

RCC 1988

In an acute inhalation toxicity test using only one concentration (5.64 mg/L, limit test), 5 rats/sex were exposed to DIPN as aerosol for 4 hours. Two of the female rats died at day 14 (mortality 2/10 total). The LC50 for acute inhalation toxicity can be assessed to be >5.64 mg/L based on the mortality observed.

Acute toxicity: dermal

For the assessment of the acute dermal toxicity, two valid studies are available. Both are performed as limit test using only one test concentration. No mortality was observed in both studies. The study with the higher dose can be considered to represent the inherent acute dermal toxicity potential of DIPN.

IBR 1986

In an acute dermal toxicity test using only one dose (10 mL/kg bw = 9250 mg/kg bw, limit test), 10 rats/sex were exposed to KMC (DIPN) for 24 hours. The skin of half of the animals was scarified. No mortality and no clinical or gross pathological findings were observed. The LD50 for acute dermal toxicity can be assessed to be >9250 mg/kg bw under the conditions of this test.

Hazleton 1984

In an acute dermal toxicity test using only one dose (4500 mg/kg bw, limit test), 5 rats/sex were exposed to KMC 113/1 (DIPN) for 24 hours. No mortality and no clinical or gross pathological findings were observed. The LD50 for acute dermal toxicity can be assessed to be >4500 mg/kg bw under the conditions of this test.

Classification can be based on the lower value.

Justification for classification or non-classification

Acute oral toxicity

The LD50 of the key study (lowest reported LD50) was 4130 mg/kg bw in rats. According to directive 67/548/EEC as well as Regulation (EC) No 1272/2008, diisopropylnaphthalene is not to be classified as toxic/harmful or acutely toxic as classification criteria are not met (LD50/ATE≤ 200 mg/kg bw).

 

Acute inhalation toxicity

In a Limit Test (analysed test substance concentration 5.67 mg/L, 4 hour exposure) according to OECD test guideline 403, DIPN was tested as aerosol. Mortality was 2 of 10 test animals. LC50 was determined as > 5.64 mg/L. According to directive 67/548/EEC as well as Regulation (EC) No 1272/2008, diisopropylnaphthalene is not to be classified as toxic/harmful or acutely toxic as classification criteria are not met (LC50/ATE≤ 5.0 mg/L).

 

Acute dermal toxicity

The lowest dermal LD50 of two valid studies (Limit Tests) was > 4500 mg/kg bw. According to Directive 67/548/EEC as well as Regulation (EC) No 1272/2008, classification of diisopropylnaphthalene as toxic/harmful or acutely toxic is not required, as classification criteria are clearly exceeded (LC50/ATE≤ 2000 mg/kg bw).