2,6-diisopropylnaphthalene

Endpoint summary

Description of key information

Subchronic (90 -day) repeated dose toxicity (feeding study, similar OECD 408): NOAEL (rat, m) = 105 mg/kg bw/day; NOAEL (rat, f) = 121 mg/kg bw/day

Study performed with 2,6-diisopropylnaphthalene (CAS No. 24157-81-1)

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

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:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.3100 (90-Day Oral Toxicity in Rodents)

Deviations:

no

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

yes

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): 2,6-DIPN, diisopropylnaphthalene
- Physical state: tan solid (flakes)
- Analytical purity: 98.6
- Lot/batch No.: DP681432
- further informations are on file with the sponsor (Platte Chemical Co., Greeley, CO, USA)
- Storage condition of test material: room temperature

Species:

rat

Strain:

other: Sprague-Dawley [Crl:CD(SD)IGS BR]

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories Inc., Portage, MI, USA
- Age at study initiation: appr. 6 weeks
- Weight at study initiation: males 160 - 219 g, females 116 - 152 g
- Fasting period before study: no data
- Housing: individually housed in suspended, stainless-steel cages
- Diet: cerified rodent diet (#8728CM meal, Harlan Teklad) ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 30 - 70
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 12 Feb 1999 To: 25 May 1999

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): appr. weekly
- Mixing appropriate amounts with (Type of food): appropriate amounts of test substance were mixed with certified rodent diet (see above). In a first step part of the diet was ground with the test substance in a mortal bowl. This premix was thoroughly mixed with the remaining rodent diet.
- Storage temperature of food: room temperature

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Homogeneity was verified for the lowest and highest concentration by taking samples from the top, middle, and bottom of the food mix. These samples were also used for analysis at different time points (periods from 7 days to 4 weeks) to establish the stability of the test substance in the food preparation mix.

Duration of treatment / exposure:

92 days

Frequency of treatment:

continuous

Dose / conc.:

750 other: mg/kg diet (nominal in diet)

Dose / conc.:

1 500 other: mg/kg diet (nominal in diet)

Dose / conc.:

3 000 other: mg/kg diet (nominal in diet)

Dose / conc.:

54 mg/kg bw/day (nominal)

Remarks:

males

Dose / conc.:

105 mg/kg bw/day (nominal)

Remarks:

males

Dose / conc.:

208 mg/kg bw/day (nominal)

Remarks:

males

Dose / conc.:

62 mg/kg bw/day (nominal)

Remarks:

females

Dose / conc.:

121 mg/kg bw/day (nominal)

Remarks:

females

Dose / conc.:

245 mg/kg bw/day (nominal)

Remarks:

females

No. of animals per sex per dose:

10

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: no data
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: no satelite groups

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes; in accordance with regulations

DETAILED CLINICAL OBSERVATIONS: Yes; in accordance with regulations

BODY WEIGHT: Yes; in accordance with regulations

OPHTHALMOSCOPIC EXAMINATION: Yes; in accordance with regulations

HAEMATOLOGY: Yes; in accordance with regulations

CLINICAL CHEMISTRY: Yes; in accordance with regulations

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: during week 12
- Dose groups that were examined:
- Battery of functions tested: motor activity, sensory reactivity (elicited behaviors)

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, organ weights were determined and a comprehensive set of organs/tissues was collected and preserved in 10% neutral-buffered formalin.
HISTOPATHOLOGY: Yes, tissues (as appropriate) from each animal in the control and high dose group were prepared and examined microscopically. Macroscopic lesions, adrenals, kidneys, and liver were also examined microscopically from each animal in the low- and mid-dose groups.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

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

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
No treatment-related, adverse effects were observed for all test substance concentrations except pupil constriction at the mean and top dose. There were no test material-related effects noted during handling, open field observation, or on sensory reactivity assessment.
There were no mortalities; all animals survived the study period until the scheduled sacrifice.

BODY WEIGHT AND WEIGHT GAIN
Body weight of highest-dosed males and females was significantly reduced (final weights about 86 and 88 % of control, respectively), Interim minor body weight changes in lower dose groups was transient and did not represent any pattern. They are not considered to be toxicologically important. Decreases in mean body weight were correlated with decreases in mean food consumption (see below).

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Food consumption was statistically reduced for males given 3000 ppm throughout the study. For 3000 ppm females, food consumption was slightly lower than controls through week 6, then comparable with controls for the remainder of the study.
Compound intake, averaged over the total study period, was 53.9, 104.6, and 207,6 mg/kg bw/day for males and 61.8, 121.4, and 244.7 mg/kg bw/day for females (750, 1500, and 3000 ppm groups respectively).

HAEMATOLOGY
In the male 3000-ppm group, slight effect on blood coagulation: mildly higher prothrombin and activated partial thromboplastin time were observed. In the female 1500- and 3000-ppm groups, red blood cell count, Hb, and haematocrit was mildly lowered. Effects were not considered to be adverse and of biological relevance.

CLINICAL CHEMISTRY
In 3000-ppm groups (males and females), slightly higher cholesterol was noticed. This effects was not considered to be adverse and of biological relevance.

ORGAN WEIGHTS
Statistically significant, absolute and/or relative organ-weight increases (adrenals, kidney and liver) noted in all female treated groups, were unrelated to dosage, except for the highest dose. In males given 3000 ppm, significantly increased kidney and adrenal weights appeared to be test material-related.

GROSS PATHOLOGY
There were no gross findings that could be attributed to the administration of the test material.

HISTOPATHOLOGY: NON-NEOPLASTIC
Test material-related changes were noted in the liver, kidney, and adrenal gland in animals given 3000 ppm.
Liver findings: increased incidence and severity of centrilobular hepatocytic hypertrophy (both sexes).
Kidney findings: tubular epithelial regeneration, degeneration/necrosis of tubular epithelium and intratubular cellular debris indicated tubular nephrosis (most prominent in males)
Adrenal gland findings: incidence and severity of cortical cell hypertrophy was increased (both sexes).

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 105 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: body weight; food consumption; organ weights; histopathology

Remarks on result:

other: NOAEL corresponds to 1500 mg/kg diet

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 121 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: body weight; organ weights; histopathology

Remarks on result:

other: NOAEL corresponds to 1500 mg/kg diet

Dose descriptor:

LOAEL

Effect level:

ca. 208 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: body weight; food consumption; organ weights; histopathology

Remarks on result:

other: LOAEL corresponds to 3000 mg/kg diet

Dose descriptor:

LOAEL

Effect level:

245 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: body weight; organ weights; histopathology

Remarks on result:

other: LOAEL corresponds to 3000 mg/kg diet

Critical effects observed:

not specified

Conclusions:

In a 90-day repeated dose toxicity feeding study, NOAEL values of 105 and 121 mg/kg bw/day for male and female Sprague-Dawley rats, respectively, were determined.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

105 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable (Klimisch score 1) study performed with the registered substance. The selected study is thus sufficient to fulfil the standard information requirements set out in Annexes VIII - X, Item 8.6,, of Regulation (EC) No. 1907/2006.

Organ:

kidney

liver

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

The subchronic repeated dose toxicity of 2,6-diisopropylnaphthalene (CAS No. 24157-81-1) was investigated in a 90-day dietary study similar to OECD guideline 408 and observing GLP provisions (Henwood, 1999). Groups of 10 Sprague-Dawley (Crl:CD(SD)IGS BR) rats per dose and sex were administered the test substance at doses of 750, 1500 and 3000 ppm. The doses corresponded to approx. 39-87, 74-163, and 153-300 mg/kg/day for males and approx. 52-92, 94-171, and 209-319 mg/kg/day for females. The administration period lasted 92 days. Food and water were provided ad libitum. Administration of the test substance led to higher prothrombin time and activated partial thromboplastin time for high-dose males, lower red blood cell count, hemoglobin, and hematocrit for females of the mid- and high-dose groups and higher cholesterol for males and females fed 3000 ppm. Since there were no correlated anatomic pathology findings, the small differences for these parameters were not considered adverse. Terminal body weights were significantly decreased in the males given 3000 ppm. Absolute and/or relative organ weight increases of potential test material relationship included adrenal, kidney, and liver in all females of treatment groups. In the males, significantly increased kidney and adrenal weights in animals of the high-dose group were considered test material-related. Increased incidence and severity of centrilobular hepatocytic hypertrophy was seen in both sexes fed with 3000 ppm. Kidney changes at 3000 ppm suggestive of tubular nephrosis include tubular epithelial regeneration, degeneration/necrosis of the tubular epithelium and intratubular cellular debris. The renal changes were most prominent in the males. Adrenal gland findings included increased incidence and severity of cortical cell hypertrophy in both sexes of high-dose animals. Test substance-related histomorphologic changes were not seen at the 750 or 1500 ppm levels. Based on the microscopic findings in high-dose animals, the no-observed-adverse-effect level (NOAEL) is 1500 ppm, corresponding to 105 and 121 mg/kg bw/day for males and females, respectively.

Justification for classification or non-classification

The available data on oral repeated dose toxicity of 2,6-diisopropylnaphthalene (CAS No. 24157-81-1) do not meet the criteria for classification according to Regulation (EC) No. 1272/2008 (CLP). Data are, therefore, conclusive but not sufficient for classification.