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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Does not meet important criteria of today standard methods (exposure period only 14 days, no examination of hematological and of clinical parametes, only limited number of organs examined)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989
Report Date:
1989

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Remarks:
; no examination of hematological and chlinical parameters, limited number of organs examined
Principles of method if other than guideline:
No guideline stated in report, but method used is similar to OECD TG 412. Goal of the study was to provide range-finding data on toxic effects of repeated exposures to diisotridecyl adipate aerosols as basis for a longer subchronic study.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Details on test material:
- Name of test material (as cited in study report): diisotridecyl adipate

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Kingston, NY, USA
- Age at study initiation: 8 weeks
- Weight at study initiation: males 180 - 195 g, females 159 - 196 g
- Housing: groups of in stainless steel hanging wire cages
- Diet (e.g. ad libitum): certified Purina rodent chow #5002, ad libitum
- Water (e.g. ad libitum): tap wateer delivered via automatic system, ad libitum
- Acclimation period: approx. 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 -22°C
- Humidity (%): 40 - 60%
- Air changes (per hr): no dta
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
air
Remarks on MMAD:
MMAD / GSD: mass median diameter: group 1: 1.1 ± 0.3 µm
group 2: 0.9 ± 0.1 µm
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 400 L inhalation chambers constructed of stainless steel and glas
- Method of holding animals in test chamber: the hanging wire cages for housing were loaded into the inhalation chambers
- Source and rate of air: no data
- Method of conditioning air: no data
- System of generating particulates/aerosols: Laskin nebulizer; pressurized air at ambient temperature passed through the hollow stem of the nebulizer and exited at high velocity through holes in its side. This high velocity air stream passed over the top of hollow feed barrels and caused the aspiration of the liquid test material up into the feed barrel. The liquid was aerosolized as it was drawn into the airstream by the relative negative pressure there. The liquid was sheared into small droplets. The larger aerosol particles were removed by impaction on the walls of a glass container around the nebulizer and by impaction in a second glass impactor. The aerosol was then diluted by the main airstream before entering the exposure chamber containing the animals. The concentration of aerosol in the chamber was controlled by varying the design of the nebulizer, air pressure in the nebulizer, and airflow through the chamber.
- Temperature, humidity, pressure in air chamber: no data
- Air flow rate: no data
- Air change rate: no data
- Method of particle size determination: cascade impaction (once during each exposure) using a glass impactor
- Treatment of exhaust air: no data

TEST ATMOSPHERE
- Brief description of analytical method used: gravimetrical determination of test substance collected on glass fiber filters by drawing test atmosphere through them
- Samples taken from breathing zone: no data

VEHICLE (if applicable)
- Justification for use and choice of vehicle: no vehicle used
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Gravimetrical determination by drawing air at a measured, controlled rate through glass fiber filters and determining the increase in weight of the filter (no significant amount of vapors was expected and vapors were not measured in the chamber air).
For nominal concentrations, the amount of test substance used for an individual test group exposure was determined by weighing. Division by the measured volume of air delivered to the exposure chamber yielded in the nominal concentration.
Duration of treatment / exposure:
14 days (10 exposures)
Frequency of treatment:
6 hours per day 5 days a week
Doses / concentrations
Remarks:
Doses / Concentrations:
0.25, and 0.51 mg/L (group 1 and 2); 0 mg/L (controls, group 3)
Basis:
analytical conc.
No. of animals per sex per dose:
10
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: highest level anticipated for human subchronic exposure (0.5 mg/L) was selected as highest dose. A lower concentration (0.25 mg/L) was included in the test to provide data on a dose-response, if any unexpected toxicity was observed with the higher dose

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: during exposure at intervals of approx. 30 min, and once daily except on weekends

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily except on weekends

BODY WEIGHT: Yes
- Time schedule for examinations: shortly before exposure at day 1 (commencement of exposure) and day 8 and prior to sacrifice

FOOD CONSUMPTION: No

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (nasal turbinates, lung, tracheobronchial lymph nodes, kidney, liver, and any gross lesion)
Statistics:
Data on body and organ weights were analyzed by Anova and Tukey's multiple range test for comparison of control and exposed groups.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
No significant clinical effects were observed in exposed animals.
No mortality was observed during the experiment.

BODY WEIGHT AND WEIGHT GAIN
Body weight was not effected by exposure.

ORGAN WEIGHTS
No treatment-related alterations in organ weights were found.

GROSS PATHOLOGY
No effects observed.

HISTOPATHOLOGY: NON-NEOPLASTIC
No treatment-related microscopic abnormalities were found in the organs examined.

Effect levels

Key result
Dose descriptor:
NOAEC
Basis for effect level:
other: Only range-finding study with a limited set of parameters examined
Remarks on result:
not determinable
Remarks:
no NOAEC identified

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
During a 14 day inhalation exposure to two graduate diisotridecyl adipate aerosol concentrations using rats as test animals, no relevant test substance related adverse effects were observed. Only a limited number of parameters were examined (clinical signs, body weight, weights of selected organs, gross pathology, histology of selected tissues). Objective of this study was to provide range-finding data on toxic effects of repeated exposures. A NOAEC was not derived.
Executive summary:

In a 14 day (subacute) inhalation toxicity study, diisotridecyl adipate was administered as aerosol to groups of 10 male and 10 female Sprague-Dawley rats by whole body exposure at concentrations of 0 (sham-control), 0.25 and 0.51 mg/L (analytical concentrations) for 6 hours per day, 5 days/week for a total of 10 days. Mass median diameter was ca 1.0 µm (respirable size). Objective of the study was to provide range-finding data on toxic effects of repeated exposures to aerosolized diisotridecyl adipate.

 

There were no compound related effects in mortality, clinical signs, body weight, weight of selected organs or gross pathology and histology of selected tissues. In addition, there was no indication of deposition of test material in and/or disposition from the lung and the nasal passages. A NOAEC was not derived (Mobil 1989).

 

This subacute inhalation toxicity study in the rat is not acceptable. It is a range finding study with only two (low) concentrations tested and only a limited number of parameters examined. It does not satisfy requirements of test guidelines in compliance with REACH.