Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: inhalation
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: The study is rated a "2" because appropriate testing methods were used; however, the study does not follow and accepted guideline or indicate compliance with GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1981

Materials and methods

Principles of method if other than guideline:
As described previously, Pegg (1979) GM Research Reports
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Unspecified DIDP; CAS No not provided

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: adult
- Weight at study initiation: 125g
- Housing: individually in polycarbonate wire top cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: MMAD = 0.98 um
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Data not available


TEST ATMOSPHERE
Repeated exposures to nonradioactive DIDP were conducted through whole body exposure in a 30L cylindrical glass jar. Animals were restrained in wire mesh cylinders and supported on a suspended screen floor. The chamber atmosphere was assayed for DIDP content on each exposure day. Cascade impactor samples for determination of aerosol particle size taken every other day during the exposure period.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
5 consecutive days, 2 days recovery and another 5 days exposure (10 total exposures)
Frequency of treatment:
6 hours/ day
Doses / concentrations
Remarks:
Doses / Concentrations:
500 mg/m3
Basis:
nominal conc.
No. of animals per sex per dose:
8 rats/dose
6 control rats
Control animals:
yes, concurrent no treatment
Details on study design:
Body weights of the animals were taken immediately before and after each 6 hour exposure period. After exposure, animals were returned to the vivarium. Control animals were exposed simultaneously in an identical chamber flushed with filtered room air. Rats were observed daily for body weight gain, appearance and gross behavior. At the end of the exposure regimen animals were held for observation for 3 weeks. Animals were sacrificed at the end of the observation period and tissue samples taken for histopathology.

Results and discussion

Results of examinations

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):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
The nominal chamber atmosphere concentration for the repeated exposure toxicity studies was 500 mg/m3. Daily, mean analytical concentrations ranged from 468 to 571 mg/m3. The mean analytical concentration for the ten exposure periods was 505 mg/m3. The mass median aerodynamic diameter of the DIDP aerosol was 0.98 um.

Animals exposed repeatedly to 500 mg/m3 DIDP exhibited no marked outward signs of toxicity during exposures. The rate of body weight gain was not different between control and exposed animals. Occasional changes in focal pulmonary histology were observed. Animals sacrificed 3 weeks following termination of exposure exhibited moderate increases in the weidth of alveolar septa with slight interstitial mixed inflammaotry reactions. Alveolar macrophages and type II pneumocytes were increased in number. Peribronchial lymphoid tissue appeared slightly more prominent in exposed animals. Liver, kidney and spleen from DIDP treated animals exhibited no obvious histologic alteration except for slight hepatic fatty metamorphosis.

Effect levels

Dose descriptor:
NOAEC
Effect level:
500 mg/m³ air
Sex:
male
Basis for effect level:
other: No systemic toxicity

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The exposure regimen did not result in lethality when animals were observed for up to 3 weeks following treatment. Pulmonary irritation, however was apparent.
Executive summary:

In a 2-week study (General Motors Research Laboratories, 1981) designed to evaluate the fate of DIDP (see Section 5.1), toxicity was also assessed. DIDP was administered to 8 male rats (6 for control) by inhalation (aerosol) at analytical concentration of 505±7 mg/m3(MMAD: 0.98 μm) 6 hours a day, 5 times per week. Rats were observed daily for body weight gain, appearance and gross behavior. Animals were sacrificed at the end of the observation period (3 weeks) and tissue samples taken for histopathology. There were no marked outward signs of toxicity during exposure. The rate of body weight gain was not different between control and exposed animals. Effects in the lungs were: moderate increase in the width of alveolar septa with slight interstitial mixed inflammatory reactions, alveolar macrophages and type II pneumocytes were increased in number, peribronchial lymphoid tissue appeared slightly more prominent. In liver, spleen and kidneys, no obvious histologic alterations were noted except for a slight hepatic fatty metamorphosis. No systemic toxicity, but local irritant effects were observed at the concentration tested, thus a NOAEL of 0.5 mg/l (500 mg/m3) can be assumed.