Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
not reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: published study results; acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1997

Materials and methods

Principles of method if other than guideline:
see Test sections "Test materials", "Test animals" and "Administration/exposure"
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
Isophorone diamine; purity not reported

Test animals

Species:
rat
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
details not reported

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
nose only
Vehicle:
air
Remarks:
aerosol/vapour atmosphere
Remarks on MMAD:
MMAD / GSD: no data
Details on inhalation exposure:
- Concentrations (substance concentrations in aerosol/vapour atmosphere): 18 (low dose group) / 200 (medium dose group) / 550 mg/m3 (high dose group)
- Doses: 9 inhalation nose-only exposures for 6 hours per day in low and medium dose groups; exposure of high dose group ended after 4 nose-onl y exposures due to unexpected mortality of 4 rats
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
low and medium dose group: 9 exposures (1 exposure/day; 6hours/day )
high dose group: 4 exposures (1 exposure/day; 6hours/day)
Frequency of treatment:
each group: 1exposure /day (6hours/day)
Doses / concentrations
Remarks:
Doses / Concentrations:
18; 200; 550 mg/m3
Basis:
no data
No. of animals per sex per dose:
10
Control animals:
other: use of control rats reported but no specific information provided
Details on study design:
- Concentrations (substance concentrations in aerosol/vapour atmosphere): 18 (low dose group) / 200 (medium dose group) / 550 mg/m3 (high dose group)

Low and medium dose groups (10 male rats/group):
- Doses: 9 inhalation nose-only exposures for 6 hours per day in low and medium dose groups;
- end of exposure period: 5 rats/dose group were sacrified for pathological examinations after collection of blood and urine samples and the remaini g 5 rats/dose group undergone a 20 day recovery period. After 20 day recovery period the rats were used for pathology examinations

High dose group (10 male rats/group):
- exposure of high dose group ended after 4 nose-only exposures (6 hours/day) due to unexpected mortality of 4 rats
- remaining 6 rats were killed and necropsied one day after fourth exposure
Positive control:
no data

Examinations

Observations and examinations performed and frequency:
Daily examinations during exposure period:
- weighing of rats
- observation for clinical signs of toxicity
Sacrifice and pathology:
Sacrifice:
- no detailed information available: see "Details on study design"
Pathology:
- microscopic examination of nose, trachea, larynx and lungs
Other examinations:
not reported
Statistics:
not reported

Results and discussion

Results of examinations

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):
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:
TOXIC RESPONSE/EFFECTS BY DOSE LEVEL:
- Mortality and time to death: 1 during 3rd exposure, 2 during 4th exposure and 1 after 4th exposure in high dose group
- Mean body weight and mean body weight gain: significantly reduced in high dose group during period of exposure
-Respiratory system: dose and compound-related microscopic alterations were observed in the nose, trachea, larynx and lungs of the rats in the med ium dose group (200 mg/m3) and in the high dose group (550 mg/m3) and only in the nose of rats of the low dose group (18 mg/m3). In all dose g roups after exposure period these alterations were in general characterized by necrosis but also repair (hypertrophy and hyperplasia) was evident at tis time. Lungs and trachea of rats of the low (18 mg/m3) and medium (200 mg/m3) dose group were normal at the end of recovery period (20 da ys) and tissue repair was still in progress in nose and larynx in these dose groups. Hence the authors expect close to full microscopic restitution.

Effect levels

Dose descriptor:
LOEC
Effect level:
18 mg/m³ air
Sex:
male
Basis for effect level:
other: substance releated effects in the nose (considered to be reversible)

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

no further information

Applicant's summary and conclusion

Conclusions:
The substance isophorone diamine was examined in an inhalation repeated toxicity study (nose-only) using male rats (10/dosage group) exposed to aerosol/vapour concentrations of 18, 200, and 550 mg/m³ (6 hours/day for 9 exposures with low and medium dose groups and for 4 exposures with the high dose group). Dose-dependent histopathology was identified in the respiratory tract. A NOEL was not reported in the published study information. The LOEC is 18 mg/m3 air.
Executive summary:

The substance isophorone diamine was examined in an inhalation repeated toxicity study (nose-only) using male rats (10/dosage group) exposed to aerosol/vapour concentrations of 18, 200, and 550 mg/m³ (6 hours/day for 9 exposures with low and medium dose groups and for 4 exposures with the high dose group). Treatment with 550 mg/m³ was associated with mortality, significantly reduced mean body weights and significantly reduced mean body weight gains. Dose-dependent histopathology was identified in the respiratory tract. In the low and medium dose groups these microscopic alterations in the respiratory tract are considered to be reversible. A NOEL was not reported in the published study information. The LOEC is 18 mg/m3 air.