Registration Dossier

Administrative data

Description of key information

Cited from SIAR for SIAM 18 (Paris, April 2004):
"From two 14-day inhalative exposure studies with rats no NOAEL could be determined. At the first study’s LOAEL of 18 mg/m3, degeneration/necrosis in the olfactory epithelium of the nose were observed. Trachea, larynx and lungs were affected at 200 mg/m3 and above (degeneration/
necrosis, hyperplasia, squamous metaplasia). At the LOAEL of the follow-up study, i.e. at 2.2 mg/m³, reversible minimal to mild degeneration of respiratory nasal mucosa in the anterior dorsal nose was observed."
Cited from SIAR for SIAM 18 (Paris, April 2004):
"In a subchronic drinking water study according to OECD TG 408, the administration of 150 mg/kg bw/day led to reduced absolute and relative kidney weights in male and female rats (histopathology being indicative for tubular nephrosis), while 59 mg/kg bw/day(males) and 62 mg/kg bw/day (females) were determined as a NOAEL."

Key value for chemical safety assessment

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
Study period:
1985-08-05 - 1985-11-13
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study
Reference:
Composition 0
Composition 0
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Version / remarks:
1981
Deviations:
no
GLP compliance:
yes
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ORGANISMS
- Source: KFM Kleintierfarm Madoerin AG, CH
- Age: 6 weeks
- Weight at study initiation:
males 136-157 g, females 117-139 g
- Number of animals: Total 80 males, 80 females; 20 per sex and group
- Fasting period before study:
- Housing: groups of 5 in Makrolon type 4 cages
- Diet: ad libitum, Kliba 343 rat maintenance diet
- Water: Distilled water for the treatment period ad libitum
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2 °C
- Humidity (%): 55 +/- 10 %
- Air changes (per hr): 10 - 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 h/12h
Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
ADMINISTRATION / EXPOSURE
- Duration of test/exposure: 13 weeks
- Type of exposure: oral, drinking water
- Post exposure period: -
- Vehicle: drinking water
- Doses:
Group 1 = control;
group 2 = 20 mg/kg bw/day;
group 3 = 60 mg/kg bw/day;
group 4 = 160 mg/kg bw/day
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentration and stability analysis of isophorone diamine were performed by gas chromatography.
The results of the stability test at room temperature showed that isophorone diamine was stable in drinking water for at least 96 h.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily (continuously)
Remarks:
Doses / Concentrations:
20, 60, or 160 mg/kg bw d (nominal) = groups 2, 3, and 4
Basis:
nominal in water
Remarks:
Doses / Concentrations:
males: 0; 21.5; 59; 150 mg/kg bw per day / females: 0; 22.6; 62; 147 mg/kg bw per day
Basis:
other: mean daily dose received (calculated) over 13 weeks
No. of animals per sex per dose:
20
Control animals:
yes
Details on study design:
Post-exposure period: none
Positive control:
no positive control
Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS AND FREQUENCY:
- Clinical signs: twice daily
- Mortality: twice daily
- Body weight: weekly
- Food consumption: weekly (7 day consumption)
- Water consumption: weekly (24 hours consumption)
- Ophthalmoscopic examination: at pretest and end of study;
10 animals per group (lowest ID numbers) and sex examined
- Haematology: end of study, 10 animals per group and sex
(highest ID numbers)
- Biochemistry: end of study, 10 animals per group and sex
(highest ID numbers)
Sacrifice and pathology:
ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
- Macroscopic: all organs listed below under "Microscopic";
weights of adrenals, kidneys, liver, testes
- Microscopic: (all rats of groups 1 and 4 plus those which had gross lesions): adrenal glands, aorta (thoracic), bone (sternum), bone marrow
(sternum), brain, cecum, colon, duodenum, epididymides, esophagus, eyes, Harderian glands, heart, ileum, jejunum, kidneys, liver, lungs with
mainstem bronchi, lymph nodes (mandibular, mesenteric), mammary gland, ovaries, pancreas, pituitary gland, prostate, rectum, salivary gland
(mandibular, sublingual), sciatic nerve, seminal vesicles, sekletal muscle, skin, spinal cord, spleen, stomach, testes, thymus, thyroid gland, tongue,
trachea, urinary bladder, uterus
Other examinations:
see addendum to the pathology report:
In an attempt to further elucidate the toxicological significance of findings in the kidneys, a larger sample of renal tissue was re-examined from rats
of all groups. In addition to the already available sections, another set of histological slides was prepared from the wet tissue of rats of groups 1 and 4 which was matched by two sections from each rat of groups 2 and 3.
Statistics:
Univariate one-way analysis of variance for significance of intergroup differences;
Dunnett-test for comparison between treated groups and control group (if normal distribution assumed)
Steel-test (if normal distribution not assumed)
Fisher's exact test for spontaneous mortalities
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):
effects observed, treatment-related
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
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:
no effects observed
Details on results:
NOAEL = 59 mg/kg bw d (males),
62 mg/kg bw d (females)
ACTUAL DOSE RECEIVED BY DOSE LEVEL BY SEX
males 21.5 / 59 / 150 mg/kg bw d
females 22.6 / 62 / 147 mg/kg bw d
TOXIC RESPONSE/EFFECTS BY DOSE LEVEL:
- Mortality and time to death:
No animal died during the study
- Clinical signs:
No treatment-related sign or symptom was noted.
- Body weight gain: Lower in group 4 than in other groups (statistically significant: males -16%; females -21%)
- Food/water consumption:
The mean food consumption of the group 4 animals was reduced when compared with that of the control rats (statistically significant for males at
week 9-13 and for females at week 8-10).
The mean water consumption was decreased when compared with the controls (statistically significant in group 4 animals):
Males group 2: -18.0%; group 3: -20.1%, group 4: -40.4%
Females group 2: -13.5%; group 3: -19.9%; group 4: -47.8%
- Ophthalmoscopic examination:
No treatment-related finding was observed in any animal.
- Clinical chemistry: The assessment of clinical biochemical data indicated no changes of toxicological significance. Some treatment-unrelated effects were noted and considered to be secondary. They were not supported by morphological findings. The following changes were statistically
significant:
urea level for group 4 males +40.4%
calcium level for group 3 females (-3.1%) and for group 4 males (-4.0%) and females (-7.1%)
phosphorus levels for group 3 males (-10.5%) and females (-15.4%) and for group 4 males (-18.7%) and females (-27.5%)
total protein levels for group 4 females -7.0%
albumin fraction (absolute) of the protein electrophoretic pattern for group 4 females -7.7%
alpha-1 globulin fraction (relative males -14.0%, females -10.4% and absolute males -18.1%, females -16.3%) of the protein electrophoretic pattern
for group 4 animals
alpha-2 globulin fraction (relative -18.6% and abolute-21.4%) for group 4 males
- Haematology: The assessment of hematological data indicated no changes of toxicological significance after 13 weeks of treatment. Some treatment unrelated effects were noted and considered to be secondary. They were not supported by morphological findings. The following changes were
statistically significant:
hemoglobin in group 4 females -6.2%
platelet count in group 4 males (+29.0%) and females (+12.5%)
reticulocyte count for group 4 females +46.7%
total leukocyte count for group 2 males (-20.2%), group 3 males (-20.2%) and females (-24.1%), and group 4 males (-22.9%) and females (-25.3%)
prolonged prothrombin time for group 4 females +4.7%
- Organ weights:
Kidney weights in group 4 males absolute +8.1% (not significant), relative +16.4% (statistically significant) and females absolute +13.5%, relative
+25.0% (both statistically significant)
Liver weights absolute +20.7%, relative +16.7% (both statistically significant) in group 3 males, absolute -13.8% (statistically significant), relative
-4.8 % (not significant) in group 4 females, absolute -3.3%, relative +3.6% (both insignificant) in group 4 males
Other absolute and relative organ weights were not affected significantly.
- Gross pathology: No treatment-related macroscopic findings were observed. A few spontaneous gross lesions were encountered in both control
and treated rats. Their incidence and severity are considered to be similar in all groups.
- Histopathology: In further examination of the kidneys (see addendum to the pathology report, Reference RCC 1989), isolated very small foci of
tubular atrophy were recorded in one organ only. The statistical analysis for positive trend with respect to dose rate yielded a significant result for males (Z=2.29, one-tailed P=0.01) and a negative one for females (Z=1.61, one-tailed P=0.55).
Under the conditions of the experiment, the test article produced morphological alterations in the kidneys of rats at 160 mg/kg bw/day (nominal; gr oup 4)
(see second addendum to the report, Reference RCC 2000). The findings consisted of an increased incidence in tubular basophilia (both sexes of
group 4), and tubular casts (both sexes of group 4) along with a higher incidence of lymphoid foci (both sexes of group 4). These changes are
indicative for tubular nephrosis. All findings were of minor severity degrees, but were statistically significant. The remainder of findings recorded
did not differ between controls and rats treated with the test article.
Frequency of findings treated (control)
-----------------------------------------------------------
Tubular basophilia males 17/20 (0/20), females 13/20 (6/20)
Tubular casts males 8/20 (1/20), females 11/20 (1/20)
Lymphoid foci males 16/20 (5/20), females 13/20 (4/20)
-----------------------------------------------------------
- Other: The remainder of findings recorded did not differ between controls and rats treated with the test article. They were considered to be within
the range of spontaneous background lesions which may be recorded in Wistar rats of this strain and age.
Dose descriptor:
NOAEL
Effect level:
60 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: histopathological alterations of kidneys
Dose descriptor:
LOAEL
Effect level:
160 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: histopathological alterations of kidneys
Dose descriptor:
NOAEL
Effect level:
59 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: histopathological alterations of kidneys
Dose descriptor:
NOAEL
Effect level:
62 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: histopathological alterations of kidneys
Dose descriptor:
NOAEL
Effect level:
> 160 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: effects on examined fertility organs
Critical effects observed:
not specified
no further remarks
Conclusions:
In this 13-week oral toxicity study according to OECD TG 408 isophorone diamine was administered in the drinking water to Wistar rats (20 animals/sex/dose) which received nominal daily doses of 0, 20, 60, and 160 mg/kg bw ( actual dose 21.5 / 59 / 150 mg/kg bw day for males, 22.6 / 62 / 147 mg/kg bw day for females). The NOAEL for isophorone diamine was 59 mg/kg bw/day for males and 62 mg/kg bw/day for females when administered orally in the drinking water to Wistar rats.
Executive summary:

In this 13-week oral toxicity study according to OECD TG 408 isophorone diamine was administered in the drinking water to Wistar rats (20 animals/sex/dose) which received nominal daily doses of 0, 20, 60, and 160 mg/kg bw ( actual dose 21.5 / 59 / 150 mg/kg bw day for males, 22.6 / 62 / 147 mg/kg bw day for females). No treatment-related clinical signs, symptoms or mortality were noted during the study. Food and water consumption and body weight gain were significantly reduced in high dose animals. In addition, animals of this group revealed higher absolute and relative liver and kidney weights. In the 60 mg/kg bw/day group there was a statistically significant decrease in total leukocyte count (-20.2 %) and increase in the absolute liver weights (+20.7 %) and the relative liver weights (+16.7 %) for males. Along with some other statistically significant hematological and clinical chemical findings in the higher dose groups, the decrease in total leukocyte count was considered to be secondary and not treatment-related, as these effects were in general not supported by morphological findings. The variations in liver weights were also considered to be not treatment related because of the lack of dose-dependency and supporting morphological findings.

However, under the conditions of the experiment, the test article produced morphological alterations in the kidneys of rats at 160 mg/kg bw/day (nominal). The findings consisted of an increased incidence in tubular basophilia (both sexes), and tubular casts (both sexes) along with a higher incidence of lymphoid foci (both sexes). These changes are indicative for tubular nephrosis and may correspond to some of the clinical chemical findings, particularly the increased urea level for high dose males (+40.4 %). All findings were of minor severity degrees, but were statistically significant. The remainder of findings recorded did not differ between controls and rats treated with the test article. They were considered to be within the range of spontaneous background lesions which may be recorded in Wistar rats of this strain and age. The NOAEL for isophorone diamine was 59 mg/kg bw/day for males and 62 mg/kg bw/day

for females when administered orally in the drinking water to Wistar rats.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
59 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The study is reliable without restrictions

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
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
Reference:
Composition 0
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 information:
Composition 1
Species:
rat
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
details not reported
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)
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
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
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.
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)
Critical effects observed:
not specified

no further information

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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LOAEC
2.2 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
The study is reliable with restrictions

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
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
Reference:
Composition 0
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 information:
Composition 1
Species:
rat
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
details not reported
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)
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
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
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.
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)
Critical effects observed:
not specified

no further information

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.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
2.2 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
The study is reliable with restrictions

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available (further information necessary)

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available (further information necessary)

Mode of Action Analysis / Human Relevance Framework

Additional information

Studies in Animals

Inhalation exposure

Cited from SIAR for SIAM 18 (Paris, April 2004):

"3-Aminomethyl-3,5,5-trimethylcyclohexylamine was evaluated for repeated inhalation toxicity in male CD(SD)BR rats (10/dosage group) exposed nose-only to nominal aerosol/vapour concentrations of 18, 200, and 550 mg/m³, 6 hours/day for two weeks (4 - 5 days/week). In total, there were 9 exposures in the low and medium dose groups, while the high dose group was ended after 4 exposures due to unexpected mortality of four rats, the other six rats being necropsied the next day. Following the last exposure, 5 rats from each group (except high dose) were sacrificed and necropsied, while the remaining were sacrificed after a subsequent 20-day recovery period. Treatment with 550 mg/m³ was associated with significantly reduced bodyweights (-7.8 % within 4 days vs +0.7 % in control group). Dose-dependent histopathology was identified in the nose (18, 200, 550 mg/m³), trachea (200, 550 mg/m³), larynx (200, 500 mg/m³), and lungs (200, 550 mg/m³). Observed effects were: Degeneration/necrosis in the olfactory epithelium (nose: 5/6 “minimal” at 18 mg/m3; 5/5 “mild” at 200 mg/m3; 1/10 “minimal”, 8/10 “mild”, 1/10 “moderate” at 550 mg/m3) and in the respiratory epithelium (nose, trachea, and larynx: 3/5 “minimal” at 200 mg/m3; 1/10 “minimal”, 6/10 “mild”, 3/10 “moderate” at 550mg/m3); hyperplasia/squamous metaplasia (nose and larynx: 5/5 “mild”, only nose at 18 mg/m3; 2/5 “mild”, 3/5 “moderate” at 200mg/m3; 1/10 “minimal”; 8/10 “mild” at 550mg/m3), and hypertrophy/hyperplasia (trachea and lungs: 2/5 “minimal” at 200mg/m3; 3/10 “minimal”, 4/10 “mild” at 550mg/m3). By the end of the 20-day recovery period, the lungs and trachea of rats exposed to 18 and 200mg/m3 were within normal limits. Tissue repair was still in progress in the nose and larynx of these same rats; however, close to full microscopic restitution was expected. A NOEL for this study could not be determined (DuPont, 1997).

In a follow-up study, the effects of repeated inhalation exposure to lower concentrations of 3- aminomethyl-3,5,5-trimethylcyclohexylamine were investigated. Again, there were 9 nose-only inhalation 6 h/day exposures within two weeks (4 or 5 per week) of male Sprague-Dawley rats (10 per group). The test concentration was 2 mg/m3 (nominal); 2.2 +/- 0.25 (range 1.0 - 3.0) mg/m3 (analytical). Each five rats per group were sacrificed and necropsied the day after the last exposure and after a two week recovery period, respectively. Microscopic studies focussed on the respiratory tract: Lungs, trachea, pharynx/lanrynx, nose (first sacrifice); nose (recovery sacrifice). The only exposure related findings were minimal (2/5) to mild (3/5) degeneration of respiratory nasal mucosa in the anterior dorsal nose. They were reversible and had resolved by the end of the recovery period (DuPont, 2001)."

Oral exposure

Partly cited from SIAR for SIAM 18 (Paris, April 2004):

"In a 13-week oral toxicity study according to OECD TG 408 (RCC Research and Consulting Company, 1986), 3-aminomethyl-3,5,5-trimethylcyclohexylamine was administered in the drinking water to Wistar rats (20 animals/sex/dose) which received nominal daily doses of 0, 20, 60, and 160 mg/kg bw ( actual dose 21.5 / 59 / 150 mg/kg bw day for males, 22.6 / 62 / 147 mg/kg bw day for females). No treatment-related clinical signs, symptoms or mortality were noted during the study. Food and water consumption and body weight gain were significantly reduced in high dose animals. In addition, animals of this group revealed higher absolute and relative liver and kidney weights" ..."In the 60 mg/kg bw/day group there was a statistically significant decrease in total leukocyte count (-20.2 %) and increase in the absolute liver weights (+20.7 %) and the relative liver weights (+16.7 %) for males. Along with some other statistically significant hematological and clinical chemical findings in the higher dose groups, the decrease in total leukocyte count was considered to be secondary and not treatment-related, as these effects were in general not supported by morphological findings. The variations in liver weights were also considered to be not treatment related because of the lack of dose-dependency and supporting morphological findings. However, under the conditions of the experiment, the test article produced morphological alterations in the kidneys of rats at 160 mg/kg bw/day. The findings consisted of an increased incidence in tubular basophilia (both sexes), and tubular casts (both sexes) along with a higher incidence of lymphoid foci (both sexes). These changes are indicative for tubular nephrosis and may correspond to some of the clinical chemical findings, particularly the increased urea level for high dose males (+40.4 %). All findings were of minor severity degrees, but were statistically significant. The remainder of findings recorded did not differ between controls and rats treated with the test article. They were considered to be within the range of spontaneous background lesions which may be recorded in Wistar rats of this strain and age (RCC Research and Consulting Company, 2000). The NOAEL was 59 mg/kg bw/day for males and 62 mg/kg bw/day for females."


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
valid OECD 408 guideline study

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
valid repeated dose inhalation study

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
valid repeated dose inhalation study

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
The substance isophorone diamine is a skin sensitizer. Any dermal exposure has to be avoided. Hence dermal exposure is considered not relevant for human and because of column 2 of Annex IX (8.6.1 and 8.6.2) of REACH regulation a dermal repeated dose toxicity study is not needed.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
The substance isophorone diamine is a skin sensitizer. Any dermal exposure has to be avoided. Hence dermal exposure is considered not relevant for human and because of column 2 of Annex IX (8.6.1 and 8.6.2) of REACH regulation a dermal repeated dose toxicity study is not needed.

Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: kidneys

Justification for classification or non-classification

Because of the results of repeated dose toxicity studies the substance isophorone diamine is not classified according to 67/548/EEC and CLP regulation (1272/2008).