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Toxicological information

Repeated dose toxicity: inhalation

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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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP guideline study of a structural analogue. PACM and DM-PACM are considered read-across analogues based on common functional groups, common precursors/break-down products, and similar physico-chemical and toxicological properties. The common structural features of the two substances are: a primary amine group, bound to a cyclic aliphatic organic substituent; a bis-cyclic structure. There are no elements other than carbon, hydrogen and nitrogen. They are identical structures except for a methyl group on each cyclohexane, ortho to the amine on DM-PACM.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report Date:
1992

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
TS-Freetext:
Laromin C 260; according to the authors, purity was >99.5%

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
nose/head only
Vehicle:
other: fresh air
Remarks on MMAD:
MMAD / GSD: The mass median aerodynamic diameter (MMAD) was 3.5, 1.5, and 2.8 µm, respectively.
Details on inhalation exposure:
Groups of 10 male and 10 female Wistar rats (age 9 weeks, mean body weights 247g and 171 g for male and female animals) were exposed by inhalation to a liquid aerosol of the test substance at concentrations of 2, 12, and 48 µg/l. A control group (10 males, 10 females) was exposed to fresh air.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysis confirmed the nominal concentrations. mean values +/- standard deviation were 2.1 +/- 0.58 µg/l, 12.4 +/- 2.63 µg/l, and 48.2 +/-10.48 µg/l.
Duration of treatment / exposure:
3 months
Frequency of treatment:
6 hours each working day (5 d/w)
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
2.1 mg/m3
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
12.4 mg/m3
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
48.2 mg/m3
Basis:
analytical conc.
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
Post-exposure period: none

Examinations

Observations and examinations performed and frequency:
Ophthalmologic examinations were carried out at the beginning and at the end of the study. The state of health was checked before, during and after exposure. Clinicochemical and hematological examinations were carried out. All animals were necropsied and assessed by gross pathology, extensive histopathological examinations were done including examination of the testes, ovaries and uterus.
Other examinations:
The body weight was determined once a week. Feed and water consumption was not measured.
Statistics:
no data

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
One female at 2 µg/l and one male at 12 µg/l died intercurrently after 37 and 48 exposures, respectively. Deaths were judged to be of spontaneous nature.
Mortality:
mortality observed, treatment-related
Description (incidence):
One female at 2 µg/l and one male at 12 µg/l died intercurrently after 37 and 48 exposures, respectively. Deaths were judged to be of spontaneous nature.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Compared to control animals statistically reduced mean body weight gain (p<0.01) and reduced body weight from day 50 onwards (p<0.01) was seen in high dose male rats. Body weight was reduced by approx 14% compared to controls on day 85. In high dose fe
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:
no effects observed
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Significant (p<0.05) reductions in hemoglobin, hemoglobin per erythrocyte, and in mean corpuscular hemoglobin concentration (MCHC) were noted in the male high dose rats only. Polychromatosis was noted. Clotting test: statistically significant clotting t
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Animals at 2µg/l: no substance-related changes noted in either test group. Animals at 12 µg/l: statistically significant, but marginal increase of alkaline phosphatase (5.658 µkat/l vs. 4.949 µkat/l in controls) and GPT (glutamate pyruvate transaminas
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Relative organ weight of liver, lung, and kidney was significantly increased in high dose male and female animals on the 1% or 5% level of significance. Relative weight of adrenals (p<0.05) and testes (p<0.01), and absolute lung weight (1.41g vs. 1.18g
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
No effects in low and medium dose animal groups. Effects in high dose animals included: Local irritative effects on the skin and slight hyperkeratosis in 7/10 male rats. Minimal to slight vacuolization of the craniodorsal olfactory epithelium in both ma
Details on results:
Toxicity was observed in the high dose group (local irritative effects, decreased body weight gain, increased relative weights of liver, lung and kidney without pathology. In high dose males only, there was increased relative weights of adrenals and testes, without pathology or histopathology. Selected liver enzymes were increased in serum, and red blood cells were increased with decreased hemoglobin but increased hemosiderin deposits in the spleen. The only effect noticed in the mid-dose group was a single clinical chemistry parameter whose value was statistically significantly different from control values, but in the absence of liver histopathology and evidence of toxicity in other enzyme levels, this was considered not biologically significant.

Effect levels

Dose descriptor:
NOAEC
Effect level:
12.2 other: mg/m3
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
food consumption and compound intake
organ weights and organ / body weight ratios
gross pathology

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

The read-across to PACM is adequate for designation of a NOAEL for risk assessment for chronic exposure, and adequate for classification and labeling
    
    
    
    
    

PACM and DM-PACM are considered read-across analogues based on structural similarity and similar physico-chemical and toxicological properties. The common structural features of the two substances are: a common functional primary amine group; the amines are bound to a cyclic aliphatic organic substituent; there are no elements other than carbon, hydrogen and nitrogen; identical structures except for a methyl group on each cyclohexane, ortho to the amine on DM-PACM similar molecular weights, both under 500 daltons, qualifiying as “low molecular weight” compounds

PACM and DM-PACM are considered read-across analogues based on structural similarity and similar physico-chemical and toxicological properties. The common structural features of the two substances are: a common functional primary amine group; the amines are bound to a cyclic aliphatic organic substituent; there are no elements other than carbon, hydrogen and nitrogen; identical structures except for a methyl group on each cyclohexane, ortho to the amine on DM-PACM similar molecular weights, both under 500 daltons, qualifiying as “low molecular weight” compounds

Selected data can be ”read-across” to4,4'-methylenebis(cyclohexanamine) (PACM, target chemical) from its analogue,2,2'-dimethyl-4,4'-methylenebis(cyclohexylamine) (dimethyl or DM-PACM, source chemical), based on structural similarity and similar physico-chemical and toxicological properties.  Both substances are part of a larger OECD chemical category of twelve members, the Primary Amine Category.  Specifically, the concept of read-across between the two cyclohexamines was promoted in the recent OECD SIAR, which identified DM-PACM as “the surrogate for cyclohexylamine, 4,4’-methylenebis- (1761-71-3)” for repeated dose toxicity and reproductive toxicity endpoints. Concerning physico-chemical properties, values from both chemicals are comparable. The freezing and boiling points, vapour pressure and Henry’s Law Constants are slightly higher for DM-PACM than for PACM, which is characteristic of increasing molecular weight. Both display low water solubility and the partitioning between n-octanol and water are comparable.  Environmental fate parameters are comparable. Both are hydrolytically stable and neither are biodegradable. However, they are not bioaccumulative and their acute toxicity levels to aquatic organisms are low. In mammalian toxicity tests, they display similar behaviours, including skin and eye corrosion and weak activity in dermal sensitisation assays. DM-PACM may be slightly more toxic than PACM; hence, reading across from DM-PACM should not underestimate the toxicity of PACM.

Selected data can be ”read-across” to4,4'-methylenebis(cyclohexanamine) (PACM, target chemical) from its analogue,2,2'-dimethyl-4,4'-methylenebis(cyclohexylamine) (dimethyl or DM-PACM, source chemical), based on structural similarity and similar physico-chemical and toxicological properties.  Both substances are part of a larger OECD chemical category of twelve members, the Primary Amine Category.  Specifically, the concept of read-across between the two cyclohexamines was promoted in the recent OECD SIAR, which identified DM-PACM as “the surrogate for cyclohexylamine, 4,4’-methylenebis- (1761-71-3)” for repeated dose toxicity and reproductive toxicity endpoints. Concerning physico-chemical properties, values from both chemicals are comparable. The freezing and boiling points, vapour pressure and Henry’s Law Constants are slightly higher for DM-PACM than for PACM, which is characteristic of increasing molecular weight. Both display low water solubility and the partitioning between n-octanol and water are comparable.  Environmental fate parameters are comparable. Both are hydrolytically stable and neither are biodegradable. However, they are not bioaccumulative and their acute toxicity levels to aquatic organisms are low. In mammalian toxicity tests, they display similar behaviours, including skin and eye corrosion and weak activity in dermal sensitisation assays. DM-PACM may be slightly more toxic than PACM; hence, reading across from DM-PACM should not underestimate the toxicity of PACM.

RS-Freetext:
Overall assessment:
No treatment-related effect was noted in animal groups at 2 and 12 µg/l apart from the increased GPT level in mid dose male rats.

Although clear effects on body weight gain were noted in the high dose groups target organ toxicity was mild and restricted to red blood cells, including the spleen (extramedulary haematopoesis) indicative of a mild anemic effect.
There were increases in clinical chemical parameters (GPT and GOT) as well as in the relative liver weight; however, no histopathological correlate was found in this study.
A substance-related effect on kidneys (slight tubular nephrosis with increased kidney weights) was of borderline significance. Other organ weight changes were seen (increased relative weights of testes and adrenals), but were considered to be secondary toxic effects due to severe impairment of the body weight.
According to the authors, under the conditions of this study, the NOAEC was 2 µg/l (0.002 mg/l), based on slightly increased GPT level (1.043 µkat/l vs. 0.845 µkat/l in controls) observed in mid dose males representing a borderline toxicity.

Selected data can be ”read-across” to4,4'-methylenebis(cyclohexanamine) (PACM, target chemical) from its analogue,2,2'-dimethyl-4,4'-methylenebis(cyclohexylamine) (dimethyl or DM-PACM, source chemical), based on structural similarity and similar physico-chemical and toxicological properties.  Both substances are part of a larger OECD chemical category of twelve members, the Primary Amine Category.  Specifically, the concept of read-across between the two cyclohexamines was promoted in the recent OECD SIAR, which identified DM-PACM as “the surrogate for cyclohexylamine, 4,4’-methylenebis- (1761-71-3)” for repeated dose toxicity and reproductive toxicity endpoints. Concerning physico-chemical properties, values from both chemicals are comparable. The freezing and boiling points, vapour pressure and Henry’s Law Constants are slightly higher for DM-PACM than for PACM, which is characteristic of increasing molecular weight. Both display low water solubility and the partitioning between n-octanol and water are comparable.  Environmental fate parameters are comparable. Both are hydrolytically stable and neither are biodegradable. However, they are not bioaccumulative and their acute toxicity levels to aquatic organisms are low. In mammalian toxicity tests, they display similar behaviours, including skin and eye corrosion and weak activity in dermal sensitisation assays. DM-PACM may be slightly more toxic than PACM; hence, reading across from DM-PACM should not underestimate the toxicity of PACM.

Selected data can be ”read-across” to4,4'-methylenebis(cyclohexanamine) (PACM, target chemical) from its analogue,2,2'-dimethyl-4,4'-methylenebis(cyclohexylamine) (dimethyl or DM-PACM, source chemical), based on structural similarity and similar physico-chemical and toxicological properties.  Both substances are part of a larger OECD chemical category of twelve members, the Primary Amine Category.  Specifically, the concept of read-across between the two cyclohexamines was promoted in the recent OECD SIAR, which identified DM-PACM as “the surrogate for cyclohexylamine, 4,4’-methylenebis- (1761-71-3)” for repeated dose toxicity and reproductive toxicity endpoints. Concerning physico-chemical properties, values from both chemicals are comparable. The freezing and boiling points, vapour pressure and Henry’s Law Constants are slightly higher for DM-PACM than for PACM, which is characteristic of increasing molecular weight. Both display low water solubility and the partitioning between n-octanol and water are comparable.  Environmental fate parameters are comparable. Both are hydrolytically stable and neither are biodegradable. However, they are not bioaccumulative and their acute toxicity levels to aquatic organisms are low. In mammalian toxicity tests, they display similar behaviours, including skin and eye corrosion and weak activity in dermal sensitisation assays. DM-PACM may be slightly more toxic than PACM; hence, reading across from DM-PACM should not underestimate the toxicity of PACM.

Selected data can be ”read-across” to4,4'-methylenebis(cyclohexanamine) (PACM, target chemical) from its analogue,2,2'-dimethyl-4,4'-methylenebis(cyclohexylamine) (dimethyl or DM-PACM, source chemical), based on structural similarity and similar physico-chemical and toxicological properties.  Both substances are part of a larger OECD chemical category of twelve members, the Primary Amine Category.  Specifically, the concept of read-across between the two cyclohexamines was promoted in the recent OECD SIAR, which identified DM-PACM as “the surrogate for cyclohexylamine, 4,4’-methylenebis- (1761-71-3)” for repeated dose toxicity and reproductive toxicity endpoints. Concerning physico-chemical properties, values from both chemicals are comparable. The freezing and boiling points, vapour pressure and Henry’s Law Constants are slightly higher for DM-PACM than for PACM, which is characteristic of increasing molecular weight. Both display low water solubility and the partitioning between n-octanol and water are comparable.  Environmental fate parameters are comparable. Both are hydrolytically stable and neither are biodegradable. However, they are not bioaccumulative and their acute toxicity levels to aquatic organisms are low. In mammalian toxicity tests, they display similar behaviours, including skin and eye corrosion and weak activity in dermal sensitisation assays. DM-PACM may be slightly more toxic than PACM; hence, reading across from DM-PACM should not underestimate the toxicity of PACM.

Selected data can be ”read-across” to4,4'-methylenebis(cyclohexanamine) (PACM, target chemical) from its analogue,2,2'-dimethyl-4,4'-methylenebis(cyclohexylamine) (dimethyl or DM-PACM, source chemical), based on structural similarity and similar physico-chemical and toxicological properties.  Both substances are part of a larger OECD chemical category of twelve members, the Primary Amine Category.  Specifically, the concept of read-across between the two cyclohexamines was promoted in the recent OECD SIAR, which identified DM-PACM as “the surrogate for cyclohexylamine, 4,4’-methylenebis- (1761-71-3)” for repeated dose toxicity and reproductive toxicity endpoints. Concerning physico-chemical properties, values from both chemicals are comparable. The freezing and boiling points, vapour pressure and Henry’s Law Constants are slightly higher for DM-PACM than for PACM, which is characteristic of increasing molecular weight. Both display low water solubility and the partitioning between n-octanol and water are comparable.  Environmental fate parameters are comparable. Both are hydrolytically stable and neither are biodegradable. However, they are not bioaccumulative and their acute toxicity levels to aquatic organisms are low. In mammalian toxicity tests, they display similar behaviours, including skin and eye corrosion and weak activity in dermal sensitisation assays. DM-PACM may be slightly more toxic than PACM; hence, reading across from DM-PACM should not underestimate the toxicity of PACM.

Selected data can be ”read-across” to4,4'-methylenebis(cyclohexanamine) (PACM, target chemical) from its analogue,2,2'-dimethyl-4,4'-methylenebis(cyclohexylamine) (dimethyl or DM-PACM, source chemical), based on structural similarity and similar physico-chemical and toxicological properties.  Both substances are part of a larger OECD chemical category of twelve members, the Primary Amine Category.  Specifically, the concept of read-across between the two cyclohexamines was promoted in the recent OECD SIAR, which identified DM-PACM as “the surrogate for cyclohexylamine, 4,4’-methylenebis- (1761-71-3)” for repeated dose toxicity and reproductive toxicity endpoints. Concerning physico-chemical properties, values from both chemicals are comparable. The freezing and boiling points, vapour pressure and Henry’s Law Constants are slightly higher for DM-PACM than for PACM, which is characteristic of increasing molecular weight. Both display low water solubility and the partitioning between n-octanol and water are comparable.  Environmental fate parameters are comparable. Both are hydrolytically stable and neither are biodegradable. However, they are not bioaccumulative and their acute toxicity levels to aquatic organisms are low. In mammalian toxicity tests, they display similar behaviours, including skin and eye corrosion and weak activity in dermal sensitisation assays. DM-PACM may be slightly more toxic than PACM; hence, reading across from DM-PACM should not underestimate the toxicity of PACM.

Selected data can be ”read-across” to4,4'-methylenebis(cyclohexanamine) (PACM, target chemical) from its analogue,2,2'-dimethyl-4,4'-methylenebis(cyclohexylamine) (dimethyl or DM-PACM, source chemical), based on structural similarity and similar physico-chemical and toxicological properties.  Both substances are part of a larger OECD chemical category of twelve members, the Primary Amine Category.  Specifically, the concept of read-across between the two cyclohexamines was promoted in the recent OECD SIAR, which identified DM-PACM as “the surrogate for cyclohexylamine, 4,4’-methylenebis- (1761-71-3)” for repeated dose toxicity and reproductive toxicity endpoints. Concerning physico-chemical properties, values from both chemicals are comparable. The freezing and boiling points, vapour pressure and Henry’s Law Constants are slightly higher for DM-PACM than for PACM, which is characteristic of increasing molecular weight. Both display low water solubility and the partitioning between n-octanol and water are comparable.  Environmental fate parameters are comparable. Both are hydrolytically stable and neither are biodegradable. However, they are not bioaccumulative and their acute toxicity levels to aquatic organisms are low. In mammalian toxicity tests, they display similar behaviours, including skin and eye corrosion and weak activity in dermal sensitisation assays. DM-PACM may be slightly more toxic than PACM; hence, reading across from DM-PACM should not underestimate the toxicity of PACM.

Applicant's summary and conclusion

Conclusions:
4,4'-Methylenebis(2-methyl-cyclohexanamine) an analogue of PACM, was tested in a 90-day inhalation toxicity study in male and female Wistar rats at concentrations of 2, 12 and 48 mg/m3 for 6 hours daily, 5 days per week. Clear toxicity was noted in animals exposed to 48 mg/m3. Local effects included degeneration of the olfactory epithelium. In the high dose group, hepatotoxicity, adverse effects on red blood cells, hemoglobin, and spleen were noted as was a reduced body weight gain. Male animals were more susceptible than females. The NOAEC was 12 mg/m3 (0.012 mg/l) in this study, based on clear toxicity observed in high dose male rats.
Selected data can be ”read-across” to 4,4'-methylenebis(cyclohexanamine) (PACM, target chemical) from its analogue, 2,2'-dimethyl-4,4'-methylenebis(cyclohexylamine) (dimethyl or DM-PACM, source chemical), based on common functional groups, common precursors/break-down products, and similar physico-chemical and toxicological properties. The read-across is adequate for designation of a NOAEC for risk assessment for chronic exposure, and adequate for classification and labeling