Cyclohexylamine

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: meets the criteria of today

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Long term toxicity of cyclohexylamine hydrochloride in the rat

Author:

Gaunt IF, Hardy J, Grasso P, Gangolli SD, Butterworth KR,

Year:

1976

Bibliographic source:

Food Cosmet. Toxicol. 14, 255-267

Materials and methods

Principles of method if other than guideline:

dietary application of 0, 600, 2000, 6000 ppm cyclohexylamine hydrochloride to male and female rats for 2 years and observation for mortality and clinical signs determination of food and water intake, weight development, hematological and clinical chemical parameters and urinary parameters. Following death or sacrifice after termination of treatment gross and histopathological examination

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Cyclohexylammonium chloride

EC Number:

225-661-4

EC Name:

Cyclohexylammonium chloride

Cas Number:

4998-76-9

IUPAC Name:

cyclohexanaminium chloride

Details on test material:

no further details

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: males: 100-165 d; females: 85-140 g
- Fasting period before study:
- Housing: in groups of 4
- Diet ad libitum
- Water ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20
- Humidity (%): 50-60

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: mixed in diet

Details on oral exposure:

dietary application of 0, 600, 2000, 6000 ppm cyclohexylamine hydrochloride to male and female rats for 2 years

Duration of treatment / exposure:

2 years

Frequency of treatment:

daily in diet

Doses / concentrations

Remarks:

Doses / Concentrations:
600, 2000, 6000 ppm cyclohexylamine hydrochlorid corresponds to appr. 0, 18/26, 60/88, 219/321 mg cyclohexylamine /kg-bw/day (in males/females)
Basis:

No. of animals per sex per dose:

48

Control animals:

yes

Details on study design:

dietary application of 0, 600, 2000, 6000 ppm cyclohexylamine hydrochloride to male and female rats for 2 years and observation for mortality and clinical signs determination of food and water intake, weight development, hematological and clinical chemical parameters and urinary parameters. Following death or sacrifice after termination of treatment gross and histopathological examination Post-exposure period: no

Positive control:

no

Examinations

Observations and examinations performed and frequency:

observation for mortality and clinical signs determination of food and water intake, weight development,
hematological parameters: Hb, PCV, RBC, Retics, leucocytes
and clinical chemical parameters:GOT, GPT, KDH, Glucose, urea, total protein, albumin
and urinary parameters: renal concentration and urinary cell excretion

Sacrifice and pathology:

Following death or sacrifice after termination of treatment gross and histopathological examination
final body weight, absolute and relative weight of brain, heartm liverm spleen, kidneys, stomach small intestine, caecum, adrenals, gonads, pituitary and thyroid, histopathological lesions, incidence of tumours

Other examinations:

no data

Statistics:

Chi square test, student's t-test, ranking method of White (1952)

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):

effects observed, treatment-related

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
no clinical signs
the rats given the highest doses apear to be healthier than control animals
at week 104
death males: 600-2000-6000 ppm: 21-18-5 versus 24 of controls
death females: 600-2000-6000 ppm:10-4-7 versus 16 of controls

BODY WEIGHT AND WEIGHT GAIN
significantly reduced in all dose groups from week 2 onwards
final body weight: 600-2000-6000 ppm
males: 623g-575g-451g versus 646 g of control
females: 360g-311g- 240 g versus 399 g of controls

COMPOUND INTAKE (if feeding study)
was time-dependent reduced in all dosage groups
the average intake of cyclohexylamine hydrochloride during the experiment
males: 24, 82, 300 mg/kg bw/day
females: 35, 120, 440 mg/kg bw/day

WATER CONSUMPTION
was time dependent increased during the experiment

HAEMATOLOGY
females, 6000 ppm during the first year of the study the hemoglobin concentration reduced
by 6-8 %
at week 104 significant differences to the respective control only at the highest dose group
(males , 6000 ppm) Hb , PCV increased; reticulocytes decreased;
total leucocytes dose-dependent significant decreased in all dose groups when compared te controls

CLINICAL CHEMISTRY
males: significant changes only; 600-2000-6000 ppm
urea (mg/100 ml): 30-32-23 versus 48 in controls
albumin (g/100 ml): 3.16-3.34-4.09 versus 2.97 in controls

ORGAN WEIGHTS
males:
--absolute organ weights dose-dependent decreased heart, liver, spleen, kidneys, adrenals. gonads, thyroid
--relative organ weights (significant changes only, mg/100 g bw)
brain, 2000, 6000 ppm: 0.36, 0.48 versus 0.34 of control; liver , 6000 ppm 2.32 versus 2.65;
spleen, 6000 ppm: 0.21 versus 0.29 of controls; kidneys, 6000 ppm: 0.56 versus 0.72
females
--absolute organ weights dose dependent decreased heart, liver, spleen, kidneys, adrenals, pituitary
--relative organ weights (significant changes only; mg/100g bw)
brain, 600, 2000, 6000 ppm: 0.56, 0.65, 0.82 versus 0.50 on controls
gonads,2000, 6000 ppm: 43.8, 54.4 versus 32.6 on controls
thyroid, 2000, 6000 ppm: 9.8, 9.1 versus 7.9 on controls

GROSS PATHOLOGY , HISTOPATHOLOGY: NON-NEOPLASTIC
Many of the lesions encountered in the histopathological examination were present with a markedly lower frequency in the rats given 2000 and 6000 ppm cyclohexylamine hydrochloride than in the controls. This was particularly noticeable in the incidences of myocardial fibrosis, mild hepatic changes, hyperplasia of the parathyroids and glomeruonephrosis
Increases in the incidences of histopathological changes were restricted to the lungs where significantly more of the rats given 6000 ppm cyclohexylamine hydrochloride had alveoli with foamy macrophages and to the testes. In the latter organ the incidence of bilateral atrophy was statistically greater in the rats given 6000 ppm than in the controls. At the intermediate level (2000 ppm) there was an increase in the incidence of testes with tubules showing few or no spermatids. There were no statistically significant increases in the incidence of testicular lesiohs in rats given 600 ppm cyclohexylamine hydrochloride.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Cyclohexylamine hydrochloride at levels up to 6000 ppm in the died did not show any carcinogenic potential

Effect levels

Dose descriptor:

LOAEL

Effect level:

600 ppm

Sex:

male/female

Basis for effect level:

other: Approx. 18 mg/kg/day; body weight gain was reduced by approx. 10%. Observations on hematologic and clinical-chemistry parameters and organ weights were observed but gave no consistent picture.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

RS-Freetext:
decreased rates of body-weight gain, reduced food intake,
reduced water intake; alterations of organ weights, lowered
concentrations of serum urea and higher concentrations of
serum albumin were observed in the treated rats compared
with the controls; rats given 2000 and 6000 ppm showed
testicular changes (atrophy or tubules with few spermatids)

Applicant's summary and conclusion

Executive summary:

Male and female Wistar rats received 600, 2000, 6000 ppm Cyclohexylamine hydrochloride in the diet for 2 years.The average intake of cyclohexylamine hydrochloride during the experiment by males: 24, 82, 300 mg/kg bw/day and by females: 35, 120, 440 mg/kg bw/day. These doses correspond to 18, 60, 219 mg/kg bw/day cyclohexylamine for males and 26, 88, 321 mg/kg bw/days cyclohexylamine for females. Main findings that could be related to treatment were a slight anemia, a failure to produce normally concentrated urine, and an increase in the number of male and female animals with foamy macrophages within the alveoli among the rats given 6000 ppm. There were testicular changes in the form of atrophy or tubules with few spermatids in males increase in rel gonad-weights given 2000 and 6000 ppm (Gaunt 1976)..

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