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Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Detailed study summary and tables available (main text in japanese)
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1997

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: Guidelines for 28-day Repeat Dose Toxicity testing of Chemicals (Japan)
Deviations:
yes
Remarks:
- recovery groups
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Benzyldimethylamine
EC Number:
203-149-1
EC Name:
Benzyldimethylamine
Cas Number:
103-83-3
Molecular formula:
C9H13N
IUPAC Name:
benzyldimethylamine
Details on test material:
TS-Freetext:
Purity: 99,93 wt%

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
no details given

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
male and female rats were given the different amountsdiluted in conr oil by gavage once daily over a period of 28 days
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 100, 200, 400 mg/kg bw/day
Basis:

No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
male and female rats were fed with 0, 50, 100, 200, 400 mg7kg bw/day over a period of 28 days,
rats dosed with 50 and 100 mg/kg bw/day were killed immediately after cessation of treatment:
groups of rats dosed with 200 and 400 mg/kg bw/day were aloud to recover for 14 days and then examined accordingly
Positive control:
not required

Examinations

Observations and examinations performed and frequency:
clinical observation once a day
mortality body weight blood examinations hematology
clinical biochemistry, urinalysis
Sacrifice and pathology:
gross pathology, organ weight.microscopic examination:
brain, liver, kidney, spleen, adrenals,ovaries, testes, thymus,
respiratory system, integumentary system, cardiovascular system, reproductive system
hematopoietic system, urinary system, digestive system
Other examinations:
no data
Statistics:
Non-parametric analysis

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 examined
Haematological findings:
no effects observed
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:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
mortality from week 2 at 400 mg/kg bw/d: males: 4/5; females.5/5
no control animal died
gross pathological examination revealed no obvious changes
histopathological examination:
inclusion bodies in hepatocytes (m+f); degeneration of adrenal cortex (f);

clinical signs.
100, 200 and 400 mg/kg bw/day, male and females: miosis
200, 400 mg/kg bw/day, male and female:: salivation
400 mg/kg bw/day, male and female: dirty fur
400 mg/kg bw/day, females: tremor before death
recovery period: 200, 400 mg/kg bw: clinical signs diappeared

BODY WEIGHT AND WEIGHT GAIN
400 mg/kg bw/day males: significantly depressed body weight.
274 g versus 334 g in control, no further information
recovery period: 361 g versus407 g in control , no further information

CLINICAL CHEMISTRY
200 mg/kg bw/day, male: not significant increase in total cholesterol which normalized during recovery period
72 mg/dl versus 51 mg/dl in controls
recovery period 53 mg/dl versus 57 mg/dl in controls
200 mg/kg bw/day, males, recovery period:
decreased Albumin/ Globulin ratio
1.06 (p<=0.05) versus 1.18 in controls
female, 200 mg/kg bw/day: significant increase in blood glucose which normalized during recovery period
116 mg/dl (p<=0.01) versus 91 mg/dl in controls
recovery period: 126 mg/dl versus 116 mg/dl in controls


ORGAN WEIGHTS (significant changes only)
males: 200 mg/kg bw/day
significantly increased absolute spleen weight but not in relative weight:
0,63 g versus 0.51 g in controls which normaluized during rcovery period
during recovery period significant increased adernal weights
absolute. 62 mg (p>=0.01)versus 51 mg
relative: 0.016 (p<=0.05) versus 0.013
female, 200 mg/kg bw/day
significantly increased liver weights which normalized during recovery:
absolute: 7.07 g (p<=0.05) versus 5.91g in controls
relative 3.251(p<= 0.05) versus 2.939

HISTOPATHOLOGY: NON-NEOPLASTIC
suvivors showed no histopathological changes

Effect levels

Dose descriptor:
NOEL
Effect level:
50 other: mg/kg
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

RS-Freetext:
Mortality:
at 400 mg/kg bw 4/5 males and 5/5 females died within the treatment period. Cause of deaths could not be determined.

Clinical signs:
100 mg/kg: m+f: miosis
200 mg/kg: m+f: miosis, salivation; reversible during recovery
400 mg/kg: m+f: miosis, salivation, dirty hair
f: premortal tremors
m: reduced weight gain: ~20% after 4 weeks; partial recovery after end of treatment

Food consumption:
no effects

Hematology:
400 mg/kg: reduced white cell number (the 1 surviving male)

Clinical chemistry:
200 mg/kg: increased total cholesterol

Urinalysis:
100 mg/kg: increased urine volume (m)
200 mg/kg: increased urine volume (m+f)
400 mg/kg: increased urine volume (m)

Organ weights:
200 mg/kg: increased absolute weight (spleen, m; liver, f)
increased relative weight (liver, f)
after recovery:
increased absolute weight (adrenals, m, slight)
increased relative weight (adrenals, m, slight)
400 mg/kg: decreased absolute weight (spleen, m)

Histopathology:
Survivors: no effects
Deceased animals: inclusion bodies in hepatocytes (m+f); degeneration of adrenal cortex (f);

Applicant's summary and conclusion

Executive summary:

N,N-Dimethylbezylamine was given by gavage to male and female Crj:CD (SD) rats in doses of 0 (corn oil), 50, 100, 200, 400 mg/kg bw/day diluted in corn oil over a period of 28 days. In addition, animals of the control group and animals treated with 200 and 400 mg/kg bw/day were obseserved after termination of treatment for further 2 weeks (recovery group). Mortalities of both males and females receiving 400 mg/kg were observed from week 2. Clinical observation revealed miosis in both sexes receiving 100 mg/kg and miosis and salivation in those receiving 200 and 400 mg/kg. Body weight gain was suppressed in males receiving 400 mg/kg. Slight increases in total cholesterol were observed in males receiving 200 mg/kg. Pathological examination revealed no abnormalities attributable to the test substance treatment. The NOEL for repeat dose toxicity is considered to be 50 mg/kg/day for both sexes (MHLW 1997).