Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was performed pre-GLP. No guideline was available. Trimethylenediamine is structural very similar to ethylenediamine (difference: chain length / one CH2-group) or ethylenediammonium dichloride (doses of ammonium and chloride not toxicological relevant), respectively. Thus, the test result is justified for read across to assess the toxicity of trimethylenediamine.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1983

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
not specified
GLP compliance:
no
Remarks:
pre-GLP
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Microbiological Associates, Inc., Walkersville, MD
- Age at study initiation: 41 days
- Weight at study initiation: 101-152 g (males) 91-110 g (females)
- Fasting period before study: no information provided
- Housing: suspended wire-bottom-and-front stainless steel cages. Three males or 5 females were housed in each cage.
- Water: ad libitum

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: no data (most likely feed only)
Details on oral exposure:
New concentrations of feed were prepared weekly, with the percentage of EDA.2HCl in the diet adjusted to maintain a constant dosage level in mg/kg for each sex according to the average body weight gain and diet consumption.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
A spectrophotometric method was employed for the analysis of EDA.2HCI in the diet.
Duration of treatment / exposure:
3 months
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
50 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
260 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1040 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
10 animals per sex
Control animals:
yes, plain diet

Examinations

Observations and examinations performed and frequency:
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION : Yes
- Time schedule for examinations: Monthly

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Immediately before sacrifice
- Parameters c examined: Red and white blood cell counts, measurement of hemoglobin and mean corpuscular volume, calculation of hematocrit, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and determination of differential white blood cell counts

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Immediately before sacrifice
- Animals fasted: No data
- How many animals:
- Parameters examined: Measurement of serum concentrations of glucose, urea nitrogen, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total protein, albumin and creatinine.

URINALYSIS: Yes
- Time schedule for collection of urine: One week before sacrifice

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
All rats were given a complete gross necropsy examination and organ weights were recorded for the brain, liver, kidneys, spleen, heart, adrenals and
testes. Tissues were taken and fixed in 10% neutral buffered formalin. All tissues were processed for paraffin embedding, sectioned at 5 microns and stained with hematoxylin and eosin. Microscopic lesions were graded as to severity, where possible, into 4 categories (mild, moderate, marked or severe)

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
No deaths or clinical signs of toxicity.

BODY WEIGHT AND WEIGHT GAIN
Body weight gain was depressed markedly for both sexes at the high dosage level

FOOD AND WATER CONSUMPTION
There was marked reduction in diet consumption in the high level dose females and a significant increase in the low level dose females. While water
consumption rates were equivalent in the male test and control animals, there was a dose-related reduction for the female test animals.

CLINICAL CHEMISTRY
Changes in clinical chemistry values included a reduction in serum glucose level and an elevation of alkaline phosphatase activity, AST and ALT activities

HAEMATOLOGY
In male rats, depression of the red blood cell counts and increased mean corpuscular volumes were seen. In the female rats, in addition to the above changes, there were also depression of hematocrit and hemoglobin values and an increase in mean corpuscular hemoglobin.

URINALYSIS
The median urinary pH at the high dosage level was lowered significantly in both sexes

ORGAN WEIGHTS
In the male rats, there was a significant reduction in liver, kidney, spleen and heart weight and a concomitant decrease in some of the relative organ weights. Similarly, in the females, there was a reduction in liver, heart, adrenal and brain weights with an decrease of relative liver weight.

PATHOLOGY
There was no dose-related gross lesions in any animal on the study. The most significant histologic changes were present in the livers of the high dosage level animals, particularly in the females. The liver changes, termed "hepatocellular pleomorphism", consisted of an increase in the size of hepatocytes and hepatocyte nuclei, increased variation in nuclear size and shape, and an increase in the number of multinucleate hepatocytes. Occasional degenerating hepatocytes were also seen.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
ca. 50 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Study result generated with EDA*2HCl as test material.
Dose descriptor:
LOAEL
Effect level:
260 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Study result generated with EDA*2HCl as test material. Clinical chemistry: elevation of alanine aminotransferase activity in males;  Haematology :Increased mean corpuscular volumes in females.
Dose descriptor:
NOAEL
Effect level:
22.6 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks:
/ recalculated to EDA
Sex:
male/female
Basis for effect level:
other: Recalculation to EDA base from the test results with EDA*2HCl
Dose descriptor:
LOAEL
Effect level:
117 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks:
/ recalculated to EDA
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOAEL
Effect level:
27.9 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks:
/calculated from EDA to trimethylenediamine
Sex:
male/female
Basis for effect level:
other: Study result generated with EDA*2HCl as test material was recalculated to EDA base and then - for read across - calculated for trimethylenediamine.
Dose descriptor:
LOAEL
Effect level:
144 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks:
/calculated from EDA to trimethylenediamine
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

High dose group: 

Diet and water consumption significantly reduced in the high dose female rats. Significant reduction in body weight gain of both sexes in the high dose group; significant reduction in absolute weights of liver and heart (both sexes), adrenal and brain (female), kidney and spleen (male) in the high dose group; increase of relative weight of brain (both sexes), spleen and heart (female) and testis in the high dose group. Significant elevation of alkaline phosphatase activity in males and females. Significant elevation of alanine aminotransferase activity in males and females of high dose groups. Increased mean corpuscular volumes in males and females. Significant increase of mean corpuscular hemoglobin and significant depression of hematocrit and hemoglobin values; significant depression of red blood cell counts, serum glucose level and urinary pH (from 6.0 to 5.0) and significant elevation of aspartate aminotransferase activity in both sexes of the high dose group; hepatocellular pleomorphism in 7/10 female and 2/10 male (control: 0/10 of each sex) in high dose group, hepatocellular degeneration and significant increased prevalence of tracheitis in male of the high dose group.

Intermediate dose group: 

Water consumption significantly reduced in female rats. Significant elevation of alanine aminotransferase activity in males of intermediate dose groups. Increased mean corpuscular volumes in females.

Low dose group:

 Water consumption significantly reduced in female rats. Significant elevation of alkaline phosphatase activity in males, this effect was not noted in the intermediate dose group.

Applicant's summary and conclusion