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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
pre-GLP Trimethylenediamine is structurally 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 teratogenic potential / developmental toxicity of trimethylenediamine.
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1987

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Rats were dosed via diet during gestation day 6-15. Standard endpoints for teratogenicity were evaluated.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
Ethylenediamine dihydrochloride was prepared from high purity ethylenediamine, 99,9%. The salt was analysed by chromatography and spectrophotometric methods, and found to be free of impurities.

Test animals

Species:
rat
Strain:
Fischer 344
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc. (Kingston, NY).
- Age at study initiation: 100 days
- Housing: stainless-steel cages
- Diet : Purina Certified Rodent Chow 5002
- Water (e.g. ad libitum): Yes

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: no data (most likely feed only)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysis indicated that the test diet preparations were accurate and homogeneous. The stability of the test diets was also confirmed. Substance was added to diet based on established diet consumption data and an established growth curve to produce the dosage goals.
Details on mating procedure:
At approximately 100 days of age, female rats were introduced into the male rats' cages. The rats were mated one male to one female to achieve a goal of approximately 20 pregnant females per treatment group, and 40 in the negative control group. Expelled vaginal plugs were used as evidence that mating had occurred
Duration of treatment / exposure:
Gestation day 6 - 15
Frequency of treatment:
daily
Duration of test:
cesarean section on gestation day 21
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
50 mg/kg bw/day
Basis:

Remarks:
Doses / Concentrations:
250 mg/kg bw/day
Basis:

Remarks:
Doses / Concentrations:
1000 mg/kg bw/day
Basis:

No. of animals per sex per dose:
20 and 40 in control group.
Control animals:
yes, concurrent no treatment

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
23 mg/kg bw/day
Based on:
test mat.
Remarks:
recalculated to EDA
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
113 mg/kg bw/day
Based on:
test mat.
Remarks:
recalculated to EDA
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
27.9 mg/kg bw/day
Based on:
test mat.
Remarks:
calculated from EDA to trimethylenediamine
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
139.6 mg/kg bw/day
Based on:
test mat.
Remarks:
calculated from EDA to trimethylenediamine
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Effect levels (fetuses)

open allclose all
Dose descriptor:
LOAEL
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: embryotoxicity
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: fetotoxicity
Dose descriptor:
LOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Dose descriptor:
LOAEL
Effect level:
113 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: embryotoxicity
Dose descriptor:
NOAEL
Effect level:
113 mg/kg bw/day
Based on:
test mat.
Remarks:
recalculated to EDA
Basis for effect level:
other: fetotoxicity
Dose descriptor:
LOAEL
Effect level:
452 mg/kg bw/day
Based on:
test mat.
Remarks:
recalculated to EDA
Basis for effect level:
other: teratogenicity
Dose descriptor:
LOAEL
Effect level:
139.6 mg/kg bw/day
Based on:
test mat.
Remarks:
calculated from EDA to trimethylenediamine
Basis for effect level:
other: embryotoxicity
Dose descriptor:
NOAEL
Effect level:
139.3 mg/kg bw/day
Based on:
test mat.
Remarks:
calculated from EDA to trimethylenediamine
Basis for effect level:
other: fetotoxicity
Dose descriptor:
LOAEL
Effect level:
557.2 mg/kg bw/day
Based on:
test mat.
Remarks:
calculated from EDA to trimethylenediamine
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Significant reduction in maternal body weight gain in the intermediate dose group during gestation day 6 - 15 and in the high dose group during gestation day 6 - 21; significant decreased diet consumption in the intermediate and high dose group during gestation day 6 - 15; significant increased number of resorptions/litter and significant decreased mean fetal body weight and reduced fetal crown-rump length in the high dose group; significant higher incidence of a shortened mandible, edematous eye bulge, shortened or missing innominate artery, unossified sternebrae in fetuses of the high dose group.

    Number of pups affected
    Dosage level (mg/kg/day)
           Control 50 250 1000
No. of litters   40 23 21 24
No. of pups   379 232 201 242
           
Pup body weight, males (g)        4.5+0.3 4.5+0.2  4.5+0.2  4.1+0.3
 Pup body weight, females (g)   4.2+0.2  4.2+0.2 4.2+0.3  3.8+0.3
           
Fetal crown rump length, males (mm)    40+2    40+2     40+2      39+2
 Fetal crown rump length, females (mm)   38+1    39+2     39+2      37+2
           
Slightly edematous eye bulge          
  F 0 0 0 4
  L 0 0 0 4
Shortened mandible           
  F 0 0 0 18
  L 0 0 0 4
Missing innominate artery          
  F 0 0 1 9
  L 0 0 1 6
Shortened innominate artery          
  F 4 2 0 27
  L 4 1 0 14

F = fetuses L = litters

The first artery to branch off of the aorta is the brachiocephalic which becomes the innominate after the left carotid branches off.  The innominate then branches into the right subclavian and right carotid artery.  When the authors stated it was missing, they really mean that the right and left carotid branch off of the brachiocephalic artery at the same time.  Thus there is no innominate.  However, this would not affect blood supply to areas served by these arteries.                                                                                        

Applicant's summary and conclusion