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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
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 toxic potential to reproduction of trimethylenediamine.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1984

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
High purity Ethylenediamine (99,9% ) was used to synthesize ethylenediammoniumchloride (EDA*2HCl). Analysis by chromatographic and spectrophotometric procedures showed the salt to be free from impurities.

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, Michigan.
- Age at study initiation: (P) 43 wks;
- Weight at study initiation: (P) Males: 112-141 g; Females: 85-111 g;
- Housing: Two or three males or three or five females were housed per cage prior to mating;
- Diet : ad libitum, Purina Certified Rodent Chow 5002.
- Water :ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 55
- Photoperiod (hrs dark / hrs light): 12 hr light cycle

Administration / exposure

Route of administration:
oral: feed
Details on exposure:
Fresh diet was prepared biweekly with the percentage of EDA*2HCl in the diet adjusted to maintain a constant dosage level in grams per kilogram
for each sex according to the average animal body weight gain and diet consumption. At monthly intervals two diet samples were analysed.
Details on mating procedure:
The F0 parents were mated afier having received dietary EDA * 2HCl for 100 days. Twenty-six females and 13 males (randomly selected from 25 males) were mated per treated group while 52 females and 26 males (randomly selected from 50 males) were mated for the control group. During mating, two females were placed in a cage with one male; at this time all rats received EDA * 2HCl at the concentration in the diet for the respective female groups. Fifteen days after cohabitation, mating was discontinued and the females were placed in individual shoebox cages fitted with wire rod metal tops.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
At monthly intervals two diet samples were analysed.
Duration of treatment / exposure:
for two generations
Frequency of treatment:
daily
Details on study schedule:
At each dose level 13 male and 26 female rats were mated in both F0 and F1 generation (control group: 26 male and 52 female rats each); continuous treatment starting 100 days prior to cohabitation of F0 rats until weaning of F2 rats.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
50 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
150 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
500 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
13 male and 26 female. Control group: 26 male and 52 female rats
Control animals:
yes, concurrent no treatment

Examinations

Parental animals: Observations and examinations:
BODY WEIGHT: Yes, measured weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Food consumption determined on each cage of animals every 2 week. Dosage adjusted to keep a constant dosage level.

Results and discussion

Results: P0 (first parental animals)

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Body weight; food consumption; organ weights;
Dose descriptor:
NOAEL
Effect level:
22.6 mg/kg bw/day
Based on:
test mat.
Remarks:
recalculated to EDA
Sex:
male/female
Basis for effect level:
other: Body weight; food consumption; organ weights; (Reclaculated to EDA base)
Dose descriptor:
NOAEL
Effect level:
27.9 mg/kg bw/day
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.

Results: F1 generation

Effect levels (F1)

open allclose all
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Body weight; food consumption; organ weights; histopathology: Hepatocellular pleomorphism
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
225.9 mg/kg bw/day
Based on:
test mat.
Remarks:
recalculated to EDA
Sex:
male/female
Basis for effect level:
other: Body weight; food consumption; organ weights; histopathology: Hepatocellular pleomorphism; (Recalculated to EDA base)
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
278.6 mg/kg bw/day
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.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Significant reduction in parental body weight gain of female rats in the intermediate and high dose group of the F0 generation, in the high dose group of the F1 generation and of male rats in the high dose group of both F0 and F1 generations. No substance-related parental deaths in the F0 or F1 generation. Significant decrease of absolute liver weight in male rats of the high dose F1 generation.

No macroscopic or histopathologic findings except a significant higher incidence of hepatocellular pleomorphism in both sexes of the high dose group of the F1 generation (6/10 male, 10/10 female; control: 0/20 each) and a significant decreased prevalence of kidney tubular mineralization in female rats of the high dose group of the F1 generation (0/10 female; control: 10/20).

In conclusion there was no evidence of fertility impairment or embryotoxic effect at dose levels that show maternal or paternal toxicity.

REPRODUCTIVE INDICES        
         
  Dosage (g/kg,lday)
  0.50 0.15 0.05 0
  F0 → F1
Fertility index (%)        
Male 92 100 92 92
Female 81 77 73 77
Gestation index (%)  100 100 100 100
Gestation survival index (%)  99.0 ± 3.4  100.0 ± 0.0  97.2 ± 11.8  99.2 ± 5.2
0- to 4-Day survival index (%)  90.0 ± 30.0  100.0 ± 0.0  94.4 ± 23.6  93.2 ± 22.4
4- to 14-day survival indexb (%)  99.4 ± 2.5  100.0 ± 0.0  94.1 ± 24.3  100.0 ± 0.0
4- to 2I-day survival indexb (%)  99.4 ± 2.5  100.0 ± 0.0  94.1 ± 24.3  99.7 ± 2.0
Pups born alive/litter  6.8 ± 3.5  8.6 ± 2.8  6.2 ± 3.9  8.4 ± 3.0
Days from first mating to parturition 28.3 ± 3.8 29.6 ± 2.0  29.8 ± 3.0  28.1 ± 3.0
  F1 → F2
Fertility index (%)        
Male  100 92 92 100
Female  92 88 73 88
Gestation index (%)  100 100 100 100
Gestation survival index (%)  98.6 ± 6.7  99.1 ± 3.1  99.4 ± 2.5  99.5 ± 2.0
0- to 4-Day survival index (%) 98.0 ± 4.1  99.3 ± 3.5 98.6 ± 3.3  98.5 ± 4.1
4- to 14-day survival index (%) 100.0 ± 0.0  98.7 ± 6.3 100.0 ± 0.0  99.6 ± 3.0
4- to 21-day survival index (%) 100.0 ± 0.0  98.3 ± 8.3 100.0 ± 0.0  99.6 ± 3.0
Pups born alive/litter 8.5 ± 3.0  8.8 ± 2.2 9.4 ± 2.8 10.0 ± 2.5
Days from first mating to parturition 28.5 ± 3.2  28.8 ± 3.3 27.3 ± 3.6  28.4 ± 3.8

Conclusion: There was no indication of reproductive toxicity in Fischer 344 rats, following exposure to dietary EDA for two generations. A read across approach is justified as trimethylenediamine is structurally very similar to ethylenediamine (difference: chain length / one CH2-group) or ethylenediammonium dichloride (applied doses of ammonium and chloride of no toxicological relevance), respectively. Thus, there is no evidence that trimethylenediamine has reproductive potential.

Applicant's summary and conclusion