Triethylamine

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1990-05-25 to 1990-08-17

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Gideline study (OECD 414)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

preinspection, according to §19b German Chemicals Act

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Tributylamine

EC Number:

203-058-7

EC Name:

Tributylamine

Cas Number:

102-82-9

IUPAC Name:

N,N-dibutylbutan-1-amine

Details on test material:

- Name of test material (as cited in study report): Tri-n-butylamine
- Physical state: colourless liquid
- Analytical purity: 99.3 %
- Purity test date: 1989-03-08
- Lot/batch No.: 470811, Code No. HOE CG 0113 OA ZD 99 001
- Storage condition of test material: at room temperature

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Lippische Versuchstierzucht Hagemann, Extertal, Germany
- Age at study initiation: sexually mature
- Weight at study initiation: 192-245 g
- Housing: individually, for mating with male rat of the same breed
- Diet (ad libitum): Altromin 1314, Altromin, Lage, Lippe, Germany
- Water (ad libitum): tap water


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 50 +/- 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 1% aqueous hydroxypropyl-methylcellulose gel

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
freshly each day immediately before administration

VEHICLE
- Amount of vehicle (if gavage): 5 ml/kg
- Lot/batch no. (if required): MM 84072811

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Examination on homogenicity and stability: extraction of the test substance with methanol, analysis with GC/FID

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: one dark period
- Further matings after two unsuccessful attempts: no, replacement by other animal
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

gd 6-15

Frequency of treatment:

1 x daily

Duration of test:

10 d

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 15, 45, 135 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

20 females

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: pretest with 10, 30, 100, 300, 600 and 900 mg/kg bw/day, lethal effects at 300 mg/kg bw/day and above

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily (morning/evening)

DETAILED CLINICAL OBSERVATIONS: No


BODY WEIGHT: Yes
- Time schedule for examinations: daily


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: ovaries and uterus (corporea lutea, implantations), dissection with macroscopic examination of internal organs


OTHER: food and water consumption monitored daily

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No data
- Number of late resorptions: No data

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No

Statistics:

The Student's t-test was used for statistical analysis

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Effects were noted only in the high-dose group:
-Transiently reduced food consumption and body weight gain after start of dosing
3 dams died prematurely (day 7 and 8). These animals showed red discoloration of the lungs.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

45 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There were no significant prenatal adverse effects.
A slight and dose related increase in the mean foetal body weight was observed, which was statistically significant in the high dose group. Observedmalformations were of spontaneous nature with respect to number and type .

Effect levels (fetuses)

1

Dose descriptor:

NOAEL

Effect level:

135 mg/kg bw/day

Basis for effect level:

other: fetotoxicity

2

Dose descriptor:

NOAEL

Effect level:

135 mg/kg bw/day

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

Summarised results on fertility and offspring    Control  15 mg/kg bw/day  45 mg/kg bw/day  135 mg/kg bw/day  Number of rats used  25  25  25  25  pregnant  20  20  20  20  evaluated  20  20  20  17 (3 died prematurely)  Corpora lutea          total  277  272  272  223  per dam  13.9 ± 2.0  13.6 ± 2.1  13.6 ± 1.7  13.1 ± 1.4  Implantations          total  272  266  257  216  per dam  13.6 ± 1.9  13.3 ± 2.3  12.9 ± 2.3  12.7 ± 1.3  Foetuses          total  252  251  242  199  per dam  12.6 ± 2.3  12.6 ± 2.4  12.1 ± 2.4  11.7 ± 2.0  Number of placentae  252  251  242  199  Resorptions          total  20  15  15  17  per dam  1.0 ± 1.6  0.7 ± 1.1  0.8 ± 1.1  1.0 ± 1.5  resorption rate (%)  7.4  5.6  5.8  7.9  Dead fetuses  0  0  0  0  Runts          total  1  0  1  0  per dam  0.1 ± 0.2  -  0.1 ± 0.2  -  Malformations          total  6  5  4  2  per dam  0.3 ± 1.3  0.3 ± 0.8  0.2 ± 0.6  0.1 ± 0.5  malformation rate (%)  2.4  2.0  1.7  1.0  Foetuses with variations (Dawson)  99  108  97  79  Variation rate (%)  78.6  86.4  80.2  79.8  Foetuses with variations (macroscopic)  0  0  0  0  Foetuses with variations (Wilson)  19  17  14  21  Variation rate (%)  15.1  13.5  11.6  21.0  Body weight foetuses (g)  3.44 ± 0.24  3.52 ± 0.50  3.71 ± 0.61  3.75 ± 0.28 (t =3.520)  Placenta weights (g)  0.57 ± 0.07  0.55 ± 0.06  0.56 ± 0.04  0.56 ± 0.06  Preimplantation loss (%)  1.8  2.2  5.5  3.1  Post implantation loss (%)  7.4  5.6  5.8  7.9

Applicant's summary and conclusion

Conclusions:

The test substance was not embryo- or foetotoxic and induced no malformations in rats at doses which produced maternal toxicity.


Control
15 mg/kg
45 mg/kg
135 mg/kg

Number of rats





used
25
25
25
25

pregnant
20
20
20
20

evaluated
20
20
20
17 (3 died pre-maturely)







Corporea lutea





total
277
272
272
223

per dam
13.9 ± 2.0
13.6 ± 2.1
13.6 ± 1.7
13.1 ± 1.4







Implantations





total
272
266
257
216

per dam
13.6 ± 1.9
13.3 ± 2.3
12.9 ± 2.3
12.7 ± 1.3







Foetuses





total
252
251
242
199

per dam
12.6 ± 2.3
12.6 ± 2.4
12.1 ± 2.4
11.7 ± 2.0







Number of placentae
252
251
242
199







Resorptions





total
20
15
15
17

per dam
1.0 ± 1.6
0.7 ± 1.1
0.8 ± 1.1
1.0 ± 1.5

Resorption rate (%)
7.4
5.6
5.8
7.9







Dead foetuses
0
0
0
0







Runts





total
1
0
1
0

per dam
0.1 ± 0.2
-
0.1 ± 0.2
-







Malformations





total
6
5
4
2

per dam
0.3 ± 1.3
0.3 ± 0.8
0.2 ± 0.6
0.1 ± 0.5

Malformation rate (%)
2.4
2.0
1.7
1.0







Foetuses with variations (Dawson)
99
108
97
79

Variation rate (%)
78.6
86.4
80.2
79.8







Foetuses with variations (macroscopic)
0
0
0
0







Foetuses with variations (Wilson)
19
17
14
21

Variation rate (%)
15.1
13.5
11.6
21.0







Body weights foetuses (g)
3.44 ± 0.24
3.52 ± 0.50
3.71 ± 0.61
3.75 ± 0.28

(t = 3.520)







Placenta weights (g)
0.57 ± 0.07
0.55 ± 0.06
0.56 ± 0.04
0.56 ± 0.06







Pre-implantation loss (%)
1.8
2.2
5.5
3.1







Post-implantation loss (%)
7.4
5.6
5.8
7.9


The test substance was not embyro- or foetotoxic and induced no malformations in rats at doses which produced maternal toxicity.

Executive summary:

Pregnant Sprague Dawley rats (20 per group) were orally treated (purity of test item 99.3%) by gavage on gestation days 6 -15 with dose 15, 45 and 135 mg/kg bw/day. three dams died prematurely on days 7 and 8. The other animals of this group showed transient reduction in food consumption and body weight gain. There were no embryo- or fetotoxic effects except a slight and dose-realted increase in foetal body weight gain, which was significant at the highest dose. The treatment did not produce malformation (Hoechst LPT, 1991). The LOAEL for maternal toxicity was 135 mg/kg bw/day. The NOAEL for developmental toxicity was 135 mg/kg bw/day, the highest dose tested.