Tributylamine

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1990-05-25 to 1990-08-17

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

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)

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

Molecular formula:

C12H27N

IUPAC Name:

tributylamine

Test material form:

liquid

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:

1x/d

Duration of test:

10 days

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Doses / concentrations 2

Dose / conc.:

15 mg/kg bw/day (actual dose received)

Doses / concentrations 3

Dose / conc.:

45 mg/kg bw/day (actual dose received)

Doses / concentrations 4

Dose / conc.:

135 mg/kg bw/day (actual dose received)

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

General toxicity (maternal animals)

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, treatment-related

Description (incidence):

3 females of high dose group died between GD 7 and 8

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

body weight of the animals of the high dose group stagnated on the first two days of test item application, but returned thereafter to normal

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

reduced food consumption in the highest dose group (up to a maximum of 18% reduction in comparison to controls on GD 8), which returned to normal on GD 11

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

red discolorated lungs in the 3 animals of high dose group which died

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Details on results:

No adverse effects were observed of the dams of the low and mid dose group. Three animals of the high dose group died which showed red discoloration of the lungs at necropsy.

Maternal developmental toxicity

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in pregnancy duration:

not examined

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined

Changes in number of pregnant:

no effects observed

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)

Key result

Dose descriptor:

NOAEL

Effect level:

45 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Maternal abnormalities

Key result

Abnormalities:

no effects observed

Description (incidence and severity):

no effects observed except mortality and transient reduction of food consumption and body weight gain

Results (fetuses)

Fetal body weight changes:

no effects observed

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

no effects observed

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. Observed malformations were of spontaneous nature with respect to number  and type

Effect levels (fetuses)

1

Key result

Dose descriptor:

NOAEL

Effect level:

135 mg/kg bw/day

Basis for effect level:

other: fetotoxicity

2

Key result

Dose descriptor:

NOAEL

Effect level:

135 mg/kg bw/day

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Key result

Abnormalities:

no effects observed

Overall developmental toxicity

Key result

Developmental effects observed:

no

Any other information on results incl. tables

Summarised results on fertility and offspring
	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

Applicant's summary and conclusion

Conclusions:

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 (tributylamine; purity of test item: 99.3%) by gavage on gestation days 6 -15 with doses of 15, 45 and 135 mg/kg/day. Three dams of the high dose group died prematurely on days 7 and 8. The other animals of this group showed transient reductions in food consumption and body weight gain. There were no embryo- or fetotoxic effects except a slight and dose-related increase in foetal body weight gain, which was significant at the highest dose. The treatment did not produce malformations (Hoechst/LPT, 1991).

The LOAEL for maternal toxicity was 135 mg/kg bw/day, the NOAEL 45 mg/kg bw/day. The NOAEL for developmental toxicity was 135 mg/kg bw/day, the highest dose tested. This study, performed according to OECD guideline 414, was judged to be reliable (RL1) and selected as key study.