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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study (OECD 414)

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
2001
Report Date:
2001
Reference Type:
publication
Title:
Unnamed
Year:
2002

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
- for inhalation exposure considering OECD - Guideline method 412
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Mono-n-Butylamin
- Physical state: liquid / colorless
- Analytical purity: 99.9%
- Lot/batch No.: Vessel 78
- Storage condition of test material: Room temperature, in closed containers under N2

Test animals

Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Boehringer Ingelheim Pharma KG, Biberach an der Riss, Germany
- Age at study initiation: about 9-10 weeks
- Weight at study initiation:
- Housing: singly in DK 111 stainless steel wire mesh cages
- Diet: rat/mouse/hamster laboratory diet, 10 mm pellets (Provimi Kliba SA, Kaiseraugst, Switzerland), ad libitum.
- Water: tap water ad libitum.
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24 °C
- Humidity (%): 30-70 %
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: glass-steel inhalation chamber, volume of 1.4 m3 (BASF AG)
- Method of holding animals in test chamber: whole body exposure
- Temperature, humidity, in air chamber: 21.2 - 22.5 %; 50.5 - 62.0 %
- Air change rate: ca. 20 x h



TEST ATMOSPHERE
- Brief description of analytical method used:
- Samples taken from breathing zone: yes/no


Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Gas chromatograph equipped with autosampler, split injector and flame ionization detector (FID) and adapted to a chromatography data system
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1-3
- Length of cohabitation: 4.00 pm - 7.30 am (15.5 h)
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
days 6-19 p.c.
Frequency of treatment:
6 h/day
Duration of test:
20 days
Doses / concentrations
Remarks:
Doses / Concentrations:
0.051, 0.151 and 0.460 mg/l
Basis:
analytical conc.
No. of animals per sex per dose:
25 (Implantation sites were present in 20, 23, 24 and 23 animals of test groups 0, 1, 2 and 3, respectively).
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: pretest

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least 3 times on exposure days and, as a rule, once during the day 0, preflow period and post-exposure observation day.


BODY WEIGHT: Yes
- Time schedule for examinations: day 0, 1, 3, 6, 8, 10, 13, 15,17, 19 and 20 p.c..


POST-MORTEM EXAMINATIONS: Yes, gross pathology
- Sacrifice on gestation day # 20


OTHER: Histopathology of head with larynx
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: all per litter
Statistics:
The Dunnett-test was used for a simultaneous comparison of several dose groups with the control. Fisher's Exact test was used for pairwise comparisons. The WILCOXIN test was used for a comparison of each dose with the control for the hypothesis of equal medians.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Treatment-related findings were confined to the anterior section (level 1) of the nasal cavity. Minimal to slight focal necrosis of the nasal mucosa was seen in five, necrosis of the underlying nasal bone in one female of the high concentration group. Necrosis was predominantly located at the nasoturbinates, thus affecting transitional epithelium. (Multi)focal squamous cell metaplasia and purulent to mixed inflammatory cell infiltration were found in all treatment groups in the anterior part of the nose (level 1). The predominant locations were the turbinates and the lateral wall. Focal hyperplasia of the transitional epithelium was observed in 6 animals of the mid and one animal of the low concentration group. Predilection sites were the nasal turbinates and the lateral wall. Incidence and severity decreased from top concentration to low concentration group for all treatment-related findings.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEC
Effect level:
0.45 mg/L air
Basis for effect level:
other: developmental toxicity
Dose descriptor:
LOAEC
Effect level:
0.051 mg/L air
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Mono-n-Butylamine elicited maternal toxicity at all tested concentrations. Maternal toxicity was substantiated by changes of the respiratory epithelium in the nasal cavity.

There were no substance-induced, concentration-related influences on the gestational parameters and no signs of prenatal developmental toxicity, especially no substance induced indications of teratogenicity, up to and including the highest concentration.

Based on these results, the no observed adverse effect concentration (NOAEC) for prenatal developmental toxicity is 0.45 mg/L air.

Applicant's summary and conclusion