Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

There are no studies available investigating effects on fertility.

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Quality of whole database:
No data available to evaluate this endpoint.
Additional information

No study on effects on fertility has to be conducted because a prenatal developmental toxicity study is available.

Effects on developmental toxicity

Description of key information
A NOAEL(oral) and LOAEL(oral) for n-butylamine (base) have been derived from the oral adminstration of n-butylamine hydrochloride and result in 66 and 265 mg base/(kg bw*d), respectively, for teratogenic effects, while the corresponding NOAEC(inhal.) was 460 mg/m3, the highest concentration tested, which produced marked maternal toxicity (nasal corrosion).   
Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
- for inhalation exposure considering OECD - Guideline method 412
GLP compliance:
yes
Species:
rat
Strain:
Wistar
Details on test animals or test system 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
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: GC/FID after absorption in DMF
- Samples taken from breathing zone: yes


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
Remarks:
Doses / Concentrations:
51.4 +-2.2; 151.8 +-9.2; and 460 +-17.5 mg/m3 [= 17, 50.1, and 151.8 mL/m3]
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
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.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
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
Description (incidence and severity):
gravid uterine weights were unaffected by exposure
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Only local effects in the upper respiratory tract due to irritation, details see below
No gross effects were observed in the uterus. Further other organs were not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Only local effects in the upper respiratory tract due to irritation, details see below
Histopathological findings: neoplastic:
not examined
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 specified
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 specified
Changes in number of pregnant:
no effects observed
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 location 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.

Key result
Dose descriptor:
LOAEC
Effect level:
51 mg/m³ air (analytical)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
NOAEC
Effect level:
460 mg/m³ air (analytical)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
other: local irritation in the upper respiratory tract
Description (incidence and severity):
Effects were observed at all exposure concentrations
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): no effects observed
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 specified
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
Key result
Dose descriptor:
NOAEC
Effect level:
460 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: developmental toxicity, highest dose tested
Key result
Abnormalities:
not specified
Key result
Developmental effects observed:
not specified

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 the highest concentration.

Based an these results, the no observed adverse effect concentration (NOAEC) for prenatal developmental toxicity is 0.45 mg/L air (152 mL/m3).

Summary of maternal and fetal data after inhalation exposure to n-butylamine (from Gamer et al. 2002, Tab. 3)

Inhalation concentration [ppm]

0

17

50

152

Females mated

25

25

25

25

Number of maternal deaths, abortions, premature births and total resorptions

0

0

0

0

Females pregnant at scheduled necropsy

20

23

24

23

Mean gravid uterus weight (g)

78.4±13.0

82.5±12.5

82.7±11.6

80.8±13.9

Mean net maternal body weight gain from day 6 post coitum (g)

42.5±8.6

46.3±10.9

47.6±9.6

40.4±9.8

Mean corpora lutea

15.9±1.9

16.8±2.4

16.8±1.4

16.4±1.6

Mean implantation sites

15.1±2.8

15.7±2.2

16.3±1.9

15.4±2.4

Mean % pre-implantation loss

5.8

6.9

3.4

5.8

Mean % post-implantation loss

6.4

6.5

10.9

7.9

Mean % early resorptions

6.4

6.5

10.1

7.1

Mean % late resorptions

0.0

1.2

0.8

0.8

Mean number of live fetuses per litter

14.1±2.6

14.4±2.3

14.5±2.2

14.2±2.5

Number of dead fetuses

0

0

0

0

Mean placenta weight (g)

0.45±0.04

0.46±0.04

0.46±0.06

0.47±0.05

Mean fetal weight (g)

3.7±0.2

3.8±0.3

3.8±0.2

3.8±0.2

Percentage of litters with any malformation

5

13

17

17

Mean % of fetuses/litter with any malformation

0.4

1.2

1.1

1.2

Group means±standard deviation

Fetal and litter incidence of external, soft tissue and skeletal malformations after inhalation exposure

to n-butylamine (from Gamer et al. 2002, Tab. 4)

Inhalation concentration [ppm]

0

17

50

152

Number of litters with live fetuses

20

23

24

23

Total number of fetuses examined (soft tissue/skeletal examination)

282 (134/148)

332 (159/173)

348 (169/179)

327 (158/169)

Number (%) of litters with external malformation

0 (0 %)

0 (0 %)

1 (4 %)

0 (0 %)

Number of fetuses (mean % fetuses/litter) with external malformation

0 (0 %)

0 (0 %)

1(0.3 %)

0 (0 %)

Number (%) of litters with soft tissue malformation

0 (0 %)

1 (4 %)

1 (4 %)

0 (0 %)

Number of fetuses (mean % fetuses/litter) with soft tissue malformation

0 (0 %)

1 (0.5 %)

1 (0.5 %)

0 (0 %)

Number (%) of litters with skeletal malformation

1 (5 %)

2 (9 %)

3 (13 %)

4 (17 %)

Number of fetuses (mean % fetuses/litter) with skeletal malformation

1 (1 %)

3 (2 %)

3 (2 %)

4 (2 %)

Number (%) of litters with any malformation

1 (5 %)

3 (13 %)

4 (17 %)

4 (17 %)

Number of fetuses (mean % fetuses/litter) with any malformation

1 (0.4 %)

4 (1 %)

4 (1 %)

4 (1 %)

Group means±standard deviation

Conclusions:
Under the conditions of this study, local effects were observed in the nose of dams. No effects on gestational parameters and offspring were evident.
Executive summary:

Twenty-five mated female Wistar rats per test group were whole-body exposed to dynamic atmospheres of Mono-n-Butylamin vapors for 6 hours per day on day 6 through day 19 post coitum (p.c.; 14 exposures). The target concentrations were 50, 150 and 450 mg/m 3. A concurrent control group was exposed to clean air.

No treatment related clinical findings were observed. A concentration dependent increase in incidence and severity of changes in the epithelium of the anterior nasal cavity (necrosis, hyper- and metaplasia, inflammatory cell infiltration) occurred. Under the conditions of this prenatal developmental toxicity study, the inhalation exposure of pregnant Wistar rats to vapours of Mono-n-Butylamin from implantation to one day prior to the expected day of parturition (days 6 - 19 p.c.) 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 (450 mg/m 3).

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
other information
Study period:
19 Jan 1994 - 14 Feb 1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: DR. K. THOMAE GmbH, Biberach an der Riss, Germany
- Age at study initiation: 75 - 82 days
- Weight at study initiation: 237 g (mean)
- Housing: singly in type DK III stainless steel wire mesh cages
- Diet: Kliba 343 feed rat/mouse/hamster (KLINGENTALMUHLE AG, Kaiseraugst, Switzerland) ad libitum
- Water: water ad libitum
- Acclimation period: 5 days.


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



Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
VEHICLE
- double distilled water
- Justification for use and choice of vehicle (if other than water): TS is water soluble
- Concentration in vehicle: 64.9 %
- Amount of vehicle (if gavage): 34.5 %
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Stability and purity verified by potentiometric titration
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1-3
- Length of cohabitation: 15.5 h
- 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:
6-15 d p.c.
Frequency of treatment:
1x/d
Remarks:
Doses / Concentrations:
100, 400, and 1000 mg/(kg*d) (in 10 ml dissolved in water)
Basis:
nominal in water
These salt doses are equivalent to approx. 66, 265, and 660 mg amine base/(kg*d) (66 % of the HCl salt).
No. of animals per sex per dose:
22-24 pregnant females per group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
The TS concentration was based on observations made from a range finding study with pregnant rats
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 1x/d

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: 1x/d


BODY WEIGHT: Yes
- Time schedule for examinations: on days 0, 1, 3, 6, 8, 10, 13, 15, 17 and 20 p.c.
Corrected body weight gain was calculated after the terminal sacrifice
(terminal body weight on d 20 p.c. minus weight of unopened uterus minus body weight on d 6 p.c.).

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes / on days 0, 1, 3, 6, 8, 10, 13, 15, 17 and 20 p.c.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data



POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: uterus, ovary, placenta

The weight of the unopened uterus, the number of corpora lutea, the number and distribution of implantations, as well as live fetuses
and dead implantations were determined.

The weight and sex ratio of fetuses was also determined. Further determinations were made of fetuses by macroscopic examinations,
soft tissue examinations were made after fixation in BOUIN's solution (approx. half of the fetuses) and skeletal examinations were made
on half of the fetuses after fixation in alcohol and staining according to the method of DAWSON (Stain Technol. 1, 123, 1926).
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: No data
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 WILCOXON test was used for a comparison of each dose with the control for the hypothesis of equal medians.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Reduced feed consumption in the high dose group on days 6–8, 8–10 and 10–13 post coitum, respectively
Food efficiency:
not examined
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:
effects observed, treatment-related
Description (incidence and severity):
gravid uterine weight was 13–14% lower than controls
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Number of abortions:
not specified
Pre- and post-implantation loss:
effects observed, treatment-related
Description (incidence and severity):
early post implantation losses (=embryonic resorptions) was increased
Total litter losses by resorption:
not specified
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
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 specified
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): cesarian section on day 20
Changes in number of pregnant:
no effects observed
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
At 1000 mg/kg bw:
- A statistically significant reduction in food consumption during days 6-13 p.c. (ca. 8% lower than the corresponding control).
- A statistically significant impairment of body weight gain (14% less than controls if calculated for the total treatment period).
- A statistically significant lower mean gravid uterus weight (ca. 13% lower than the control group).
- A statistically significant increased number of resorptions, increased post-implantation loss value,
and lower mean percentage of live fetuses
- A statistically significant decrease in the mean placental weight (20%).
Key result
Dose descriptor:
NOAEL
Effect level:
400 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Key result
Abnormalities:
not specified
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): fetal weights were reduced about 8% in the high dose group
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
effects observed, treatment-related
Description (incidence and severity):
3 fetuses in high dose group vs. 0 in the other groups
On a percentage of affected litters there was no significant effect
Skeletal malformations:
no effects observed
Visceral malformations:
effects observed, treatment-related
Description (incidence and severity):
3 fetuses in mid dose group, 6 in high dose group, respectively; 0 in other groups
On a percentage of affected litters there was no significant effect
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
At 400 mg/kg bw/d
- A statistically significant increase in the rate of fetuses with soft tissue malformations was seen. Namely, 3 fetuses from 3 different
litters showed the same or similar malformations of the heart, great vessel or the diaphragm as seen at the 1000 mg/kg bw .

At 1000 mg/kg bw/d:
- Lower mean percentage of live fetuses
- Decrease in fetal body weight (8%)
- Slight, but statistically significant increase in the rate of external, soft tissue and total malformations was observed.
This included the occurrence of two rare external malformations of the tail (filiformed or kinky tail) in 3 fetuses from 3 different litters
and several malformations of the heart, the great vessels and the diaphragm in 6 fetuses out of 4 litters.
- A statistically significant increased rate of fetuses with skeletal retardations (esp. incomplete ossification of the skull and sternebra(e)) was noted.
This last finding should be seen in relation to the lower mean fetal body weights.
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Key result
Dose descriptor:
LOAEL
Effect level:
400 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
external: tail
visceral/soft tissue: cardiovascular
visceral/soft tissue: musculoskeletal system
Description (incidence and severity):
400 mg/kg bw/d: Namely, 3 fetuses from 3 different litters showed the same or similar malformations of the heart, great vessel or the diaphragm, as observed in the 1000 mg/kg bw/d group (6 fetuses out of 4 litters), and there additionally two rare external malformations of the tail (filiformed or kinky tail) in 3 fetuses from 3 different litters
Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
400 mg/kg bw/day
Treatment related:
yes
Relation to maternal toxicity:
developmental effects in the absence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
yes

Summary of maternal and fetal data after oral exposure to n-butylamine hydrochloride

(from Gamer et al. 2002, Tab. 1)

Dose [mg/kg*day]

0

100

400

1000

Females mated

25

25

25

25

Number of maternal deaths, abortions, premature births and total resorptions

0

0

0

0

Females pregnant at scheduled necropsy

22

24

22

24

Mean gravid uterus weight (g)

77.5 ±15.9

78.1 ±11.3

76.5 ±15.7

67.1 ±11.6*

Mean net maternal body weight gain from day 6 post coitum (g)

44.0 ±6.6

42.8 ±9.9

50.4 ±8.8

45.8 ±9.5

Mean corpora lutea

16.3 ±2.2

16.9 ±1.9

16.0 ±2.4

15.9 ±2.1

Mean implantation sites

14.3 ±2.6

15.4 ±2.2

15.0 ±2.2

14.3 ±2.6

Mean % pre-implantation loss

12.1

8.8

6.3

9.8

Mean % post-implantation loss

5.7

9.5

11.0

12.5*

Mean % early resorptions

4.3

6.4

8.2

10.0

Mean % late resorptions

1.4

3.1

2.8

2.5

Mean number of live fetuses per litter

13.5 ±2.8

13.9 ±2.2

13.4 ±2.9

12.5 ±2.5

Number of dead fetuses

0

0

0

0

Mean placenta weight (g)

0.44 ±0.04

0.43 ±0.04

0.41 ±0.03

0.35 ±0.04**

Mean fetal weight (g)

3.8 ±0.3

3.8 ±0.2

3.8 ±0.2

3.5 ±0.3**

Percentage of litters with any malformation

18

21

36

46*

Mean % of fetuses/litter with any malformation

2.5

1.6

3.8

6.2*

group means +- S.D.  

* P 0.05;  ** P 0.01

Fetal and litter incidence of external, soft tissue and skeletal malformations after oral administration of n-butylamine hydrochloride (from Gamer et al. 2002, Tab. 2)

Dose [mg/kg*day]

0

100

400

1000

Number of litters with live fetuses

22

24

22

24

Total number of fetuses examined (soft tissue/skeletal examination)

296 (144/152)

333 (161/172)

295 (143/152)

300 (143/157)

Number (%) of litters with external malformation

0 (0 %)

0 (0 %)

0 (0 %)

3 (13 %)

Number of fetuses (mean % fetuses/litter) with external malformation

0 (0 %)

0 (0 %)

0 (0 %)

3 (1 %)

Number (%) of litters with soft tissue malformation

0 (0 %)

0 (0 %)

3 (14 %)

4 (17 %)

Number of fetuses (mean % fetuses/litter) with soft tissue malformation

0 (0 %)

0 (0 %)

3 (3 %*)

6 (4 %*)

Number (%) of litters with skeletal malformation

4 (18 %)

5 (21 %)

6 (27 %)

7 (29 %)

Number of fetuses (mean % fetuses/litter) with skeletal malformation

7 (5%)

5 (3 %)

7 (5 %)

10 (6 %)

Number (%) of litters with any malformation

4 (18%)

5 (21 %)

8 (36 %)

11 (46 %*)

Number of fetuses (mean % fetuses/litter) with any malformation

7 (4%)

5 (2 %)

10 (4 %) 

19 (6 %*)

group means +- S.D.

*) P 0.05

Conclusions:
Under the conditions of this study, the NOAEL for developmental effects was 100 mg/(kg bw*d), the NOAEL for maternal effects was 400 mg/(kg bw*d).
Executive summary:

Pregnant Wistar rats were administered 0, 100, 400 or 1000 mg mono-n-butylamine hydrochloride/kg body weight/day by gavage on days 6 through 15 post coitum (sperm-positive=day 0). Oral n-butylamine HCl 1000 mg/kg reduced maternal feed consumption, increased early post-implantation losses (embryonic resorptions), reduced fetal and placental weight, and retarded skeletal development (incomplete skull and sternebral ossification), and produced malformations (filiform/kinked tail, enlarged cardiac ventricular chamber(s), malpositioned heart, aortic arch atresia, diaphragmatic hernia); 100 mg/kg was the no-observed-adverse effect level (NOAEL) for prenatal developmental toxicity; 400 mg/kg, the maternal no-effect level, produced only malformations (aortic arch atresia, malpositioned heart, diaphragmatic hernia).

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
265 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
reliable developmental toxicity study
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
460 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
reliable developmental toxicity study
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

n-Butylammonium chloride has been tested in an OECD 414 developmental toxicity study after oral exposure. However, the chloride salt used masks the inherent substance properties of n-butylamine, namely its high corrosivity. Using the n-butylammonium chloride, much higher systemic doses could be reached in the absence of local corrosive effects, which would not be feasible with the n-butylamine base. Because the severe local effects of n-butylamine will prevail systemic effects at any dose level, the toxicity study conducted with its chloride salt is not considered for substance evaluation regarding repeated and/or developmental toxicity.

The lowest observed adverse effect level (LOAEC) of 265 mg base/(kg bw*d) - which produced no maternal toxicity - would result in an exposure concentration of approx. 980 mg/m3#) - a concentration that produces severe nasal corrosion.

Even the oral NOAEL correlates with an exposure concentration which is too high as to be tolarable (240 mg/m3). This demonstrates that developmental adverse effects during pregnancy are very unlikely to occur, since potentially teratogenic concentrations cannot be tolerated by the host.

___________________________

#) Calculation: based on default values of 15.7 L/h (respiration volume female rat) and 0.35 kg body weight (female rat) (Guidance Chapter R.8, Table R.8 -17):

Exposure concentration C = dose / respiration volume per kg bw and day (here: exposure time per day = 6 h/d, rat):

C = [265 mg/(kg*d)] / [0.27 m3/6h]

= [265 mg/(kg*d)] / [0.27 m3/d]

= ~ 980 mg/m3

Mode of Action Analysis / Human Relevance Framework

In the absence of any information on species specific modes of action the available information is regarded as relevant for humans.

Justification for classification or non-classification

According to the study results and taking into account that due to the corrosive properties of the substance no systemic concentration/dose could be reached which would produce developmental toxic effects it is concluded that the substance has not to be classified with respect to reproductive and developmental toxicity according to Regulation (EC) No 1272/2008.

After exposure through the relevant exposure route (inhalation) no substance induced toxicity to reproduction is expected. Therefore it needs to be considered that using n-butylammonium chlorid allows to use much higher dose which would not be feasible with the n-butylamine base. Consequently, effects occuring at very high doses of n-butylammonium chloride are not relevant for human exposure and would probably not observed with the n-butylamine base, because severe local effect would prevail at even lower doses which would become decisive for the overall evaluation.

Additional information