Hexylamine

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

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

Adequacy of study:

key study

Study period:

2005-10-12 through 2007-07-30

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP guideline study Please refer to section 13 (read across statement).

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: Crl:CD (SD) IGS

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

water

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: 14 days
- Proof of pregnancy: sperm in vaginal smear; referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): singly

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

Males 47-48 days; females 42-46 days

Details on study schedule:

- Age at mating of the mated animals in the study: 13 weeks

Remarks:

Doses / Concentrations:
0, 37.5, 75, 100/150 mg/kg bw/day
Basis:
analytical conc.

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

Statistics:

no data

Reproductive indices:

reproductive function calculations (see below)

Offspring viability indices:

Number of live / dead pups at birth; sex ratio; viability at day 4 post partum
Pup clinical observations
Pup weight at birth and at day 4 post partum

Clinical signs:

no effects observed

Body weight and weight changes:

not examined

Food consumption and compound intake (if feeding study):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Histopathological findings: non-neoplastic:

not examined

Other effects:

no effects observed

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Dose descriptor:

NOAEL

Effect level:

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

Sex:

male

Basis for effect level:

other: see 'Remark'

Dose descriptor:

NOAEL

Effect level:

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

Sex:

female

Basis for effect level:

other: see 'Remark'

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

not examined

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

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

Sex:

male/female

Basis for effect level:

other: clinical signs; mortality; body weight live birth index; litter size; pup weight; sex ratio; survival index;

Reproductive effects observed:

not specified

There was no statistically significant change in any of the dose groups compared to the control group in any of the parameters examined in the parental animals or in the offspring.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

GLP study, similar to OECD Test Guidelines with acceptable deviations.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Oral:

Octylamine-HCl was examined for its potential for repeated toxicity, developmental and neurotoxicity in a combined OECD TG 422 study under GLP conditions. The dose levels used (0, 37.5, 75, an 100/150 mg/kg bw/day; oral gavage; 12 rats/sex/dose) were selected based on the results of two range finding studies, one in the range 100-1000 mg/kg bw/day, and one in the range 3-100 mg/kg bw/day. The high dose group was initially dosed at 150 mg/kg bw/day, but this was lowered 100 mg/kg bw/day by test day 14 because two mortalities were seen in this group. Therefore, this dose level is called “100/150 mg/kg bw/day”. It should however be mentioned that subsequent examinations revealed that these mortalities resulted from maldosing and were not related to the test substance. The parameters examined in parental animals (gestation length, reproductive function indices [mating index, fertility index, gestation index, implantation efficiency], and corpora lutea counts) and in the offspring (viability at birth and on post partum day 4, sex ratio, weight at birth and on post partum day 4, clinical signs) were comparable across all groups including the control group. The NOAEL for reproduction toxicity was therefore 100 mg/kg bw/day under the conditions of this study. Overall, there were no signs of toxicity to reproduction seen in parental rats or offspring in a valid OECD TG 422 oral gavage screening study receivingoctylamine hydrochloride up to and including 100 mg/kg bw/day (DuPont, 2007).

Short description of key information:
Oral:
In a study assessing the toxicity to reproduction the NOAEL of the read across substance Octylamine-HCl was found to be 100 mg/kg bw.

Justification for selection of Effect on fertility via oral route:
only one study available

Effects on developmental toxicity

Description of key information

oral:
The NOAL for developmental toxicity of the read across substance butylammonium chloride was determined to be 100 mg/kg bw, the LOAEL 400 mg/kg bw.
inhalation:
The NOAEC for developmental toxicity of the read across substance butylamine was determined to be 460 mg/m3.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

key study

Study period:

19 Jan 1994 - 14 Feb 1994

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study Please refer to section 13 (read across statement).

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

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: 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.

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%).

Dose descriptor:

NOAEL

Effect level:

400 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
At 400 mg/kg bw
- 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::
- 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.

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Dose descriptor:

LOAEL

Effect level:

400 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Abnormalities:

not specified

Developmental effects observed:

not specified

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

Reference 2

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: GLP and Guideline study (OECD 414) Please refer to section 13 (read across statement).

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Version / remarks:

- for inhalation exposure considering OECD - Guideline method 412

Deviations:

no

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., 6 h/day

Frequency of treatment:

daily

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.

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.

Dose descriptor:

LOAEC

Effect level:

51 mg/m³ air (analytical)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEC

Effect level:

460 mg/m³ air (analytical)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Abnormalities:

not specified

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 on these results, the no observed adverse effect concentration (NOAEC) for prenatal developmental toxicity is 0.46 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

 

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

400 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

GLP and OECD Guideline 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:

GLP and OECD Guideline study

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Oral:

In a study conducted according to OECD Guideline 414 the read across substance Butylammonium chloride was tested for its developmental toxicity using Wistar rats. 22-24 pregnant females per dose group were used. Test concentrations were 100, 400, and 1000 mg/ (kg*d), applied once daily by gavage in 10 mL dissolved in water for a duration of 6-15 days after conception. These salt doses are equivalent to approx. 66, 265, and 660 mg amine base/ (kg*d) (66 % of the HCl salt). Rats were observed once daily. After termination of the study, the ovaries and uterine content was examined as well as fetuses. Based on the effects recorded (reduced food consumption, impairment in body weight gain and lower mean gravid uterus weights) the NOAL for maternal toxicity was found to be 400 mg/kg bow/day (corresponding to 265 mg/kg*d). Signs of developmental toxicity occurred at the intermediate and the high dose level (400 and 1,000 mg/kg body weight/day). In both groups rare soft tissue, mainly cardiovascular malformations occurred; in addition, infrequent tail malformations were obtained exclusively in a few fetuses of the highest dose level. Further signs of developmental toxicity (e.g. slightly increased embryo lethality, reduced placental and fetal body weights, increased rate of fetuses with retarded ossification) were only seen at 1,000 mg/kg. The no observed adverse effect level (NOAEL) for the fetal organisms 100 mg/ (kg bw*d). This corresponds to 66 mg/ (kg*d) of butylamine (base). The LOAEL for teratogenicity was found to be 400 mg/kg bw/day.

Inalation:

In a second read across study, conducted according to OECD Guideline 412, the test substance was applied as vapour to rats in the following concentrations: 51.4 +/-2.2; 151.8 +/-9.2; and 460 +/-17.5 mg/m3, corresponding to 17, 50.1 and 151.8 mL/m3. Pregnant rats were exposed for a duration of 20 days, 6 hours per day. 25 animals per dose were used. Observations were recorded twice a day. Ovaries and uterine content were examined after termination of the test as well as fetuses. The LOAC for maternal toxicity was determined to be the lowest dose tested (51 mg/m3), as changes in the respiratory epithelium in the nasal cavity were found. The NOAEC for developmental toxicity was found to be 460 mg/m3, which was the highest dose tested.

Justification for selection of Effect on developmental toxicity: via oral route:
only one study available

Justification for selection of Effect on developmental toxicity: via inhalation route:
only one study available

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available studies are considered reliable and suitable for classification purposes under 67/548/EEC. As a result the substance is not considered to be classified for toxicity to reproduction under Directive 67/548/EEC, as amended for the 31st time in Directive 2009/2/EG.

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As a result the substance is not considered to be classified for toxicity to reproduction under Regulation (EC) No 1272/2008, as amended for the sixth time in Regulation EC 605/2014.