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The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
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:
guideline study
Remarks:
Guideline study conducted in accordance with another substance. Repeated dose toxicity of 3,3'-[butane-1,4-diylbis(oxy)]bispropanamine can be reliably predicted based on read-across to 3,3'-Oxybis(ethyleneoxy)bis(propylamine) (CAS 4246-51-9). For justification of the read-across please refer to IUCLID section 13.
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: EPA, Health Effects Test Guidelines; OPPTS 870.3650: Combined Repeated Dose Toxicity Study With the Reproduction/Developmental Toxicity Screening Test
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
3,3'-[butane-1,4-diylbis(oxy)]bispropanamine
EC Number:
230-745-9
EC Name:
3,3'-[butane-1,4-diylbis(oxy)]bispropanamine
Cas Number:
7300-34-7
Molecular formula:
C10H24N2O2
IUPAC Name:
3-[4-(3-aminopropoxy)butoxy]propan-1-amine
Specific details on test material used for the study:
- Purity: 99.7 %

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at supplied: 10-11 weeks
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sulzfeld, Germany
- Weight at study initiation: Males: 321 - 322 g, Females 205 - 209 g
- Fasting period before study: no
- Housing: individually in Makrolon type M III cages;
- Exceptions:
- During overnight matings, male and female mating partners were housed together in Makrolon type M III cages
- Pregnant animals and their litters were housed together until PND 4 (end of lactation).
- For motor activity (MA) measurements the animals were housed individually in polycarbonate cages (floor area of about 800 cm2) and
small amounts of bedding material
- The cages with the test animals were arranged on the racks in such a way that uniform experimental conditions (ventilation and light) were ensured.
- Diet, ad libitum: Ground Kliba maintenance diet mouse-rat “GLP” meal, supplied by Provimi Kliba SA, Kaiseraugst, Switzerland
- Water, ad libitum: drinking water
- Acclimation period: On the day of arrival the animals were subjected to an appropriate acclimatization period.

ENVIRONMENTAL CONDITIONS
- Temperature: 20-24°C
- Humidity: 30-70%
- Air changes (per hr): 15
- Photoperiod: 12-hour light/12-hour dark cycle

IN-LIFE DATES: From: 2012-01-09 To: 2013-03-12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The appropriate amount of test substance was weighed out depending on the desired concentration. Then, drinking water was filled up to the desired volume, subsequently released with a magnetic stirrer. During administration of the test substance, preparations were kept homogeneous by stirring with a magnetic stirrer. The test substance preparations were produced at least once a week and were stored at room temperature.

VEHICLE
- Justification for use and choice of vehicle: solubility
- Concentration in vehicle:
1.00 mg/100 mL (100 mg/kg bw/d)*, 3.00 mg/100 mL (300 mg/kg bw/d)*, 10.00 and 6.00 mg/100 mL (1000 and 600 mg/kg bw/d)*
*) The dose refers to the body weight of the individual rats determined most recently.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The stability of the test substance in drinking water for a period of 7 days at room temperature was proven during the study. Homogeneity and concentration control analyses of the test-substance preparations were performed in all concentrations at the start of the administration period. Additionally, samples from all concentrations as reverse samples for concentration control analysis were taken at the end of the study. The various analyses confirmed the stability over 7 days and homogeneity and concentration in the vehicle.
Duration of treatment / exposure:
Males were exposed for 59 days (prior to mating, during mating, and up to termination) and females 62 days (prior to mating, during mating, during post-coitum, and at least 4 days of lactation).
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Remarks:
reduced to 600 mg/kg bw/day on study day 7
No. of animals per sex per dose:
10 animals
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
A cageside examination was conducted at least once daily for any signs of morbidity, pertinent behavioral changes and signs of overt toxicity.
The littering and lactation behavior of the dams was generally evaluated in the mornings in combination with the daily clinical inspection of the dams.
On weekdays (except public holidays) the parturition behavior of the dams was inspected in the afternoons in addition to the evaluations in the mornings.

DETAILED CLINICAL OBSERVATIONS: Yes
Detailed clinical observations (DCO) were performed in all animals prior to the administration period and thereafter at weekly intervals. The animals were transferred to a standard arena (50 × 37.5 cm with sides of 25 cm high).
The following parameters were examined: abnormal behavior when handled, fur, skin, posture, salivation, respiration, activity/arousal level, tremors, convulsions, abnormal movements, impairment of gait, lacrimation, palpebral closure, exophthalmus, feces (appearance/consistency), urine, pupil size

BODY WEIGHT: Yes
Body weight was determined before the start of the administration period in order to randomize the animals. During the administration period body weight was determined on study day 0 (start of the administration period) and thereafter once a week at the same time of the day (in the morning).
The body weight change of the animals was calculated from these results.
The following exceptions are notable for the female animals:
- During the mating period the parental females were weighed on the day of positive evidence of sperm (GD 0) and on GD 7, 14 and 20.
- Females with litter were weighed on the day of parturition (PND 0) and on PND 4.
- Females without a litter and without positive evidence of sperm in the vaginal smear were weighed weekly. These body weight data were solely used for the calculations of the dose volume.

FOOD CONSUMPTION:
Generally, food consumption was determined once a week for male and female parental animals, with the following exceptions:
- Food consumption was not determined during the mating period (male and female F0 animals)
- Food consumption of the F0 females with evidence of sperm was determined on GD 0-7, 7-14, 14-20.
- Food consumption of F0 females, which gave birth to a litter, was determined for PND 1-4.
Food consumption was not determined in females without positive evidence of sperm (during the mating period of dams used in parallel) and females without litter (during the lactation period of dams used in parallel).

FOOD EFFICIENCY: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
Drinking water consumption was monitored by daily visual inspection of the water bottles for any changes in volume.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: In the morning towards the end of the administrative period
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: first 5 surviving parental males and the first 5 surviving females with litter (in order of delivery) per group
- Parameters examined: see Table 1 in 'Any other information on materials and methods incl. tables'.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: In the morning towards the end of the administrative period
- Animals fasted: Yes
- How many animals: first 5 surviving parental males and the first 5 surviving females with litter (in order of delivery) per group
- Parameters examined: see Table 2 in 'Any other information on materials and methods incl. tables'.

URINALYSIS: Yes
- Time schedule for collection of urine: overnight towards the end of the administrative period
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters examined: see Table 3 in 'Any other information on materials and methods incl. tables'.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Functional observational battery (FOB) was performed in all animals towards the end of the administration period
- Dose groups that were examined: all animals

- Battery of functions tested:
Home cage observations:
Attention was paid to: Posture, Tremors, Convulsions, Abnormal movements, Gait abnormalities.
Open field observations:
Behavior when removed from cage, fur, skin, salivation, nose discharge, lacrimation, eyes/pupil size, posture, palpebral closure, respiration, tremors, convulsions, abnormal movements, impairment of gait, activity/arousal level, feces (number of fecal pellets/appearance/consistency) within two minutes, urine (appearance/quantity) within two minutes, number of rearings within two minutes.
Sensorimotor tests/reflexes:
Approach response, touch response, vision ("visual placing response"), pupillary reflex, pinna reflex, audition ("startle response"), coordination of movements ("righting response"), behavior during "handling", vocalization, pain perception ("tail pinch"), grip strength of forelimbs, grip strength of hindlimbs, landing foot-splay test, other findings.

Motor activity (MA) measured on the same day as the FOB was performed.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
All parental animals were sacrificed by decapitation under isoflurane anesthesia. The exsanguinated animals were necropsied and assessed by gross pathology.
Organ weights: Weight assessment was carried out on all animals.
- The following weights were determined: Anesthetized animals, Epididymides, Testes.
- The following weights were determined in 5 animals/sex and test group (females with litters, same animals as used for clinical pathology examinations): Adrenal glands, Brain, Heart, Kidneys, Liver, Spleen, Thymus

HISTOPATHOLOGY: Yes
The following organs/ tissues were preserved in neutral-buffered 4% formaldehyde or in modified Davidson’s solution: Adrenal glands, All gross lesions, Aorta, Bone marrow (femur), Brain, Cecum, Cervix, Coagulating glands, Colon, Duodenum, Eyes with optic nerve, Esophagus, Extraorbital lacrimal gland, Epididymides (modified Davidson’s solution), Femur with knee joint, Heart, Ileum, Jejunum (with Peyer’s patches), Kidneys, Larynx, Liver, Lungs, Lymph nodes (axillary and mesenteric), Mammary gland (male and female), Nose (nasal cavity), Ovaries (modified Davidson’s solution), Oviducts, Pancreas, Parathyroid glands, Pharynx, Pituitary gland, Prostate gland, Rectum, Salivary glands, (mandibular and sublingual), Sciatic nerve, Seminal vesicles, Skeletal muscle, Spinal cord (cervical, thoracic and lumbar cord), Spleen, Sternum with marrow, Stomach (forestomach and glandular stomach), Target organs,Testes (modified Davidson’s solution), Thymus, Thyroid glands, Trachea, Urinary bladder, Uterus, Vagina.
For further evaluation proceeding, see Table 4 in 'Any other information on materials and methods incl. tables'.
Other examinations:
The supplier assayed the food used in the study for chemical and microbiological contaminants.
The drinking water is regularly assayed for chemical contaminants.
The bedding and the enrichment are regularly assayed for contaminants (chlorinated hydrocarbons and heavy metals).
Statistics:
Please refer to 'Any other information on materials and methods incl. tables'.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
Parental animals:
No rat died prematurely in the present study.
No test substance-related, adverse findings were noted.
Reproductive Performance: No test substance-related, adverse findings were noted.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
On study day 7 (premating) mean body weight of male animals in test group 3 (1000 and 600 mg/kg bw/d) was significantly decreased (-6%). Although not significantly altered, mean body weight loss in female animals was observed after 7 days of treatment.
Mean body weight change values during premating were significantly decreased in male animals of test group (1000 and 600 mg/kg bw/d) between study days 0-7 (-84%) and 0-13 (-48%). Although not significantly altered mean body weight change value in female animals was observed between study days 0-7 days. All mentioned findings were assessed as being related to treatment.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
In test group 3 (1000 and 600 mg/kg bw/d) food consumption during premating was significantly decreased in male animals between study days 0-7 (-17%) and 0-13 (-11%) as well as in female animals between study days 0-7 (-19%). These findings were assessed as being related to treatment with the test substance by irritating the upper digestive tract.
No other findings were observed for male and female animals in test group 1 and 2 (100 and 300 mg/kg bw/d) nor for male and female animals of test group 3 (1000 and 600 mg/kg bw/d) after reducing the dose level.
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
No test substance-related, adverse findings were noted.
Haematological findings:
no effects observed
Description (incidence and severity):
No test substance-related effects.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No test substance-related effects.
Urinalysis findings:
no effects observed
Description (incidence and severity):
No test substance-related effects.
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
Home cage observations: No test substance-related effects were observed.
Open field observations: No test substance-related effects were observed.
Sensorimotor tests/reflexes: No test substance-related effects were observed.
Quantitative Parameters: No test substance-related effects were observed.
Motor activity measurement: There were no significant deviations concerning the overall motor activity (summation of all intervals) and regarding the single intervals in male and female animals of all test groups in comparison to the concurrent control group.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No test substance-related effects.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Treatment of male and female Wistar rats with up to 1000 and 600 mg/kg bw/d of the test substance led to treatment-related findings in the upper digestive tract (starting at 100 mg/kg bw/d in males and 300 mg/kg bw/d in females). The hyperplasia, hydropic degeneration of squamous cells and inflammatory cell infiltrates, occasionally with multinucleated giant cells in the forestomach as well as the hyperemia, eosinophilic cytoplasmic change, increased mitotic figures, submucosal edema and inflammatory cell infiltrates in the glandular stomach were regarded to be signs of a slight irritating effect of the test substance. These findings were almost exclusively observed around or at the margo plicatus and in the glandular stomach in the fundic area. They were regarded to be adverse. The increase in thickness in the duodenum (only males >= 300 mg/kg bw/d) was also regarded to be treatment-related and as the specific mechanism could not be determined, it was also judged to be adverse in nature. All these adverse findings described above are regarded to be local irritating effects but no systemic toxicity.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Treatment of male and female Wistar rats with up to 1000 and 600 mg/kg bw/d of the test substance led to treatment-related findings in the upper digestive tract (starting at 100 mg/kg bw/d in males and 300 mg/kg bw/d in females). The hyperplasia, hydropic degeneration of squamous cells and inflammatory cell infiltrates, occasionally with multinucleated giant cells in the forestomach as well as the hyperemia, eosinophilic cytoplasmic change, increased mitotic figures, submucosal edema and inflammatory cell infiltrates in the glandular stomach were regarded to be signs of a slight irritating effect of the test substance. These findings were almost exclusively observed around or at the margo plicatus and in the glandular stomach in the fundic area. They were regarded to be adverse. The increase in thickness in the duodenum (only males >= 300 mg/kg bw/d) was also regarded to be treatment-related and as the specific mechanism could not be determined, it was also judged to be adverse in nature. All these adverse findings described above are regarded to be local irritating effects but no systemic toxicity.
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
Findings which occurred either individually or were biologically equally distributed over control and treatment groups, were considered to be incidental or spontaneous in origin and without any relation to treatment.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks:
parental systemic toxicity
Effect level:
600 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Starting dose: 1000 mg/kg bw/d, reduced to 600 mg/kg bw/d on study day 7
Dose descriptor:
NOAEL
Remarks:
local effect
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
histopathology: non-neoplastic
Dose descriptor:
NOAEL
Remarks:
local
Effect level:
< 100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
histopathology: non-neoplastic
Dose descriptor:
NOAEL
Remarks:
reproductive toxicity
Effect level:
600 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Starting dose: 1000 mg/kg bw/d, reduced to 600 mg/kg bw/d on study day 7
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Effect level:
600 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Starting dose: 1000 mg/kg bw/d, reduced to 600 mg/kg bw/d on study day 7

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion