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Diss Factsheets

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2015-09-09 - 2016-05-18
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report date:
2016

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
22 Jan 2001
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Version / remarks:
May 2008
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Version / remarks:
Aug 1998
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
testing lab.
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-ethylhexylamine
EC Number:
203-233-8
EC Name:
2-ethylhexylamine
Cas Number:
104-75-6
Molecular formula:
C8H19N
IUPAC Name:
2-ethylhexylamine
Specific details on test material used for the study:
- Lot/batch No.: 000STD77L0
- Expiration date of the lot/batch: 10 Feb 2017

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Strain: Crl:WI(Han)
- Age at study initiation: about 10-12 weeks
- Weight at study initiation: 143.2 - 185.8 g
- Housing: individually in Polycarbonate cages type III with wooden gnawing blocks and dust-free wooden bedding
- Diet: Ground Kliba maintenance diet mouse/rat "GLP", Provimi Kliba SA, Kaiseraugst, Switzerland; ad libitum
- Water: tap water ad libitum
- Acclimation period: between the start of the study (beginning of the experimental phase) and the first administration (GD 6)

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

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The aqueous test substance preparations were prepared at the beginning of the administration period and
thereafter at intervals, which took into account the period of established stability.

VEHICLE
- Concentration in vehicle: The animals of the control groups were treated with the vehicle (0.5% Carboxymethylcellulose suspension in drinking
water)
- Amount of vehicle: The volume administered each day was 10 mL/kg body weight
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The stability of the test substance in 0.5% carboxymethyl cellulose suspension in drinking water at room temperature over a period of 7 days had been verified prior to the start of the study.
The samples were also used to verify the homogeneity of the low and the high concentrations (8 and 75 mg/kg bw/d). Three samples of the low and the high concentrations (one from the top, middle and bottom in each case) were taken from the beaker while a magnetic stirrer was running.
The samples were analyzed via HPLC-MS.

Based on the analytical results it is concluded that 2-Ethylhexylamine is stable in 0.5 % carboxymethyl cellulose in drinking water over a period of 7 days at room temperature. All determined concentrations were in the range of 90 % - 110 % of the nominal concentration.
Details on mating procedure:
- Impregnation procedure: purchased timed pregnant
The animals were paired by the breeder (“time-mated”); the day of evidence of mating (= detection of vaginal plug/sperm) was referred to as GD 0.
The animals arrived on the same day (GD 0) at the experimental laboratory. The following day was designated as “GD 1”.
Duration of treatment / exposure:
GD 6-19
Frequency of treatment:
once daily
Duration of test:
on GD 20, all surviving females were sacrificed
Doses / concentrationsopen allclose all
Dose / conc.:
8 mg/kg bw/day (nominal)
Dose / conc.:
25 mg/kg bw/day (nominal)
Dose / conc.:
75 mg/kg bw/day (nominal)
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Details on study design:
The doses for this study were selected based on a previously performed maternal toxicity study. 2-Ethylhexylamine was administered as an aqueous
suspension to groups of 7 time-mated female Wistar rats by gavage at doses of 50 and 150 mg/kg body weight/day (mg/kg bw/d) from gestation
days (GD) 6 through 19. Three animals of the high dose group (150 mg/kg bw/d) were found dead (at day 7, 8 and 14 of the study). Four animals
were sacrificed unscheduled for animal welfare reasons (at day 15 of the study).
Severe clinical findings (i.e. tremors, abdominal position, semiclosed eyelid, convulsions, salivation and piloerection) were documented during the
conduct of the study.
At the 50 mg/kg bw/d dose clinical findings (i.e. salivation and plough nose-first into bedding) were observed. Based on these data doses of 8, 25
and 75 mg/kg bw/d were selected for this prenatal developmental toxicity study.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day on working days or once a day on Saturday, Sunday or on public holidays (GD 0-20)

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: A cage-side examination was conducted at least once daily before and after treatment period (GD 0-5 and 20). During treatment period (GD 6-19) all rats were checked daily for any signs of morbidity, pertinent behavioral changes and/or signs of overt toxicity before
administration as well as within 2 hours and within 5 hours after administration

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

FOOD CONSUMPTION: Yes
- Time schedule for examinations: GD 0-1, 1-3, 3-6, 6-8, 8-10, 10-13, 13-15, 15-17, 17-19 and 19-20

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: gross pathology
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
- Number of dead fetuses: Yes
Fetal examinations:
- Weight of each fetus: Yes
- Sex: Yes
- Weight of placentas: Yes
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
Statistics:
- DUNNETT's test: Food consumption, body weight, body weight change, corrected body weight gain (net maternal body weight change), carcass
weight, weight of unopened uterus, number of corpora lutea, number of implantations, number of resorptions, number of live fetuses, proportions
of preimplantation loss, proportions of postimplantation loss, proportions of resorptions, proportion of live fetuses in each litter, litter mean fetal body weight, litter mean placental weight
- FISHER's exact test: Female mortality, females pregnant at terminal sacrifice, number of litters with fetal findings
- WILCOXON test: Proportions of fetuses with malformations, variations and/or unclassified observations in each litter

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, non-treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Gross pathological findings:
effects observed, non-treatment-related
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
- MORTALITY:
There were no substance-related or spontaneous mortalities in any females of all test groups.

- CLINICAL SYMPTOMS:
Most of the females (21 out of 25) of the high-dose group (75 mg/kg bw/d) showed transient salivation during the treatment period. Salivation occurred in the respective animals only within the 2-hour examination interval (i.e. <2h after treatment) and was initially observed
on GD 7.
During the 5-hour examination interval (i.e. >2h<5h after treatment), no clinical signs or changes of general behavior were detected in any female of all test groups.
No further clinical signs or changes of general behavior, which may be attributed to the test substance, were detected.

- FOOD CONSUMPTION:
The mean food consumption of the dams in all test groups was generally comparable to the concurrent control throughout the entire study period.
This statement includes the statistically significantly decreased food consumption value on GD 8-10 as well as the statistically significantly increased value on GD 13-15 in test group 3, respectively.

- BODY WEIGHT:
The mean body weights (BW) and the average body weight gains (BWC) of the low-, mid- and high-dose dams were in general comparable to the
controls throughout the entire study period.

- CORRECTED (NET) BODY WEIGHT GAIN:
The corrected body weight gain of test groups 1-3 revealed no difference of any biological relevance to the concurrent control group. Mean carcass weights remained also unaffected by the treatment.

- UTERUS WEIGHT:
The mean gravid uterus weights of the animals of test groups 1-3 (8, 25 and 75 mg/kg bw/d) were not influenced by the test substance. The
differences between these groups and the concurrent control groups revealed no dose-dependency and were assessed to be without biological
relevance.

- NECROPSY FINDINGS:
No necropsy findings which could be attributed to the test substance were seen in any dam.
There occurred one spontaneous finding in test group 2 (25 mg/kg bw/d), i.e. dilated renal pelvis. This finding was detected in two mid-dose animals and was therefore assessed as incidental.

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:
no effects observed
Changes in number of pregnant:
no effects observed
Details on maternal toxic effects:
- EFFECTS ON MATERNAL DEVELOPMENTAL TOXICITY:
The conception rate was 100% in all test groups (0, 8, 25 and 75 mg/kg bw/d).
No test-substance related findings in conception rate, in the mean numbers of corpora lutea, implantation sites and viable fetuses or the number of resorptions and the value calculated for postimplantation loss.

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
maternal toxicity
Effect level:
75 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: There were substance-related effects.
Key result
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Effect level:
75 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: There were no substance-related effects.

Maternal abnormalities

Key result
Abnormalities:
no effects observed

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:
effects observed, non-treatment-related
Skeletal malformations:
effects observed, non-treatment-related
Visceral malformations:
no effects observed
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
Fetal external and skeletal unclassified observations as well as fetal soft tissue and skeletal variations were observed.
Details on embryotoxic / teratogenic effects:
- SEX DISTRIBUTION:
Comparable to the concurrent control fetuses.

- WEIGHT OF PLACENTAE:
Comparable to the concurrent control group.

- WEIGHT OF FETUSES:
No test substance related effects were observed.

- FETAL EXTERNAL MALFORMATIONS:
One fetus with an external malformation was recorded in test group 2 (25 mg/kg bw/d). The total incidence of external malformations in treated animals did not differ significantly from the concurrent control group and was covered by the historical control data.

- FETAL EXTERNAL VARIATIONS:
No external variations were recorded.

- FETAL EXTERNAL UNCLASSIFIED OBSERVATIONS:
One unclassified external observation, i.e. placentae fused, was recorded in one control fetus (0 mg/kg bw/d). This finding was not considered biologically relevant.

- FETAL SOFT TISSUE MALFORMATIONS:
No soft tissue malformations were recorded.

- FETAL SOFT TISSUE VARIATIONS:
Two soft tissue variations were detected, i.e. dilated renal pelvis and dilated ureter. The incidences of these findings were both statistically significantly increased in the mid-dose group (25 mg/kg bw/d). As a consequence, the total incidence of fetal soft tissue variations was also increased in this group. As these incidences were not related to dose, they were assessed as incidental findings.

- FETAL SOFT TISSUE UNCLASSIFIED OBSERVATIONS:
No unclassified soft tissue observations were recorded.

- FETAL SKELETAL MALFORMATIONS:
One fetus of the mid-dose group (25 mg/kg bw/d) showed skeletal malformations affecting the skull. This fetus had an associated external finding.
The total incidence of skeletal malformations in treated animals did not differ significantly from the control group and was comparable to the histiorical control data.

- FETAL SKELETAL VARIATIONS:
For all test groups, skeletal variations of different bone structures were observed, with or without effects on corresponding cartilages.
The observed skeletal variations were related to several parts of fetal skeleton and appeared without a relation to dosing. The overall incidences of skeletal variations were comparable to the historical control data.

- FETAL SKELETAL UNCLASSIFIED CARTILAGE OBSERVATIONS:
Some isolated cartilage findings without impact on the respective bone structures, which were designated as unclassified cartilage observations, occurred in all test groups. The observed unclassified cartilage findings were related to the skull, the sternum and ribs and did not show any relation to dosing.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
75 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: There were no treatment-related effects.

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion