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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Cross-reference
Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting 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 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Specific details on test material used for the study:
purity: 99.9 %
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Male and female Wistar rats, strain Crl:WI(Han), supplied by Charles River Laboratories, Research Models and Services, UK
Route of administration:
inhalation: aerosol
Type of inhalation exposure (if applicable):
nose/head only
Vehicle:
air
Details on exposure:
For each concentration the test substance was supplied to a two-component atomizer at a constant rate by means of an infusion pump. The aerosol was generated with compressed air mixed with conditioned dilution air and passed into the inhalation system.
Details on mating procedure:
Each of the male and female animals was mated overnight in a 1:1 ratio for a maximum of 2 weeks. Throughout the mating period, each female animal was paired with a predetermined male animal from the same test group. Mating was accomplished by placing the female in the cage of the male mating partner from about 16.00 h until 07.00-09.00 h of the following morning. Deviations from these specified times were possible on weekends and public holidays and were reported in the raw data. A vaginal smear was prepared after each mating and examined for sperm. If sperm was detected, pairing of the animals was discontinued. The day on which sperm was detected was denoted "gestation day (GD) 0" and the following day "GD 1".
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
6 hours
Frequency of treatment:
daily
Details on study schedule:
After 2 weeks of premating treatment the F0 animals were mated to produce F1 generation pups. Mating pairs were from the same test group. Mating was discontinued as soon as sperm was detected in the vaginal smear. F0 animals were examined for their reproductive performance including determination of the number of implantation sites and the calculation of postimplantation loss for all F0 females. A detailed clinical observation (DCO) was performed in all F0 animals before test substance administration and thereafter at weekly intervals. Food consumption of the F0 parents was determined regularly during premating and after the mating period and during the gestation and lactation periods in dams. In general, body weights of F0 animals were determined once a week. During gestation and lactation period, F0 females were weighed on gestation days (GD) 0, 7, 14 and 20, on the
parturition day (postnatal day [PND] 0) and on PND 4. Pups were sexed on PND 0 and weighed one day after birth and on PND 4. Their viability was recorded twice daily on each working day or only in the morning on Saturday and Sunday. Clinicochemical and hematological examinations as well as urinalyses were performed in 5 randomly selected F0 parental animals of either sex towards the end of the administration period. At the end of the administration period a functional observational battery was performed and motor activity was measured in 5 randomly selected F0 parental males and females per test group. All surviving F0 parental animals were sacrificed assessed by gross pathology. Organ weights were recorded and a histopathological examination was performed.
Dose / conc.:
3.88 mg/m³ air (analytical)
Remarks:
±0.63 mg/m3
Dose / conc.:
16.6 mg/m³ air (analytical)
Remarks:
±3.1 mg/m3
Dose / conc.:
41.2 mg/m³ air (analytical)
Remarks:
±6.5 mg/m3
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Reproductive performance:
no effects observed
Description (incidence and severity):
For all F0 parental males, which were placed with females to generate F1 pups, copulation was confirmed. Thus, the male mating index was 100% in all test groups (0, 4, 16 and 40 mg/m³). Fertility was proven for most of the F0 parental males within the scheduled mating interval for F1 litter. One male of the 4 mg/m³ test group did not generate F1 pups. The apparently infertile male rat did not show histopathological findings that could explain infertility. Thus, the male fertility index was 90% in the 4 mg/m³ test group and 100% in all remaining groups including the control. This reflected the normal range of biological variation inherent in the strain of rats used for this study. All respective values were within the range of the historical control data of the test facility.
The female mating index calculated after the mating period for F1 litter was 100% in all test groups (0, 4, 16 and 40 mg/m³).
The mean duration until sperm was detected (GD 0) amounted to 3.1, 3.1, 2.7 and 3.3 days (0, 4, 16 and 40 mg/m³). All sperm positive rats delivered pups or had implants in utero with the exception of one low-dose female, that did not become pregnant.
The female fertility index varied between 90% (4 mg/m³) and 100% (all other test groups). These values reflect the normal range of biological variation inherent in the strain of rats used for this study. All respective values were within the range of the historical control data of the test facility and did not show any relation to dosing. There were no corroborative histopathological findings in the sexual organs of the nonpregnant female rat. The mean duration of gestation values varied between 22.0 (test groups 4 and 16 mg/m³) and 22.2 days (test groups 0 and 40 mg/m³) without any relation to dosing. The gestation index was 100% in all test groups including the control. Implantation was not affected by the treatment since the mean number of implantation sites was comparable between all test substance-treated groups and the controls, taking normal biological variation into account (10.6, 11.1, 12.3 and 11.4 implants per dam at 0, 4, 16 and 40 mg/m³, respectively).
Dose descriptor:
NOAEC
Remarks:
reproductive performance, fertility
Effect level:
>= 40 mg/m³ air
Based on:
test mat.
Sex:
male/female
Dose descriptor:
NOAEC
Remarks:
systemic toxicity
Effect level:
>= 40 mg/m³ air
Based on:
test mat.
Sex:
male/female
Dose descriptor:
LOAEC
Remarks:
local effects
Effect level:
16 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
dermal irritation
Dose descriptor:
NOAEC
Remarks:
local effects
Effect level:
4 mg/m³ air
Based on:
test mat.
Sex:
male/female
Critical effects observed:
no
Furthermore, there were no indications for test substance-induced intrauterine embryo-/fetolethality since the postimplantation loss did not show any significant differences between the test groups, and the mean number of F1 pups delivered per dam remained unaffected (9.3, 10.1, 11.6 and 10.7 pups per dam at 0, 4, 16 and 40 mg/m³, respectively). The rate of liveborn pups was not affected by the test substance, as indicated by live birth indices of 97% (test group 16 mg/m³) and 100% (all other test groups). Moreover, the number of stillborn pups was comparable between the test groups.
Dose descriptor:
NOAEC
Remarks:
developmental toxicity
Generation:
F1
Effect level:
>= 40 mg/m³ air
Based on:
test mat.
Sex:
male/female
Critical effects observed:
no
Reproductive effects observed:
no
Conclusions:
The NOAEC for reproductive performance and fertility in male and female Wistar rats was 40 mg/m³ (highest dose tested).
Executive summary:

2-(2-Aminoethoxy)ethanol was administered via inhalation to groups of 10 male and 10 female Wistar rats (F0 animals) at concentrations of 4, 16, and 40 mg/m³. For all F0 parental males, which were placed with females to generate F1 pups, copulation was confirmed. Thus, the male mating index was 100% in all test groups (0, 4, 16 and 40 mg/m³). Fertility was proven for most of the F0 parental males within the scheduled mating interval for F1 litter. One male of the 4 mg/m³ test group did not generate F1 pups. The apparently infertile male rat did not show histopathological findings that could explain infertility. Thus, the male fertility index was 90% in the 4 mg/m³ test group and 100% in all remaining groups including the control. This reflected the normal range of biological variation inherent in the strain of rats used for this study. All respective values were within the range of the historical control data of the test facility. The female mating index calculated after the mating period for F1 litter was 100% in all test groups (0, 4, 16 and 40 mg/m³). The mean duration until sperm was detected (GD 0) amounted to 3.1, 3.1, 2.7 and 3.3 days (0, 4, 16 and 40 mg/m³). All sperm positive rats delivered pups or had implants in utero with the exception of one low-dose female, that did not become pregnant. The female fertility index varied between 90% (4 mg/m³) and 100% (all other test groups). These values reflect the normal range of biological variation inherent in the strain of rats used for this study. All respective values were within the range of the historical control data of the test facility and did not show any relation to dosing. There were no corroborative histopathological findings in the sexual organs of the nonpregnant female rat. The mean duration of gestation values varied between 22.0 (test groups 4 and 16 mg/m³) and 22.2 days (test groups 0 and 40 mg/m³) without any relation to dosing. The gestation index was 100% in all test groups including the control. Implantation was not affected by the treatment since the mean number of implantation sites was comparable between all test substance-treated groups and the controls, taking normal biological variation into account (10.6, 11.1, 12.3 and 11.4 implants per dam at 0, 4, 16 and 40 mg/m³, respectively). Furthermore, there were no indications for test substance-induced intrauterine embryo-/fetolethality since the postimplantation loss did not show any significant differences between the test groups, and the mean number of F1 pups delivered per dam remained unaffected (9.3, 10.1, 11.6 and 10.7 pups per dam at 0, 4, 16 and 40 mg/m³, respectively). The rate of liveborn pups was not affected by the test substance, as indicated by live birth indices of 97% (test group 16 mg/m³) and 100% (all other test groups). Moreover, the number of stillborn pups was comparable between the test groups.

Thus, the NOAEC for reproductive performance and fertility in male and female Wistar rats was 40 mg/m³.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report date:
2010

Materials and methods

Test guideline
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 (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-(2-aminoethoxy)ethanol
EC Number:
213-195-4
EC Name:
2-(2-aminoethoxy)ethanol
Cas Number:
929-06-6
Molecular formula:
C4H11NO2
IUPAC Name:
2-(2-aminoethoxy)ethan-1-ol
Test material form:
liquid
Specific details on test material used for the study:
- purity 99.9%

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Male and female Wistar rats, strain Crl:WI(Han), supplied by Charles River Laboratories, Research Models and Services, UK

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose/head only
Vehicle:
clean air
Remarks on MMAD:
MMAD / GSD: 4 mg/m³ (n=2)
MMAD: 0.8-not detectable
SD: 2.5-not detectable

16 mg/m³ (n=2)
MMAD: 3.0-2.6
SD: 1.8-1.7

40 mg/m³ (n=2)
MMAD: 1.9-2.6
SD: 1.9-1.6
Details on inhalation exposure:
For each concentration the test substance was supplied to a two-component atomizer at a constant rate by means of an infusion pump. The aerosol was generated with compressed air mixed with conditioned dilution air and passed into the inhalation system.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentrations of the inhalation atmospheres were analyzed by gas chromatography in all test groups including control. Daily means were calculated based on 2 measured samples per concentration and exposure. From the daily mean values of each concentration, mean concentrations and standard deviations for the entire study were derived.
In the control group, one sample per exposure period was analyzed.
The analyses were carried out at the Analytical Chemistry Laboratory of the Experimental Toxicology and Ecology of BASF SE, Ludwigshafen, Germany.
Duration of treatment / exposure:
females: 46-48 days
males: 29 days
Frequency of treatment:
6 hours daily
Doses / concentrationsopen allclose all
Dose / conc.:
3.88 mg/m³ air (analytical)
Remarks:
± 0.63 mg/m3
Dose / conc.:
16.6 mg/m³ air (analytical)
Remarks:
± 3.1 mg/m3
Dose / conc.:
41.2 mg/m³ air (analytical)
Remarks:
± 6.5 mg/m3
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:
After 2 weeks of premating treatment the F0 animals were mated to produce F1 generation pups. Mating pairs were from the same test group. Mating was discontinued as soon as sperm was detected in the vaginal smear. F0 animals were examined for their reproductive performance including determination of the number of implantation sites and the calculation of postimplantation loss for all F0 females. A detailed clinical observation (DCO) was performed in all F0 animals before test substance administration and thereafter at weekly intervals. Food consumption of the F0 parents was determined regularly during premating and after the mating period and during the gestation and lactation periods in dams. In general, body weights of F0 an mals were determined once a week. During gestation and lactation period, F0 females were weighed on gestation days (GD) 0, 7, 14 and 20, on the parturition day (postnatal day [PND] 0) and on PND 4. Pups were sexed on PND 0 and weighed one day after birth and on PND 4. Their viability was recorded twice daily on each working day or only in the morning on Saturday and Sunday. Clinicochemical and hematological examinations as well as urinal ses were performed in 5 randomly selected F0 parental animals of either sex towards the end of the administration period. At the end of the administration period a functional observational battery was performed and motor activity was measured in 5 randomly selected F0 parental males and female per test group. All surviving F0 parental animals were sacrificed assessed by gross pathology. Organ weights were recorded and a histopathological examination was performed.
Sacrifice and pathology:
All F0 parental animals were sacrificed under pentobarbitone anesthesia by exsanguination from the abdominal aorta and vena cava. The exsanguinated animals were necropsied and assessed by gross pathology, special attention being given to the reproductive organs. All pups with scheduled sacrifice on PND 4 were sacrificed under isoflurane anesthesia with CO2. All pups were examined externally, eviscerated and their organs were assessed
macroscopically, paying particular attention to potential changes of pericardial blood vessels. All pups that die before schedule or were sacrificed in a moribund state were examined externally, eviscerated and their organs were assessed macroscopically, paying particular attention to potential changes of pericardial blood vessels.

Results and discussion

Effect levels

open allclose all
Dose descriptor:
NOAEC
Remarks:
systemic toxicity
Effect level:
>= 40 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed up to the highest tested dose.
Dose descriptor:
LOAEC
Remarks:
local effect
Effect level:
16 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
gross pathology
histopathology: non-neoplastic
Dose descriptor:
NOAEC
Remarks:
local effects
Effect level:
4 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed at this dose.
Dose descriptor:
NOAEC
Remarks:
reproductive performance and fertility
Effect level:
>= 40 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed up to the highest tested dose.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Under the conditions of this Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test the no observed adverse effect concentration (NOAEC) for general systemic toxicity as well as reproductive performance, fertility and developmental toxicity in male and female Wistar rats was 40 mg/m³. The NOAEC for local signs of toxicity in male and female Wistar rats was 4 mg/m³.
Executive summary:

2-(2-Aminoethoxy)ethanol was administered via inhalation to groups of 10 male and 10 female Wistar rats (F0 animals) at concentrations of 4, 16, and 40 mg/m³. Regarding clinical examinations, no signs of general systemic toxicity were observed in male and female parental animals at any dose level during the entire study period. During the exposure period, the target concentrations were maintained as constant and stable as could be provided with liquid aerosol generation techniques in the concentration range tested. Fertility indices for male and female animals were not impaired by test-substance administration even at a dose level of 40 mg/m³. In addition, live birth and viability indices of pups in all test groups were not influenced. Concerning clinical pathology no treatment-related, adverse effects were observed up to a dose level of 40 mg/m3. With regard to pathology, treatment-related microscopic changes were observed in larynx (level 1) and consisted of increased squamous metaplasia of the respiratory epithelium and chronic (active) inflammation at level 1 of the larynx only to a marginal or slight degree. This was observed in both sexes. Histopathological examination of the mid- and low-dose groups of the larynx at this level 1 revealed that these treatment-related findings (squamous metaplasia and chronic [active] inflammation) were also observed in the mid-dose group (16 mg/m³), however, to a lesser severity degree compared to the high-dose groups (40 mg/m³). Other macroscopic and/or microscopic changes observed were either non-dose related and/or considered to be normal background changes. No treatment-related changes were observed in both sexes at a concentration of 4 mg/m³.