Registration Dossier

Administrative data

Endpoint:
repeated dose toxicity: oral
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
a short-term toxicity study by the oral route does not need to be conducted because an appropriate inhalation study is available and inhalation is the most appropriate route of administration as based on the provided thorough and rigorous exposure assessment
Cross-reference
Reason / purpose:
data waiving: supporting information
Reference
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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP; guideline study according to OECD 422
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals 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:
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
Remarks:
Doses / Concentrations:
0; 3.88±0.63; 16.6±3.1; 41.2±6.5 mg/m3
Basis:
analytical conc.
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
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.
Dose descriptor:
NOAEC
Effect level:
40 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: general systemic toxicity; reproductive performance and fertility
Dose descriptor:
NOAEC
Effect level:
4 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: local effects
Critical effects observed:
not specified
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.

Data source

Materials and methods

Results and discussion

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion