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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

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

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 1,2-Propylendiamin techn.
- Physical state: liquid
- Analytical purity: > 99.0 %
- Impurities (identity and concentrations): 0.24 % water
- Lot/batch No.: Tank 41 D439 1,2-PDA techn.
- Expiration date of the lot/batch: 2011-08-04
- Storage condition of test material: Room temperature

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Sulzfeld, Germany
- Age at study initiation: about 8 weeks
- Weight at study initiation: mean body weight: 244 g (male), 167 g (female)
- Housing: 5 animals per cage in Polysoldon cages on Type Lignocel fibres (dustfree bedding) with wooden gnawing blocks
- Diet: mouse/rat laboratory diet “GLP”, 10 mm pellets (Provimi Kliba SA, Kaiseraugst, Basel Switzerland) ad libitum
- Water: tap water ad libitum
- Acclimation period: 9-10 days

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

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose/head only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: aerodynamic exposure system (cylindrical inhalation chamber made of stainless steel sheeting and cone-shaped outlets and inlets
- Method of holding animals in test chamber: glass exposure tubes
- System of generating vapors: thermostated vaporizer with thermostat and continous infusion pumps
- Air flow rate: 1.5 m³/h

TEST ATMOSPHERE
- Brief description of analytical method used: HPLC
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
6 h per day
Frequency of treatment:
20 exposures (5 days per week for 4 weeks)
Doses / concentrationsopen allclose all
Dose / conc.:
5 mg/m³ air (analytical)
Dose / conc.:
18.5 mg/m³ air (analytical)
Dose / conc.:
100 mg/m³ air (analytical)
No. of animals per sex per dose:
5
Control animals:
yes

Examinations

Observations and examinations performed and frequency:
Mortality, Clinical observations, Body weight data, Food consumption, Ophtalmology
Sacrifice and pathology:
Clinical pathology (hematology, clinical chemistry), Pathology (necropsy, organ weights, histology)
Statistics:
Dunnett´s test, Kruskal-Wallis test, Wilcoxon test

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
The body weight change of the male and female animals of the low concentration (5 mg/m³) was significantly slightly increased on study days 17-21 in males and 24-28 in females compared to controls. These results are regarded as incidental and not treatment related because no dose realationship could be detected.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Spontaneous findings such as remainders of the pupillary membrane or corneal stippling were observed in several animals of all test groups and the control group without any concentration-response relationship.
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
In male rats of test group 1 and 3 (5 and 100 mg/m³) the relative monocyte counts were lower compared to controls. This decrease was not dose-dependent and it was the only deviated parameter in hematology. Therefore, it was regarded as incidental rather than treatment-related.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
In females of all dose groups the glucose level was higher compared to controls. The increase was not dose dependent and it was not accompanied by an alteration of any other clinical pathology parameter. Therefore, this alteration was regarded as incidental and not treatment-related.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
Compared to the control group (group 0), there were no significant absolute mean organ weight changes observed in both sexes with the exception of intermediate group 2 female thymus weights only. This was significantly decreased compared to the control group. However, this was considered to be a non-dose related incidental finding with no relation to treatment.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
- Changes were observed in the mucosa of the nose in the high-dose group (100 mg/m³) animals of both sexes ( Acute inflammation and/or degeneration in the olfactory/respiratory epithelium and atrophy and/or necrosis (largely of olfactory epithelium)).
- Erosion/ulceration of the olfactory epithelium was observed in the high-dose animals of both sexes as well.
- Suppurative exudate was also observed in the nasal cavity of high-dose animals and in one male intermediate-dose animal.
- At the intermediate-dose level of 20 mg/m³ (test group 2), acute inflammation and degeneration were also observed as well as some occasional necrosis, however, all to a lesser severity degree compared to the high-dose group. No erosion/ulceration or atrophy of the olfactory epithelium was observed at this dose level.
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed

Effect levels

open allclose all
Dose descriptor:
NOAEC
Effect level:
100 mg/m³ air
Sex:
male/female
Basis for effect level:
other: for systemic toxicity
Dose descriptor:
NOAEC
Effect level:
5 mg/m³ air
Sex:
male/female
Basis for effect level:
other: for local effect in nasal cavity

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Due to lack of any exposure-related systemic toxicity, the NOAEC for systemic toxicity of the test substance was 100 mg/m³ (highest dose). Due to exposure-related local effects in the nasal cavity, observed in a concentration-related manner, the NOAEC for local effects was 5.0 mg/m³ (lowest dose).
Executive summary:

To determine the potential toxicity of the test substance after inhalation exposure, a 28-day inhalation study was carried out according to OECD 412 and EC No 440/2008. Wistar rats, 5 male and 5 female animals per test group, were head-nose exposed to vapor on 6 hours per day, on 5 consecutive days per week for 4 weeks (20 exposures). The target concentrations were 5, 20 and 100 mg/m³ test substance in synthetic air. On each exposure day clinical examination was performed before, during and after exposure. Body weight was determined prior to the preflow period at the start of exposure and twice weekly (Monday + Friday) during exposure period. Food consumption of the animals was determined weekly. After the last exposure, blood was sampled from the animals, hematology and clinical chemistry parameters were determined as indicated in the guideline. The animals were then subjected to gross necropsy (including macroscopic examination of the major internal organs and collection of organ weight data). Selected tissues were processed histopathologically and were evaluated by light microscopy.

Inhalation exposure of rats to the test substance for 28 day (20 exposures) did not lead to any exposure-related systemic toxicity as indicated by clinical chemical, hematological examinations of the blood as well as histological examinations at termination of the study. Local effect in the nasal cavity comprised acute inflammation, degeneration, atrophy, erosion/ulceration, necrosis of the epithelium (olfactory/respiratory epithelium) and suppurative exudate in the lumen. These effects were observed in a concentration-related manner.

Under the current test conditions, the No Observed Adverse Effect Concentration (NOAEC) for systemic toxicity was the highest tested concentration of 100 mg/m³, the NOAEC for local effect in nasal cavity was 5.0 mg/m³.