Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
(1996)
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann, Borchen, Germany
- Strain: Hsd Cpb:WU
- Age at study initiation: 8-10 weeks old
- Weight at study initiation: mean weight 216 g (for males) and 187 g (for females)
- Fasting period before study: 16-17 h
- Housing: in goups of 3 animals
- Diet and Water: ad libitum
- Acclimation period: at least 5 days
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
Application volume: 10 ml/kg bw
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations: several times on the day of administration, and at least once daily during the observation period.
- Frequency of weighing: directly before administration, after one week (only females) and at the end of the observation period or after death.
- Necropsy of survivors performed: yes
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No mortality was observed after the application or during the 15-days post-application period.
Clinical signs:
No signs of intoxication occured during the observation time at all animals.
Body weight:
Body weight development of male and female rats was not affected.
Gross pathology:
The animals sacrificed at the end of study showed no noticeable gross pathological findings.
Other findings:
None
Executive summary:

An oral toxicity study (OECD TG 423) with a starting dose of 2000 mg/kg bw was performed with 3 male and 3 female rats. No mortality, no clinical signs and no gross pathological findings were observed after application of the test substance in the 15-days observation period. Therefore, the LD50 was estimated to be > 2000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan-Winkelmann, Borchen, Germany
- Strain: Hsd Cpb:WU (SPF)
- Age at study initiation: animals of the weigth class used are 2-3 months old
- Housing: singly
- Diet and Water: ad libitum
- Acclimation period: at least 5 days
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure chamber volume: internal volume 3.8 L
- Mode of exposure: directed flow nose-only exposure
- Generation of athmospheres: In order to increase the efficiency of the generation of respirable particles and to prevent larger particles from entering the chamber a preseparator/baffle system was used. Under dynamic conditions the test substance was nebulized into a baffle (pre-separator) from which the substance was conveyed into the intake of the cylindrical inhalation chamber. The test substance was nebulized using a binary nozzle with conditioned compressed air.

TEST ATMOSPHERE
- Samples taken from breathing zone: yes
- Brief description of analytical method used: gravimetric and analytical. For analytical method: The test atmosphere was determined by gas chromatography after sampling on Florisil.

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: analysed using a Berner-Type Aeras low-pressure critical orifice cascade impactor. Aerosol mass < 3 µm:80.7%.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 1.73 µm/1.89
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
5000 mg/m³ (target concentration)
4492 mg/m³ (analytical concentration)
4923 mg/m³ (gravimetrical concentration)
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Body weights measured before exposure, on days 3 and 7, and weekly thereafter. Appearance and behaviour of each rat examined carefully several times on the day of exposure and at least once daily thereafter, except on weekend (once daily).
- Necropsy of survivors performed: yes
- Other examinations performed: examinations of reflexes, rectal temperature (directly after cessation of exposure)
- Control animals: exposed to conditioned air.
Statistics:
Analysis of variance (ANOVA).
For necropsy findings: pair-wise Fisher test after the R x C chi-squared test, in accordance with Gad and Weil (1982).
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 4 923 mg/m³ air
Exp. duration:
4 h
Sex:
male/female
Dose descriptor:
other: NO(A)EL
Effect level:
< 4 923 mg/m³ air
Exp. duration:
4 h
Remarks on result:
other: basis for effect level: mild and transient irritation on the respiratory tract
Mortality:
No mortality was observed after exposure to concentrations up to and including 4923 mg/m³.
Clinical signs:
other: Clinical signs were reduced motility, piloerection, ungroomed hair-coat, bradypnea, and labored breathing pattern. All signs resolved within the first three postexposure days.
Body weight:
Compared to control animals the test substance caused a mild and transient decrease in body weigth gain.
Gross pathology:
Necropsy findings were unobtrusive.
Other findings:
A mild statistically significant decrease in body temperature was observed, giving further evidence for a mild upper respiratory tract irritation potential of the substance (reflex changes in breathing pattern induced by upper respiratory tract irritants are associated with a decline in the metabolic rate and body temperature of rodents based on published evidence; see Jaeger and Gearhart, Toxicology 25, 299-309, 1982; Mautz and Bufalino,Respiration Physiology, 76, 69-78, 1989).
Executive summary:

An acute inhalation toxicity study with the test item was performed on Wistar rats according to OECD TG 403. In this study the animals were nose only exposed to the aerolized substance at the targeted limit concentration of 5000 mg/m³ (gravimetrical concentration 4923 mg/m³). Animals exposed to conditioned air under otherwise identical conditions served as control. The test substance aerosol was of adequate respirability (MMAD 1.73 µm; GSD 1.89).

No mortality occurred in the course of the study. Signs (reduced motility, piloerection, ungroomed hair-coat, bradypnea, labored breathing pattern, decrease in body weight gain, and mild decrease in body temperature) were transient and resolved within the first three postexposure days. Necropsy findings were unobtrusive. Experimental evidence suggests that the aerosol is apparently a mild upper respiratory tract irritant (characteristic reflex changes in breathing patterns). Based on this study the LC50 (4h) of the substance is > 4923 mg/m³ and the NO(A)EL (4 h) < 4923 mg/m³.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating conc.
Value:
4 923 mg/m³

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Based on an acute oral toxicity study in rats according to OECD TG 423 the LD50 of the substance is > 2000 mg/kg bw. In this study no mortality, no clinical signs and no gross pathological findings were observed.

Acute dermal toxicity studies were not available.

No mortality occurred in an acute aerosol inhalation toxicity study according to OECD TG 403 up to the targeted limit concentration of 5000 mg/m³ (gravimetrical concentration 4923 mg/m³). Signs (reduced motility, piloerection, ungroomed hair-coat, bradypnea, labored breathing pattern, decrease in body weight gain, mild decrease in body temperature) were transient and resolved within the first three postexposure days. Necropsy findings were unobtrusive. Experimental evidence suggests that the aerosol is apparently a mild upper respiratory tract irritant (characteristic changes in breathing patterns). Based on this study the LC50 (4h) is > 4923 mg/m³ and the NO(A)EL (4 h) < 4923 mg/m³.


Justification for selection of acute toxicity – oral endpoint
Only one study available

Justification for selection of acute toxicity – inhalation endpoint
Only one study available

Justification for classification or non-classification

No classification is warranted for acute oral and inhalation toxicity according to Regulation (EC) No 1272/2008, Annex I.

No classification is also warranted for acute dermal toxicity. Although no acute dermal toxicity study is available an assessment of this endpoint is possible based on the available information:

The substance has a low acute toxicity (LD50 > 2000 mg/kg bw; LC50 > 4923 mg/m³), with slight signs of respiratory tract irritation as the only effect. It is noteworthy that there does not appear to be any route-dependent systemic toxicity by reviewing the results of the acute oral and inhalation toxicity studies. Oral repeated dose toxicity studies revealed a NOAEL of 200 mg/kg bw/day with only mild effects (cortical tubular vacuolation, considered to be due to a storage process) at the next higher dose of 1000 mg/kg bw/day. With the expectation that systemic availability after dermal exposure will not exceed systemic availability after oral exposure and taking into account the toxicity profile of the substance (low toxicity and no apparent route-dependent toxicity), it is not expected that testing on acute dermal toxicity would lead to a hazard classification for the substance. Therefore, it can be concluded that the available data are conclusive for non-classification of acute dermal toxicity.

This is in line with the publicly available ECHA Endpoint specific guidance Draft Version 5.0 (Public) – October 2015, Chapter R.7a: “In some cases, it may be possible to draw conclusions about the potential for acute dermal toxicity without further testing, on the basis of the data available from acute oral toxicity and/or dermal absorption studies” and further published literature (Moore, Regulatory Toxicology and Pharmacology, 2013, 66, 30-37; Creton, St. et al, Critical reviews in Toxicology, 2010, 40, No.1, 50-83).