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Acute Toxicity: inhalation

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Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Read across justification is presented from the structurally analogous quaternary ammonium compounds, di-C12-18-alkyldimethyl, chlorides to the quaternary ammonium compounds, di-C12-18-alkyldimethyl, nitrites.

In the stomach the gastic juice is acidic, made up of acids and enzymes. In such an evironment it is highly unlikely that the quaternary ammonium compounds, di-C12-18-alkyldimethyl, nitrites substance (s) will remain ionically bound to each other and thus are prone to dissociation in which case the released cation(s) will associate with other anions and the released anion will associate with cations. Thererfore, it is suggested read-across that data from the corresponding quaternary ammonium compounds, di-C12-18-alkyldimethyl, chlorides is considered approriate in that such substances are likely to dissociate in a similar manner.

Furthermore, in 1988, the US EPA, Office of Pesticides and Toxic Substances issued a Notice to producers, Formulators, Distributors and Registrants regarding quaternary ammonium compounds with regard to "Clustering" of such quaternary ammonium compounds.

Prior to this, EPA had required each quat compound to be individually coded and registered as a new chemical, even when the chemical structure of individual compounds differed only slightly in alkyl distribution and chain lengths. This procedure was continued with the new generations of quats having two, three, and four chains. As a result, EPA records showed that some 211 registered technical grade active ingredient products containing varying concentrations of Quats, each coded separately on the basis of alkyl chain length and percentage carbon distribution within the chain. At this time, there are approximately eight to ten thousands (8-10,000) registered end-use formulations.

However, questions were raised regarding whether the EPA could cluster or group the quats and pick one or more representative members of each cluster to be used in toxicity studies, instead of requiring separate studies on each quat. These same questions were raised when the EPA issued its March 4, 1987 Data Call-In Notice requiring all registrants of antimicrobial active ingredients to submit subchronic and chronic toxicological data to support the continued registration of their products.

In response to these questions, EPA·solicited information from industry, the public, academia, industry cooperative work groups, the state of California, and Canada. EPA then reviewed all of the assembled information along with the chemical structure of most of the quats. Based on the results of this review, EPA developed the following four groupings of currently registered quat compounds:

Group I. The alkyl or hydroxyalkyl (straight chain) substituted Quats
Group II. The non-halogenated benzyl substituted Quats (includes hydroxybenzyl, ethylbenzyl, hydroxyethybenzyl, napthylmethyl, dodecylbenzyl, and alkyl benzyl)
Group III. The di-and tri-chlorobenzyl substituted
Group IV. Quats with unusual substituents (charged heterocyclic ammonium compounds).

Fundamental to this discussion EPA determined that "X-" in all of these structures would be attributed to "any anionic species". Therefore, this would mean in terms of toxicological evaluation the coutner anion in such quaternary ammonium compounds could be regarded as; e.g halogen (Cl-, Br-, I-,), saccharinate or cyclohexylsulphamate. It is therefore suggested here that nitrite (NO2-) could also be regarded as a pertinent anion.

Since the US EPA deem that such a clustering of structures for toxicological evaluation is well founded then it would seem that to consider read-across data from quaternary ammonium compounds, di-C12-18-alkyldimethyl, chlorides to the closely structurally analogous quaternary ammonium compounds, di-C12-18-alkyldimethyl, nitrites to be equally justifiable.

Furthermore, in certain organic solvents it has been reported that the exchange constants between nitrite and chloride in quaternary ammonium salts (QAS) are approximately equal. [Zhurnal Analiticheskoi Khimii, 2010, Vol. 65, No. 6, pp. 579–584. (E.M. Rakhman’ko, M.S. Markovskaya, L.S. Stanishevskii, Yu.S. Zubenko, A.R. Tsyganov)]


Cross-reference
Reason / purpose for cross-reference:
read-across: supporting information

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
not specified
Qualifier:
according to guideline
Guideline:
EPA OPP 81-3 (Acute inhalation toxicity)
Deviations:
not specified
GLP compliance:
yes
Test type:
other: Standard acute method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Didecyldimethylammonium chloride
EC Number:
230-525-2
EC Name:
Didecyldimethylammonium chloride
Cas Number:
7173-51-5
Molecular formula:
C22H48N.Cl
IUPAC Name:
Didecyldimethylammonium chloride
Test material form:
liquid
Specific details on test material used for the study:
- Name of test material (as cited in study report): Armoblen 400
- Composition of test material, percentage of components:- cocobenzyldimethylammoniumchloride: 40% w/v, dicocodimethylammoniumchloride: 37.5% w/v, total amount of quarternary ammonium compounds:77.3% w/v, water: 7.7%
- Purity test date: 21 December 1989
- Batch No.: RCD/VRE-55
- Expiration date of the lot/batch: December 1990
- Storage condition of test material: In dark at room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River UK Ltd., Margate, UK
- Weight at study initiation: ca. 200 g on the day of exposure
- Housing: 5/sex in polypropylene cages with detachable wire mesh tops and floors
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 d


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24
- Humidity (%): 35-65


IN-LIFE DATES: From: 21 February 1990 To: 30 April 1990

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: Unchanged (no vehicle)
Remark on MMAD/GSD:
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.):
0.34 mg/L : MMAD 1.9 µm, gsd 3.5
0.17 mg/L : MMAD 1.1 µm, gsd 2.7
0.24 mg/L : MMAD 0.8 µm, gsd 0.8

Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Perspex whole body chamber (square section with pyramidal top)
- Exposure chamber volume: ca. 120 L
- Method of holding animals in test chamber: Wire mesh partitions to provide 10 separate animal compartments
- Source of air: Filtered and oil-free compressed air
- Method of conditioning air: Dried
- System of generating particulates/aerosols: Atomiser
- Method of particle size determination: Cascade impaction (Andersen mini-sampler & Marple cascade impactor (model 296))
- Treatment of exhaust air: Passage through a collection filter
- Temperature, humidity, pressure in air chamber: Temperature measured at 30-min intervals (22-23 ºC ), relative humidity not measured (reason: aqueous solution). However, as dried air was used and the test material contained only 7.7 % water, relative humidity could have been measured. Pressure in air chamber: not indicated. However, as the whole body chamber was placed in a hood, this is not as important.

TEST ATMOSPHERE
- Brief description of analytical method used:
Five air samples (5 L for Groups 2 and 4 (0.34 and 0.24 mg/L), 10 L for Group 3 (0.17 mg/L)) were taken from the chamber during each exposure and the collected material was analysed to determine the concentration of Armoblen 400 in the chamber air. Each air sample was withdrawn, at 4 L/min, through a weighed glass fibre filter (Whatman GF/A) mounted in an open face filter holder. The volume of the air sample was measured with a wet-type gas meter. Two further air samples were taken using an Andersen mini-sampler or a series 290 Marple cascade impactor (Model 296), and the collected material was weighed to determine the particle size distribution of Armoblen 400. The samples were taken at approximately 1.5 and 3.5 h from the start of exposure. The filters from the open face sampler were transferred to extraction columns and compacted with a glass rod. The Armoblen 400 was eluted with five 2 mL portions of methanol into a 20 mL volumetric flask and diluted to volume with methanol.
The filters from the Andersen and Marple samplers were similarly treated to give a final volume of 5 mL. The stages of the Andersen and Marple samplers were washed off with small amounts of methanol into 5 mL volumetric flasks. The extracts were diluted with mobile phase to obtain solutions for HPLC-analysis with expected maximum concentrations of Armoblen 400 of 150 pg/mL.

- Samples taken from breathing zone: Taken from the whole body chamber.

TEST ATMOSPHERE (if not tabulated)
-Concentrations:
0.34 mg/L (± 6%); nominal: 2.21 mg/L
0.17 mg/L (± 13%); nominal: 0.52 mg/L
0.24 mg/L (± 17%); nominal: 0.88 mg/L

- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.):
0.34 mg/L : MMAD 1.9 µm, gsd 3.5
0.17 mg/L : MMAD 1.1 µm, gsd 2.7
0.24 mg/L : MMAD 0.8 µm, gsd 0.8

Analytical verification of test atmosphere concentrations:
yes
Remarks:
HPLC
Duration of exposure:
ca. 4 h
Concentrations:
0, 0.17, 0.24 and 0.34 mg/L
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 21 d
- Frequency of observations and weighing: Observations continuously during exposure and at least twice daily thereafter; body weight daily
- Food and water intake: Daily
- Necropsy of survivors performed: Yes
- Other examinations performed: Lung weight, histopathology of lungs, liver and kidneys
Statistics:
LC50 determination by log probit method of Miller LC and Tainter ML, Proc Soc Exp Bio Med 57 (2), 1944: 261-264

Results and discussion

Preliminary study:
Not applicable
Effect levelsopen allclose all
Key result
Sex:
male
Dose descriptor:
LC50
Effect level:
0.22 mg/L air (analytical)
Based on:
test mat.
95% CL:
> 0.17 - < 0.27
Exp. duration:
4 h
Key result
Sex:
female
Dose descriptor:
LC50
Effect level:
0.28 mg/L air (analytical)
Based on:
test mat.
95% CL:
> 0.21 - < 0.35
Exp. duration:
4 h
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
0.25 mg/L air (analytical)
Based on:
test mat.
95% CL:
> 0.22 - < 0.28
Exp. duration:
4 h
Mortality:
Control group: 0/10
0.17 mg/L: 1 male (1/10)
0.24 mg/L: 3 males and 1 female (4/10)
0.34 mg/L: 5 males and 4 females (9/10)
Clinical signs:
other: The signs seen during exposure were considered to be consistent with inhalation of an irritant aerosol. Closing or partial closing of the eyes and exaggerated respiratory movement were seen in all rats exposed to test material. Additional signs observed i
Body weight:
There were moderate to marked decreases of bodyweight or reductions in the rate of bodyweight gain for up to 8 d in male rats and for up to 14 d in female rats following exposure at 0.17 mg/L or 0.24 mg/L. Subsequently weight gain for rats that survived exposure to test material was similar to that of the control rats.
Gross pathology:
The findings for rats that died as a result of exposure to test material were typified by congestion of the lungs, fluid in the tracheae and gas-filled stomachs. Macroscopic abnormalities in a proportion of rats that survived exposure to test material were a swollen appearance of the lungs and gas-filled stomachs and intestines.
Other findings:
The food and water consumption for the rat that survived exposure at 0.34 mg/L was variable and reduced. Food consumption was reduced for up to 12 d following exposure to Armoblen 400 at concentrations of 0.24 or 0.17 mg/L. The water consumption for these groups was reduced for up to 14 d following exposure. The lung weight to bodyweight ratio was increased, due to a high lung weight, for most rats that died as a result of exposure to test material.

Histopathology
Group 2 (0.34 mg/L)
Decedents
Treatment-related changes were seen in the 5 male and 4 female decedents. The distribution of these lesions was as follows: focal alveolar wall necrosis in 3 males; diffuse congestion in 3 males and 4 females; eosinophilic material in alveoli in 5 males and 4 females; alveolitis in 2 males and 4 females; focal alveolar oedema in 1 male; perivascular oedema in 4 males.
Survivors
Treatment-related changes were seen in the single female rat surviving to the end of the observation period. These were as follows: focal alveolitis; focal bronchiolitis; prominent bronchiolar goblet cells.

Group 3 (0.17 mg/L)
Decedents
Treatment-related changes were seen in the single decedent male. These were as follows: diffuse congestion; eosinophilic material in alveoli; alveolitis; focal alveolar oedema.
Survivors
Treatment-related changes were seen in one of the 4 males and in one of the 5 females surviving to the end of the observation period. The distribution of these lesions was as follows: focal bronchiolitis in 1 male; prominent bronchiolar goblet cells in 1 male; foreign body giant cells in 1 male; focal alveolar haemorrhage in 1 female. A focus of emphysema was also seen in one surviving female. The significance of this finding in a single animal is unclear, but possibility that it is related to treatment cannot be excluded. No abnormalities were detected in 3 males and 3 females surviving to the end of the observation period.

Group 4 (0.24 mg/L)
Decedents
Treatment-related changes were seen in the 3 male decedents and 1 female decedent. The distribution of these lesions was as follows: diffuse or focalcongestion in 2 males and 1 female; eosinophilic material in alveoli in 2 males and 1 female; alveolitis in 1 male and 1 female; focal alveolar oedema in 1 male; focal alveolar haemorrhage in 1 female; perivascular oedema in 1 female.
Survivors
Treatment-related change was seen in one of the two males and one of the 4 females surviving to the end of the observation period. This lesion was: foreign body giant cells. No abnormalities were detected in 1 male and 3 females surviving to the end of the observation period.

Applicant's summary and conclusion

Interpretation of results:
Category 2 based on GHS criteria
Conclusions:
Under the test conditions, the acute 4 h LC50 of the test material (containing cocobenzyldimethylammoniumchloride - 40% w/v, dicocodimethylammoniumchloride - 37.5 % w/v and water - 7.7 %) was found to be 0.25 mg/L (0.22 -0.28 mg/L) and it is classified as Category 2 according to CLP Regulation (EC 1272/2008).
Executive summary:

The acute inhalation toxicity of the test substance (containing cocobenzyldimethylammoniumchloride - 40% w/v, dicocodimethylammoniumchloride - 37.5 % w/v and water - 7.7 %) was investigated in a syudy conducted according to OECD guideline 403 and EPA-Guideline 81 -3 in compliance with GLP.

The study was assigned a reliability score of 1 in accordance with the criteria for assessing data quality set forth by Klimisch et al. (1997).

Four groups of ten rats each (five males and five females) were given a single, 4 h whole body exposure at concentration levels of 0, 0.17, 0.24 and 0.34 mg/L. The animals were observed for 21 d after the day of exposure and were then killed for gross and histopathological examination of the lungs. Body weight, food and water intake and lung weight were also determined.

There were no deaths in the control group; one animal (male) died at 0.17 mg/L, four animals died at 0.24 mg/L (3 males, 1 female), and nine animals died at 0.34 mg/L (5 males, 4 females). Clinical signs of toxicity noted were (partial) closing of the eyes and exaggerated respiratory movement during exposure in all test groups and gasping and wetness around the mouth during exposure at 0.34 mg/L. Clinical signs were noted in survivors throughout the 21 d observation period. Decrease of body weight, reduced body weight gain and reduced food and water intake was generally seen up to 14 d.

Abnormalities noted at necropsy in survivors were increased relative lung weight, swollen appearance of the lungs and gas-filled stomach and intestines. Animals that died showed congestion of the lungs, fluid in the trachea and gas-filled stomachs. Histopathological lung changes in survivors generally consisted of focal alveolitis and bronchiolitis; changes in deceased animals generally consisted of focal alveolar wall necrosis, diffuse congestion, focal alveolar wall oedema and focal alveolar wall haemorrhage.

Under the test conditions, the acute 4 h LC50 of the test material (containing cocobenzyldimethylammoniumchloride- 40% w/v, dicocodimethylammoniumchloride-37.5 % w/v and water 7.7 %) was found to be 0.25 mg/L (0.22 -0.28 mg/L) and it is classified as Category 2 according to CLP Regulation (EC 1272/2008).

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