Quaternary ammonium compounds, dicoco alkyldimethyl, nitrites

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

29 May, 1996 - 12 June, 1996

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 substance, didecyldimethylammonium chloride to quaternary ammonium compounds, di-C12-18-alkyldimethyl, nitrites.

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:

1996

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Test material

Test material information

Constituent 1

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:

The test substance contains ca. 50% didecyldimethylammonium chloride (CAS no.: 7173-51-5) and 20% isopropanol (CAS no.: 67-63-0) in water.

Test animals

Species:

rat

Strain:

Wistar

Remarks:

Wistar strain Crl:(WI) BR (outbred, SPF-quality)

Sex:

male/female

Details on test animals or test system and environmental conditions:

Species: Rat
Strain: Wistar strain Crl:(WI) BR (outbred, SPF-quality)
Source: Charles River, Sulzfeld, Germany.
Sex: Males and females
Age/weight at study initiation: Approx. 9 weeks, 373 g (mean males) and 240 g (mean females)
Number of animals per group: 5 males and 5 females
Control animals: No

Administration / exposure

Vehicle:

water

Details on dermal exposure:

Postexposure period: 15 days
Type: Dermal
Concentration: 2000 mg/kg bw for 24 hours (dose volume: 10 ml/kg in distilled water)
Vehicle: Distilled water
Concentration in vehicle: 200 mg/ml (20%)
Total volume applied: 10 ml/kg
Controls: No

Doses:

Limit test at 2000 mg/kg bw.

No. of animals per sex per dose:

10

Control animals:

no

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 1 000 mg/kg bw

Based on:

act. ingr.

Clinical signs:

other: Lethargy was noted in all animals, between days 2 and 4. Hunched posture was observed in four females between days 2 and 6. Skin effects in the treated area: Swelling, necrosis and hardening of the back, scabs and brown skin on the back were noted in all

Gross pathology:

No abnormalities were found at macroscopic post mortem examination Of the animals.

Other findings:

At removal of the bandages (day 2) it was noticed that the bandages of two Females (number 9 and 10) had shifted caudally.
The clinical signs shown by these animals were not significantly different compared to the other females. The exposure to the test
substance was therefore considered sufficient.

Any other information on results incl. tables

No mortality occurred. Effects noted were lethargy in all animals between day 2 and 4 and skin effects which consisted of swelling, redness, erythema and necrosis of the skin. The majority of the skin effects persisted until the end of the observation time. No abnormalities were found at macroscopic post mortem examination.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The acute dermal LD50 of the test substance in rats was determined to be >2000 mg/kg bw (i.e. >1000 mg a.i./kg bw).

Executive summary:

A study performed was performed according to GLP and OECD 402 and EU B.3 “Acute Dermal Toxicity” to investigate the dermal toxicity of the test item.

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

Five male and five female rats received a dermal dose of 2000 mg/kg bw for 24 h (dose volume: 10 ml/kg in distilled water) under occlusive dressing for 24 h. One day before exposure (day -1) an area of approximately 5x7 cm on the back of the animal was clipped.
24 h, after which dressings were removed and residual test substance removed using a tissue moistened with tap water.

Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice on day 15.

No mortality occurred. Effects noted were lethargy in all animals between day 2 and 4 and skin effects which consisted of swelling, redness, erythema and necrosis of the skin. The majority of the skin effects persisted until the end of the observation time. No abnormalities were found at macroscopic post mortem examination. Effects are limited to local irritation/corrosion of the skin, without involvement of systemic toxicity.

The acute dermal LD50 of the test substance in rats were determined to be >2000 mg/kg bw (i.e. >1000 mg a.i./kg bw).

As quaternary ammonium compounds do not easily pass biological membranes, dermal absorption of these compounds is very limited. The dermal toxicity of aqueous DDAC solutions is related to its corrosivety and therefore more related to the concentration of the administered solution than of the actual amount in mg/kg. Due to the direct corrosive effect, there is danger of irreversible damage to the skin upon exposure to the undiluted solution. Further toxicity is secondary to the local tissue damage, rather than the result of percutaneously absorbed material. Some reviews mention comparable dermal LD₅₀data in rat from literature which is in the range 2000 – 3000 mg/kg bw.

Toxicity is related to concentration dependent cytotoxicity, with a lack of specific systemic toxicity. The toxicity (and efficacy as based on same mechanism of action) show a dependence on chain length, with an optimum at C₁₀-C₁₂. Therefore this test using C₁₀-chainlength can be seen as worst case representative for the whole group of DDAC compounds between C₈and C₁₈.

Furthermore, additional tests for acute dermal toxicity are not ethical due to its corrosive effects and can thus not be performed.