Quaternary ammonium compounds, di-C12-18-alkyldimethyl, chlorides

Endpoint summary

Description of key information

The oral LD50 value of the test substance was determined to be 720 mg a.i./kg bw in rats, suggesting a moderate acute toxicity potential.

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

Study period:

From June 11, 1980 to August 13, 1980

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Principles of method if other than guideline:

Not applicable

GLP compliance:

no

Remarks:

Pre-GLP

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Sprague-Dawley, Madison, USA
- Age at study initiation: approximately 7 wk
- Weight at study initiation: 202-300 g
- Fasting period before study: Overnight
- Housing: 5 animals/sex/cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 7 d

ENVIRONMENTAL CONDITIONS
The animals were kept in temperature and humidity controlled quarters

IN-LIFE DATES: From: June 11, 1980 To: August 13, 1980

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED:
The average specific gravity of test substance was 890 mg/mL and the highest dose level was 3200 mg/kg bw. The maximum volume given to the animals was, therefore, 2.85 mL/kg bw.

Doses:

270, 430, 670, 1050, 1310, 2050 and 3200 mg/kg bw

No. of animals per sex per dose:

8

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 d
- Frequency of observations and weighing: animals were observed 1, 2.5, and 4 h after dosing. After that the animals were observed daily for clinical signs and twice daily for mortality. The bodyweight of the animals were determined at Day 0, 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: no

Statistics:

No data

Preliminary study:

Not applicable

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

ca. 930 mg/kg bw

95% CL:

ca. 750 - ca. 1 140

Remarks on result:

other: equivalent to 698 mg a.i./kg bw (563 - 855)

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

ca. 1 000 mg/kg bw

95% CL:

ca. 250 - ca. 4 090

Remarks on result:

other: equivalent to 750 mg a.i./kg bw (188 - 3068)

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

ca. 960 mg/kg bw

95% CL:

ca. 630 - ca. 1 470

Remarks on result:

other: equivalent to 720 mg a.i./kg bw (473 - 1103)

Mortality:

No rats died in the 270 and 430 mg/kg bw groups. All rats died in the 2050 and 3200 mg/kg bw groups. There was a decreased level of mortality in the females at 1310 mg/kg bw compared to the two lower doses and to males at the same dose.

Clinical signs:

other: Clinical signs such as diarrhoea, red stained around nose and mouth, hair loss, ataxia, decreased limb tone and hypoactivity were reported during the course of the study in most animals in the 670 mg/kg bw, 1050 mg/kg bw, 1310 mg/kg bw, 2050 mg/kg be and

Gross pathology:

- The major signs reported at necropsy in animals that died during the study were external signs of diarrhoea and bloody discharge from the nose eyes and mouth.
- Adhesions involving the stomach and surrounding structures were seen at 1310 mg/kg bw, and were thought to suggest the presence of an inflammatory lesion involving the entire wall of the stomach with extension from the gastric serosa to adjacent tissues and healing fibrosis.
- Animals which received the higher dosage levels and died on test sooner possibly did not have adequate time for the lesion to develop. All other observations were considered incidental and not test related. A number of females that died during the study were partially cannibalised.

Other findings:

Dosage level of 270 mg/kg bw
Sixteen rats (eight male, eight female) were euthanized at the termination of the study and necropsied. Five of the males had lesions observed in the lungs which varied from red or white, pinpoint foci to a dark red, firm lobe. These lesions were noted to involve either the whole lung or a portion of one-lobe. The stomach in one female was noted to have a mildly thickened cardia mucosa. There were no visible lesions observed in the remaining animals.

Dosage level of 430 mg/kg bw
Sixteen rats (eight male, eight female) were euthanized at the termination of the study and necropsied. The lungs in one male were noted to have mild, diffuse, pinpoint, white, raised areas. Two females were noted to have mild hydromecra. There were no visible lesions observed in the remaining animals.

Dosage level of 670 mg/kg bw
Sixteen rats (eight male, eight female) were euthanized at the termination of the study and necropsied. Three males and five females died on test (DOT). One male DOT animal was noted to have a 4 mm crusty lesion on the skin of the right flank and the gastrointestinal tract distended with gas. The other two DOT male animals had a bloody nasal discharge and external signs of diarrhea (perianal fecal staining). Three of the DOT female animals had been partially cannibalized. The lungs in one of these three were noted to be mottled red to dark red and wet. Of the five DOT female animals, three had blood around the nose and mouth, one had a bloody ocular discharge, and two had external signs of diarrhea (perianal fecal staining). One female DOT animal had no visible lesions. The remaining animals in this group were euthanized at the termination of the study and except for scattered, white, raised areas (pinpoint to 1 mm in the lungs of one male, there were no visible lesions observed.

Dosage level of 1050 mg/kg bw
Sixteen rats (eight male, eight female) were necropsied. Two males and three females were euthanized at the termination of the study and had no visible lesions. The remaining ani!:ials died on test and each was noted to have external signs of diarrhea (perianal fecal staining). Four male and three female DOT animals had blood around the nose and mouth. One male and one female were noted to have a bloody ocular discharge. One female DOT animal had been cannabilized around the head and neck.

Dosage level of 1310 mg/kg bw
Sixteen animals (8 male, 8 female) were necropsied. Six males and four females died on test, all of which were noted to have external signs of diarrhea (perianal fecal staining). Two of the male DOT animals also had blood around the nose and mouth (one seen as bloody nasal discharge), as did all four of the female DOT animals. In addition, one female DOT animal had a bloody ocular dis­ charge and its tail was cannibalized. The remaining two males and four fe les were euthanized at the termination of the study. The stomach of each animal had adhesions .to the surrounding organs and/or abdominal wail. In addition, two of the females were noted to have small (4 mm and 8 mm) ulcers at the base of the tail. The spleen in each of the remaining two females was noted to be enlarged and the stomach wall (cardia) in one was greatly thickened.

Dosage level of 2050 mg/kg bw
Sixteen rats (eight male, eight female) were necropsied. All died on test and each.was noted to have external signs of diarrhea (perianal fecal staining). Eleven animals had blood around the nose and mouth and five had a bloody ocular discharge.

Dosage level of 3200 mg/kg bw
Sixteen rats (eight male, eight female) were necropsied. All the animals died on test. One male had no visible lesions. Each of the remaining animals had external signs of diarrhea (perianal fecal staining). Twelve animals had blood around the nose and/or mouth, two of which were seen as a.nasal discharge. Seven animalshad a bloody ocular discharge.

Table 1. Mortality rates in male and female rats administered the test substance by gavage

Dose (mg/kg bw)	Male Mortality	Female Mortality
270	0/8	0/8
430	0/8	0/8
670	3/8	5/8
1050	6/8	5/8
1310	6/8	4/8
2050	8/8	8/8
3200	8/8	8/8

 

For result details, kindly refer to the attached background material section of the IUCLID.

Conclusions:

Under the studyconditions, the acute oral LD50 of test substance in rats was determined to be 960 mg/kg bw (630 - 1470) [equivalent to 720 mg a.i./kg bw (473 - 1103)].

Executive summary:

A study was performed to determine the acute oral toxicity of the test substance, C12-18 DAQ (75% active in hydroalcoholic solution), according to the method equivalent or similar to OECD guideline 401.The test substance was administered undiluted by gavage to groups of 8 male and 8 female rats at dose levels of 270, 430, 670, 1050, 1310, 2050 and 3200 mg/kg bw. The animals were observed 1, 2.5, and 4 h after dosing. After that the animals were observed daily for clinical signs and twice daily for mortality. The bodyweight of the animals were determined at Day 0, 7 and 14. Necropsy was performed on all animals.A decrease in bodyweight was observed for animals at higher dose levels.None of the animals of both sexes died at 270 and 430 mg/kg bw; all animals died at 2050 and 3200 mg/kg bw.In the surviving animals no specific lesions were detected. Some animals had discoloration of the lungs others showed mild hydrometra of the uterus, ulcer on the tail or adhesion of the non glandular region of the stomach to liver, spleen, cecum and abdominal wall. The signs observed in the animals that died during the study were: diarrhea, bloody nasal discharge or blood around the nose and mouth, bloody ocular discharge.Under the studyconditions, the acute oral LD50 of the test substance in rats was determined to be 960 mg/kg bw (630 - 1470) [equivalent to720 mg a.i./kg bw (473 - 1103)] (Thompson, 1980).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

720 mg/kg bw

Quality of whole database:

Although pre-GLP, the study was conducted equivalent or similar to OECD guideline 401 and sufficiently reliable. Results are fully in-line with information on comparable quats (DDAC)

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because the substance is classified as corrosive to the skin

Reason / purpose for cross-reference:

data waiving: supporting information

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Oral exposure

A study was performed to determine the acute oral toxicity of the test substance, C12-18 DAQ (75% active in hydroalcoholic solution), according to the method equivalent or similar to OECD guideline 401.The test substance was administered undiluted by gavage to groups of 8 male and 8 female rats at dose levels of 270, 430, 670, 1050, 1310, 2050 and 3200 mg/kg bw. The animals were observed 1, 2.5, and 4 h after dosing. After that the animals were observed daily for clinical signs and twice daily for mortality. The bodyweight of the animals were determined at Day 0, 7 and 14. Necropsy was performed on all animals.A decrease in bodyweight was observed for animals at higher dose levels.None of the animals of both sexes died at 270 and 430 mg/kg bw; all animals died at 2050 and 3200 mg/kg bw.In the surviving animals no specific lesions were detected. Some animals had discoloration of the lungs others showed mild hydrometra of the uterus, ulcer on the tail or adhesion of the non glandular region of the stomach to liver, spleen, cecum and abdominal wall. The signs observed in the animals that died during the study were: diarrhea, bloody nasal discharge or blood around the nose and mouth, bloody ocular discharge.Under the studyconditions, the acute oral LD50 of the test substance in rats was determined to be 960 mg/kg bw (630 - 1470) [equivalent to720 mg a.i./kg bw (473 - 1103)] (Thompson, 1980).

Dermal exposure

In accordance with Annex VII, Section 8.5, Column 2, additional acute toxicity study for dermal route does not need to be conducted because the substance is classified as corrosive to the skin.  

Inhalation exposure

A study was performed to determine the acute toxicity of a mixture of two quaternary ammonium compounds (QAC) (77.3% QAC active) following inhalation exposure to the rats, according to OECD Guideline 403 and EPA Guideline 81-3, in compliance with GLP. The mixture consisted of 77.3% w/v QAC: (a) cocobenzyl dimethyl ammonium chloride (CAS no. 68424-85-1; EC no. 270-325-2): 40% w/v (b) dicoco dimethyl ammonium chloride (CAS no. 8001-54-3; EC no. 263-087-6): 37.5% w/v. Four groups of ten rats each (five males and five females) were given a single, 4 -h whole body exposure at three concentration levels with a MMAD (mass median aerodynamic diameter) / GSD (geometric standard deviation): (TG403 indicates a preferable MMAD of 1 -4µm with GSD 1.5 -3) (a) 340 mg/m3: MMAD 1.9 µm, GSD 3.5 (b) 170 mg/m3: MMAD 1.1 µm, GSD 2.7 (c) 240 mg/m3: MMAD 0.8 µm, GSD 1.5. The animals were observed for 21 d after 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 170 mg/m3, four animals died at 240 mg/m3 (3 males, 1 female), and nine animals died at 340 mg/m3 (5 males, 4 females). Clinical signs observed during exposure are consistent with inhalation of an irritant substance and included (partial) closing of the eyes and exaggerated respiratory movement during exposure in all test groups, gasping and wetness around the mouth during exposure at 340 mg/m3. Clinical signs were noted in survivors throughout the 21 -d observation period. Decrease of body weight, reduced weight gain, and reduced food and water intake was generally seen up to 14 day. 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 stomach. 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. The acute 4-h LC50 value of the test substance was found to be 250 mg/m3 (220 -280 mg/m3) [equivalent to 190 mg QAC/m3 (170 - 220)]. The study results clearly fit the pulmonary exposure of a corrosive substance deep in the lungs (MMAD < 1 µm) resulting to local damage. Immediately at the start of the exposure all the animals of the 0.24 and 340 mg/m3 groups showed exaggerated respiratory movements and partially closed eyes. After 15 minutes also all animals of the 170 mg/m3 group showed these effects. The exposures damaged alveolar and bronchiolar walls leading to pulmonary oedema and subsequent death. Under the study conditions, the 4 h LC50 of the QAC mixture was found to be 250 mg/m3 (equivalent to 190 mg QAC/m3), when tested at an MMAD ≤ 1µm (Jackson, 1980). 

Although the study is not performed on the substance itself it indicates that the expected effects are local and of an irritant and corrosive nature. The mechanism of toxicity is clear and is related to its physico-chemical properties resulting to local effects at the place of contact, rather than systemic toxicity. Following it physical state and physico-chemical properties exposures to the substance by inhalation will be unlikely. Furthermore, the strong irritant nature of aerosols with this substance would further limit the likelihood for continued exposure by inhalation. 

The substance is a sticky solid with a low vapour pressure. Due to it physical state and physical chemical properties, it is unlikely that it will form inhalable dust, mist or fumes when handled and used in solid form. In case inhalable forms of the substance (either pure or in aqueous solutions) are created under particular conditions (e.g. spraying, elevated temperature/pressure), appropriate risk management measures such as closed systems, exhaust ventilation or wearing of respirators are implemented to control exposure. Under such conditions, the risk to humans following inhalation exposure can be considered minimal and further testing involving vertebrate animals may also be omitted, in accordance with Annex XI, section 1.2 (weight of evidence) of the REACH regulation.   

Justification for classification or non-classification

Based on the oral LD50 value, the test substance warrants an ‘Acute Tox. 4; H302: harmful if swallowed’ classification according to EU CLP criteria (Regulation EC 1272/2008). In addition for the inhalation route, although C12-18 DAQ is classified to be corrosive (see section 5.3) and this drives its mechanism of action of toxicity, its inherent low vapour pressure prohibits the occurrence of respiratory irritation or corrosion by vapour for the pure forms. However, for its typical marketed form, which is a liquid, there is a potential for inhalation exposure due to formation of droplets and/or aerosols. Therefore, this warrants an additional labelling as: EUH071 — ‘Corrosive to the respiratory tract’ for the typical marketed forms only, according to EU CLP criteria (Regulation EC 1272/2008).

Further, the available data does not show indication that classification for STOT-SE cat 1 or 2 is indicated. For STOT-SE Cat 3: dialkyl quats are not narcotic.