Quaternary ammonium compounds, di-C8-10-alkyldimethyl, chlorides

Endpoint summary

Description of key information

In a reliable acute toxicity study, a structurally similar substance was administered to Sprague Dawley rats (5 animals/sex/dose) by oral gavage at a dose level of 500, 300, 200 or 100 mg/kg bw (single administration). Mortalities were observed at all dose groups except for in the 100 mg/kg bw group. The most prevalent clinical changes for all dose groups noted during the observation period included urine and fecal stains, saliva discharge and stains, dried red stains on muzzle and around eyes, eye squinting, piloerection, ataxia, body tremors, laboured and shallow respiration, slight to severe depression, viscous red blood like discharge from mouth, bloated appearance to the abdomen, and spasms in the abdominal area. The most common abnormalities found at macroscopic post-mortem examination included effects in the liver, kidneys, stomach, intestines and the spleen. The oral LD50 is 238 mg/kg bw.

In an acute dermal toxicity study a structurally similar substance was administered to New Zealand White rabbits (5 animals/sex/dose) by occlusive dressing at dose levels of 552, 1104, 3328 or 4448 mg/kg bw (single administration). A decrease in mean body weight was observed in all treatment groups in a dose response relationship. There was an increased incidence of pale kidneys in animals at the highest treatment level as compared to controls. Distended atria and/or ventricles were also noted in three animals at the highest dose levels. One animal in the 3328 mg/kg bw treatment group was noted to have a heavily pigmented gel in the large intestine. The acute dermal toxicity of the substance is 3342 mg/kg bw in the rabbit. The substance was a corrosive as evidenced by adverse signs at the site of application.

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:

4th June 1991 - 13th August 1991

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)

Deviations:

yes

Remarks:

On day 1 on the screening portion of the study, the test animals receiving 0.3 g/kg bw of test material inadvertently did not receive a PM observation. This devaition has not compromised any aspect of the study as reported by the study author.

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 225 - 399 g
- Fasting period before study: yes, fasted overnight prior to dosing
- Housing: groups of two in wire mesh suspension cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: four days before being used

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12-hour light/12-hour dark cycle

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

The test material was administered undiluted and as a 20% w/v formulation in distilled water. Based on the results from this initial phase, a dilution of 5% w/v in distilled water was selected for administration.

Doses:

0.5 g/kg bw
0.3 g/kg bw
0.2 g/kg bw
0.1 g/kg bw

No. of animals per sex per dose:

Five/sex/dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days.
- Frequency of observations and weighing: All animals were observed closely for gross signs of systemic toxicity and mortality several times during the day of dosing, and at least twice daily thereafter for a total of 14 days. Body weights was measured for each animal on the day of dosing, on day 7 of the observation period or following the death of any animals which does not survive this period.
- Necropsy of survivors performed: A gross necropsy was performed on any animal which dies. A gross necropsy was performed on each surviving animal at the end of the study.
- Other examinations performed: clinical signs, body weight,organ weights.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

238 mg/kg bw

Based on:

test mat.

95% CL:

> 0.198 - < 0.287

Mortality:

At the top dose of 0.5 g/kg bw mortality occurred in all 10 animals.
Seven out of 10 animals died at 0.3 g/kg bw dose.
Four out of 10 animals died following dosing of 0.2 g/kg bw.
No mortality was observed at the 0.1 g/kg bw dose.

Clinical signs:

The most prevalent clinical changes for all dose groups noted during the observation period included urine and fecal stains, saliva discharge and stains, dried red stains on muzzle and around eyes, eye squinting, piloerection, ataxia, body tremors, laboured and shallow respiration, slight to severe depression, viscous red blood like discharge from mouth, bloated appearance to the abdomen, and spasms in the abdominal area.

Body weight:

No change to body weights were noted during the study.

Gross pathology:

Gross necropsy findings in one animal which survived the observation period included an enlarged spleen, the stomach wall appeared transparent, a lobe of the liver, the stomach, and the spleen appeared to be attached together by a membrane-like structure. With the exception of the above animal, all other animals which survived the observation period exhibited no gross pathological findings. In the animals that were found dead the following common findings were observed: Lungs, spleen and liver mottled, stomach wall white in colour and distended with gas, stomach contained substance/paste, intestines were yellow and greatly distended, kidneys appeared pale and congested.

Phase 1:

Dose (g/kg bw)	Concentration	Mortality  (no. dead/no.dosed)
4.0	Undiluted	10/10
1.0	Undiluted	9/10
0.4	Undiluted	10/10
0.16	Undiluted	7/10
0.0632	20% w/v in distilled water	3/10

Phase 2:

Dose (g/kg bw)	Mortality (no. dead/no.dosed)
0.5	10/10
0.3	7/10
0.2	4/10
0.1	0/10

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

The rat oral LD50 is 238 g/kg bw in male and female animals, with 95% confidence limites of 0.198 g/kg bw to 0.287 g/kg bw.

Executive summary:

In an acute toxicity study the substance was administered to Sprague Dawley rats (5 animals/sex/dose) by oral gavage at a dose level of 500, 300, 200 or 100 mg/kg bw (single administration). Mortalities were observed at all dose groups except for in the 100 mg/kg bw group. The most prevalent clinical changes for all dose groups noted during the observation period included urine and fecal stains, saliva discharge and stains, dried red stains on muzzle and around eyes, eye squinting, piloerection, ataxia, body tremors, laboured and shallow respiration, slight to severe depression, viscous red blood like discharge from mouth, bloated appearance to the abdomen, and spasms in the abdominal area. The most common abnormalities found at macroscopic post-mortem examination included effects in the liver, kidneys, stomach, intestines and the spleen. There were no adverse effects noted for body weight gain.The oral LD50 is 238 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

238 mg/kg bw

Quality of whole database:

Sufficient to address requirements.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

3rd March 1987 - 17th March 1987

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 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

The dosages were changed to: Group Treatment Level (mg/kg bw) 1 552 2 1104 3 3328 4 4448

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

Substance was stored at room temperature at all times.

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Housing: Suspended stainless steel wire mesh bottom cages.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days prior to initiation of study.

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 hours light/dark cycle.

Type of coverage:

occlusive

Vehicle:

other: 10% v/v solution of ethanol/water.

Details on dermal exposure:

On the day prior to dosing, the fur was clipped from the dorsal area of the trunk of each rabbit. The exposed area on the trunk of each animal measured approximately 12x20 cm and constitutred 10% of the animal's total body surface. On the following day, the appropriate material was applied uniformly over the exposed skin, or as much of the area as possible. An occlusive binder was secured around the trunk of each animal immediately after treatment.

Duration of exposure:

24 hours.

Doses:

552, 1104, 3328 or 4448 mg/kg bw.

No. of animals per sex per dose:

Five/sex/dose

Control animals:

yes, concurrent vehicle

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observed for mortality and toxic effects for 8 hours after dosing and daily thereafter until day 15. Particular attention was given to observations of tremours, convulsions, seizures, lethargy and other signs of cardiac and/or central nervous system toxicity. Individual body weights were determined on days 1, 8 and 15 or at death.
- Necropsy of survivors performed: yes. Animals which died during the study were also subjected to a gross necropsy examination at the time of death or when found dead. During necropsy examinations, particular attention was directed to abnormalities of the heart and its auxialiary vascular system.

Statistics:

LD50 was calculated using the Probit Analysis method.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

3 861 mg/kg bw

Based on:

test mat.

95% CL:

> 0 - < 4 292

Mortality:

Individual mortality data is presented below in the table.
No deaths occurred among the vehicle control animals.

Clinical signs:

No clinical effects related to the treatment with the vehicle were noted.
The substance was irritating to the skin in all animals at all doses, these effects were characterised by eschar formation at the treatment sites within 24 hours after administration.Adverse effects were first noted at the 1104 mg/kg bw group when compared to controls. Reduced faecal production was present throughout the test population within 72 hours post administration and lasted for 1 to 4 days. One animal also displayed decreased activity, nasal discharge, mucoid excretions, an apparent bloody snout, faecal stains of the haircoat and soft stools. A second animal from this dose level displayed mucoid excretions and nasal discharge. In the higher dose levels these effects were more prevalent and the reduced faecal production was extended in duration. These events were often accompanied by emaciation and late deaths. Decreased activity was more prevalent in all animals and random but significant clinical findings included prostration, ataxia, tremours, laboured breathing and mucoid excretions. Isolated findings in one to three animals included nasal discharge, apparent bloody snouts, rales, soft stools, faecal/urine stains of the haircoat and anogenital areas.

Body weight:

A decrease in mean body weight was observed in all treatment groups in a dose response relationship. At the lowest level a minimal weigh loss (3-127 g) was observed in some 70% animals on day 8. The weight loss was a transient event and recovery to control levels was observed by day 15. At increasing dose levels, the incidence of weight loss within each test population, the amount of weight loss and the delayed recovery to control levels increased. At 1104 mg/kkg bw dose level the weight lost between days 1 and 8 was only partially recovered by day 15. At the two higher dose levels, the weight loss persisted in survivors.
By contrast, the mean body weight of male and female vehicle control animals increased at each measurement interval.

Gross pathology:

Gross necropsy findings were minimal. There was an increased incidence of pale kidneys in animals at the highest treatment level as compared to controls.Distended atria and/or ventricles were also noted in three animals at the highest dose levels.One animal in the 3328 mg/kg bw treatment group was noted to have a heavily pigmented gel in the large intestine.

Mortality data:

Treatment	Dose level	No. of Deaths/No. Dosed
		Males	Females	Sexes Combined
10% Ethanol/Water	5.56 ml/kg bw	0/5	0/5	0/10
Substance (80% active)	552 mg/kg bw	0/5	0/5	0/10
	1104 mg/kg bw	0/5	0/5	0/10
	3328 mg/kg bw	3/5	2/5	5/10
	4448 mg/kg bw	5/5	3/5	8/10

Conclusions:

The acute dermal toxicity of the substance is 3342 mg/kg bw in the rabbit. The substance was a corrosive as evidenced by adverse signs at the site of application.

Executive summary:

In an acute dermal toxicity study an 80% solution of the substance was administered to New Zealand White rabbits (5 animals/sex/dose) by occlusive dressing at a dose levels of 552, 1104, 3328 or 4448 mg/kg bw (single administration). The exposure was for 24 hours after which the animals were observed for 14 days and observed for mortlaity, signs of clinical toxicity, changes to body weight gain and gross pathology was conduted at necropsy. There was dose-dependent mortalities and signs of clinical toxicity. A decrease in mean body weight was observed in all treatment groups in a dose response relationship. Gross necropsy findings were minimal. There was an increased incidence of pale kidneys in animals at the highest treatment level as compared to controls.Distended atria and/or ventricles were also noted in three animals at the highest dose levels.One animal in the 3328 mg/kg bw treatment group was noted to have a heavily pigmented gel in the large intestine. The acute dermal toxicity of the substance is 3342 mg/kg bw in the rabbit. The substance was a corrosive as evidenced by adverse signs at the site of application.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

3 342 mg/kg bw

Quality of whole database:

Sufficient to address requirements.

Justification for classification or non-classification

On the basis of the harmonized classification of DDAC, the substance is classified as Acute tox 4 (H302).