Registration Dossier

Administrative data

Description of key information

Acute toxicity oral: LD50 = 1675 mg/kg bw (females), rat, m/f, oral: gavage (OECD 401, GLP)

Acute toxicity inhalation: LC50 > 1.97 mg/L over 4h, rat, m/f, inhalation: aerosol, whole body (OECD 403, GLP)

Acute toxicity dermal: LD50 > 2000 mg/kg bw, rat, m/f, semiocclusive (OECD 402, GLP)

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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Peer-reviewed assessment report (attached in section 13)
Qualifier:
according to guideline
Guideline:
EPA OPP 81-1 (Acute Oral Toxicity)
Version / remarks:
US EPA FIFRA Guideline §81-1
Deviations:
yes
Remarks:
Purity of the test compound was not determined by the laboratory prior to conduct of the test
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
not applicable
GLP compliance:
yes
Remarks:
self-certified to US EPA regulations at 40 CFR Parts 160 and 792
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
clear reddish brown liquid
Species:
rat
Strain:
other: albino rats (Crl:CD®BR)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc. Portage MI USA
- Age at study initiation: young
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 2.51 mL/kg
Doses:
1500, 1950 and 2535 mg/kg bw
No. of animals per sex per dose:
5/sex/dose
Control animals:
other: not required
Details on study design:
- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 726 mg/kg bw
Based on:
test mat.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
1 675 mg/kg bw
Based on:
test mat.
Sex:
male
Dose descriptor:
LD50
Effect level:
1 779 mg/kg bw
Based on:
test mat.
Mortality:
All deaths occurred within 3 days of dosing. Mortality was 2/10, 9/10 and 8/10 for the 1500, 1950 and 2535 mg/kg bw groups, respectively.
Clinical signs:
Clinical signs included ataxia in 24 animals, hypoactivity (21 rats), ocular discharge (16 rats), urogenital staining, hypothermia (cool to touch, 13 rats), dried red material around the eye(s), forelimb(s), and/or nose, laboured respiration (11 rats), prostrate positioning (10 rats), abnormal excretion (5 rats), and dried yellow material around the mouth. With the exception of dried yellow urogenital staining noted for two rats, all surviving animals appeared normal by day 7 or earlier and throughout the remainder of the study.
Body weight:
There were no remarkable changes in body weights for all animals.
Gross pathology:
Histopathological changes indicated an irritant effect on the gastrointestinal tract. Three animals had an hemorrhagic thymus gland. Two rats had dark red lungs and red fluid contents in the urinary bladder. One animal had enlarged cervical lymph nodes, and one had opacity in the right eye. There were no other gross necropsy findings neither in the animals that survived to the scheduled euthanisation nor in those that were found dead.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
As information was provided via a peer-reviewed assessment report, it can be considered as sufficiently reliable to assess the acute toxicity of ethoxyquin towards rats. Based on mortality data, an oral LD50 of 1779 mg/kg bw was calculated for male rats, of 1675 mg/kg bw for females, and of 1726 mg/kg bw for both sexes combined. Since the LD50 was below the limit of 2000 mg/kg bw, ethoxyquin shall be classified as being harmful if swallowed, i.e. acute toxic cat. 4 acc. to Regulation 1272/2008.
Executive summary:

In an acute oral toxicity study (US EPA FIFRA Guideline §81-1, which is equivalent to OECD 401), groups of fasted, young adult albino rats (Crl:CD®BR)(5/sex/dose) were given a single oral dose ofneat ethoxyquinat doses of 1500, 1950 and 2535 mg/kg bw and observed for 14 days.

 

Oral LD50Males = 1779 mg/kg bw

Females = 1675 mg/kg bw

Combined = 1726 mg/kg bw

 

Ethoxyquin is of slight Toxicity based on the LD50 in females, and should be classified as acute toxic cat. 4.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 675 mg/kg bw
Quality of whole database:
The database is of a high quality, as there is a study available assessed with Klimisch 2. All toxicity data relatively consistently indicate that ethoxyquin is not very harmful. The lowest LD50 of 1675 mg/kg in females rats was chosen as a precaution, and the other values indicate that an underestimation of the actual hazard is unlikely. The tonnage-driven data requirements under REACH are so fully met, no further testing is required.

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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Peer-reviewed assessment report (attached in section 13)
Qualifier:
according to guideline
Guideline:
EPA OPP 81-3 (Acute inhalation toxicity)
Version / remarks:
US EPA FIFRA Guideline § 81-3
Deviations:
yes
Remarks:
Purity of the test compound was not determined by the laboratory prior to conduct of the test.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
not applicable
GLP compliance:
yes
Remarks:
self-certified to US EPA regulations at 40 CFR Parts 160 and 792
Test type:
other: application of highest technically achieveable dose
Limit test:
no
Species:
rat
Strain:
other: Crl:CD®BR rats
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, MI
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
not specified
Mass median aerodynamic diameter (MMAD):
3.2 µm
Geometric standard deviation (GSD):
2.4
Remark on MMAD/GSD:
100 % of the particles < 10 microns and 13.4 % < 1.18 microns
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: glass and stainless steel whole-body exposure inhalation chamber (NYU type)
- Exposure chamber volume: 0.5 m3 (500 L)
- Source and rate of air: The exposure chamber was operated at 134 to 143 litres per minute (LPM). An airflow of 100 LPM is sufficient to sustain 12 air changes per hour in a 0.5 m3 chamber; therefore, the protocol specified 12 to 15 air changes per hour was met and/or exceeded.

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution:
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): The test material was administered as a liquid droplet aerosol (3.2 micron MMAD with a geometric standard deviation of 2.4; 100 % of the particles < 10microns and 13.4 % < 1.18 microns) at an airborne concentration of 1.97 mg/L. The nominal concentration for the test atmosphere should have been 9.2 mg/L but was not reached for technical reasons.
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
4 h
Concentrations:
1.97 mg/L
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were monitored on Day 0 (initiation) and for the following 14 days before scheduled sacrifice.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 1.97 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Mortality:
One animal was euthanised in extremis on Day 1 following exposure whereas all the other rats survived throughout the dosing and observation periods.
Clinical signs:
other: Clinical signs during and immediately after the exposure included salivation (during the exposure); wet and/or dried yellow material on various external surfaces, salivation, dried red material around nose, and dried yellow material around right eye at on
Body weight:
A male and a female rat lost 27 and 3 grams, respectively, from Day 0 to Day 3. An additional female rat gained no weight from Day 0 to Day 3. All animals that survived recovered to or surpassed their initial (Day 0) body weights by Day 14.
Other findings:
There were no other significant clinical findings or body weight changes during the study.

Conclusion:

Ethoxyquin was of rather low acute inhalative toxicity to rats although the death of one female animal on Day 1 was considered to be treatment-related because of the toxic signs of impaired muscle coordination, hypothermic body temperature, and depressed and shallow respiration. The necropsy observation of dark red intestinal contents indicated possible effects on the gastrointestinal tract.

The remaining five males and four females survived through the 14-day observation period with only very minor and transitory effects on body weight and no exposure-related gross pathologic abnormalities. The occurrence of tremours in 6 of 10 animals following inhalation exposure, however, might suggest a neurotoxic potential and is considered to be in line with the frequent observation of ataxia in the acute oral toxicity study.

Because of the study design (whole-body exposure), the toxic signs might be also (at least partly) due to oral intake of traces of the test substance from the fur and it cannot be certainly stated that they were exclusively caused by inhalation.

On the basis of this study, the acute inhalation LC50 of ethoxyquin for both sexes was found to be in excess of 1.97 mg/L. In accordance with Annex VI of Commission Directive 2001/59/EC, ethoxyquin does not need to be classified with respect to acute inhalation toxicity.

Interpretation of results:
study cannot be used for classification
Conclusions:
As information was provided via a peer-reviewed assessment report, it can be considered as sufficiently reliable to assess the acute inhalation toxicity of ethoxyquin towards rats. On the basis of this study, the acute inhalation LC50 of ethoxyquin for both sexes was found to be in excess of 1.97 mg/L. In accordance with Annex VI of Commission Directive 2001/59/EC, ethoxyquin does not need to be classified with respect to acute inhalation toxicity. Based on this data however, a LC50 of 5 mg/l cannot be excluded, and so not the necessity for a classification as acute toxic cat. 4 acc. Regulation 1272/2008.
Executive summary:

In an acute inhalation toxicity study (US EPA FIFRA Guideline § 81-3, equivalent to OECD 403), groups of Crl:CD®BR rats (5/sex) were exposed by inhalation route ethoxyquin for 4 hours to whole body at a concentration of 1.97 mg/L.  Animals then were observed for 14 days.

 

LC50combined > 1.97  mg/L

 

One animal was euthanise din extremis on Day 1 following exposure whereas all the other rats survived throughout the dosing and observation periods. Ethoxyquin is classified as being of low Toxicity, classification as acute toxic cat. 4 acc. Regulation 1272/2008 cannot be excluded.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Value:
1 970 mg/m³
Quality of whole database:
The database is of acceptable quality. The endpoint is not necessarily required as exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Peer-reviewed assessment report (attached in section 13)
Qualifier:
according to guideline
Guideline:
EPA OPP 81-2 (Acute Dermal Toxicity)
Version / remarks:
US EPA FIFRA Guideline §81-2
Deviations:
yes
Remarks:
Purity of the test compound was not determined by the laboratory prior to conduct of the test.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
not applicable
GLP compliance:
yes
Remarks:
self-certified to US EPA regulations at 40 CFR Parts 160 and 792
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Crl:CD®BR albino rats
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc. Portage MI USA
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: clipped, intact skin

REMOVAL OF TEST SUBSTANCE yes
Duration of exposure:
24h
Doses:
2000 mg/kg bw / 1.98 mL/kg bw
No. of animals per sex per dose:
5/sex/dose
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, dermal findings
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
There were no deaths up to the limit dose of 2000 mg/kg bw
Sex:
male/female
Dose descriptor:
LD0
Effect level:
>= 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
There were no deaths up to the limit dose of 2000 mg/kg bw
Mortality:
There were no deaths up to the limit dose of 2000 mg/kg bw.
Clinical signs:
There were no test material-related clinical observations up to the limit dose of 2000 mg/kg bw.
Body weight:
There were no body weight changes up to the limit dose of 2000 mg/kg bw.
Gross pathology:
There were no gross necropsy findings up to the limit dose of 2000 mg/kg bw.
Other findings:
The test material induced very slight to slight erythema on eight rats. Ten sites had desquamation. There was no edema or other dermal findings. With the exception of desquamation noted for two females, all dermal irritation completely subsided by day 12 or earlier.
Interpretation of results:
GHS criteria not met
Conclusions:
As information was provided via a peer-reviewed assessment report, it can be considered as sufficiently reliable to assess the acute dermal toxicity of ethoxyquin towards rats. Ethoxyquin was found to be of a low order of acute toxicity following exposure of rats via the dermal route. On the basis of this study and in accordance with Annex VI of Commission Directive 2001/59/EC ethoxyquin shall not be classified with respect to acute dermal toxicity. The same applies to Regulation 1272/2008, as the LD50 is clearly above the limit dose for classification of 2000 mg/kg bw.
Executive summary:

In an acute dermal toxicity study (US EPA FIFRA Guideline §81-2, which is equivalent to OECD 402), groups of Crl:CD®BR albino rats (5/sex/dose) were dermally exposed to neat ethoxyquin for 24hours at a limit dose of 2000 mg/kg bw.  Animals then were observed for 14 days.

Dermal LD50> 2000 mg/kg bw

Dermal LD0≥ 2000 mg/kg bw

There were no deaths, test material-related clinical observations, body weight changes, or gross necropsy findings in this limit test. The test material induced very slight to slight erythema on eight rats.

Ethoxyquinis of low Toxicity and does not need to be classified according to Regulation 1272/2008.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The database is of a high quality, as there is one study available assessed with Klimisch 2. All toxicity data relatively consistently indicate that ethoxyquin is not harmful when applied dermally. The LD50 value is > 2000 mg/kg and does not trigger classification. The magnitude of the value indicates that an underestimation of the actual hazard is unlikely. The tonnage-driven data requirements under REACH are so fully met, no further testing is required.

Additional information

Justification for classification or non-classification

In the available OECD 401 study, an oral LD50 of 1779 mg/kg bw was calculated for male rats, of 1675 mg/kg bw for females, and of 1726 mg/kg bw for both sexes combined. Since the LD50 was below the limit of 2000 mg/kg bw, ethoxyquin shall be classified as being harmful if swallowed, i.e. acute toxic cat. 4 acc. to Regulation 1272/2008.

Out of precautionary reasons, the lowest available LD50 of 1675 mg/kg in females rats was chosen, and so ethoxyquin must be classified as acute toxic Cat. 4 according to Regulation 1272/2008.

 

On the basis of the inhalation toxicity study, the acute inhalation LC50 of ethoxyquin for both sexes was found to be in excess of 1.97 mg/L. In accordance with Annex VI of Commission Directive 2001/59/EC, ethoxyquin does not need to be classified with respect to acute inhalation toxicity. Based on this data however, a LC50 of 5 mg/l cannot be excluded, and so not the necessity for a classification as acute toxic cat. 4 acc. Regulation 1272/2008. In consequence, the available study is not sufficient for classification.

 

On the basis of the available study performed in rats and in accordance with Annex VI of Commission Directive 2001/59/EC ethoxyquin shall not be classified with respect to acute dermal toxicity. The same applies to Regulation 1272/2008, as the LD50 is clearly above the limit dose for classification of 2000 mg/kg bw.