Registration Dossier

Administrative data

Description of key information

Acute oral toxicity: The oral LD50 in male/female Sprague-Dawley rats was determined to be 688.1 mg/kg bw in a study conducted similarly to OECD Guideline 401 (Mallory VT, 1991).

Acute dermal toxicity: In a study conducted according to OECD Guideline 402, the acute dermal LD50 was determined to be greater than 2000 mg/kg bw in male and female Sprague-Dawley rats (Clouzeau, 1992).

Acute inhalation toxicity: No reliable data were available. However, this endpoint is waived as specific data are available for the oral and dermal exposure routes.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
31 January 1990 - 5 March 1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): 6398-24-1, Project #90-018
- Physical state: clear colorless liquid
- Analytical purity: responsibility of the Sponsor
- Stability under test conditions: no apparent change in the physical state of the test article during administration
- Other: specific gravity= 0.8725 g/ml
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Wilmington, Massachusetts
- Age at study initiation: young adults
- Mean weight at study initiation:
500 mg/kg dose group: males: 184.2 g, females: 175.0 g
800 mg/kg dose group: males: 266.6 g, females: 203.6 g
1250 mg/kg dose group: males: 260.6 g, females: 209.6 g
2000 mg/kg dose group: males: 254.6 g, females: 199.6 g
- Housing: individually in stainless steel 1/2" wire mesh cages, sized in accordance with the "Guide for the Care and Use of Laboratory Animals" of
the Institute of Laboratory Animal Resources, National Research Council.
- Diet (e.g. ad libitum): Wayne Teklad Lab Blox, ad libitum
- Water (e.g. ad libitum): fresh tap water, ad libitum
- Acclimation period: minimum 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C±3°C
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): 12h dark/12h light


Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Not applicable
Doses:
Dose-range finding study: 500, 2500 and 5000 mg/kg
Definitive test: 500, 800, 1250 and 2000 mg/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Viability was checked daily. Clinical effects were observed for at 1, 4 and 24h after dosing and once daily thereafter. Body weights were recorded at study initiation, days 7 and 14 or when found dead.
- Necropsy of survivors performed: yes
Statistics:
LD50 calculations performed via Litchfield and Wilcoxon on Pharmacological Calculations System, version 4.1.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
688.1 mg/kg bw
95% CL:
546.9 - 865.6
Sex:
male
Dose descriptor:
LD50
Effect level:
998.9 mg/kg bw
95% CL:
734 - 1 359.5
Sex:
female
Dose descriptor:
LD50
Effect level:
598.4 mg/kg bw
95% CL:
348.6 - 1 027.3
Mortality:
2/10 animals died at the 500 mg/kg dose;
6/10 animals died at the 800mg/kg dose;
10/10 animals died at both the 1250 and 2000 mg/kg dose levels.
Clinical signs:
Signs observed included decreased activity, piloerection, descreased muscle tone, abnormal gait, abnormal stance, diarrhea, chromodacryorrhea, dyspnea and prostration.
Body weight:
Final compared to initial body weight: body weight increase in both males and females at the 500 mg/kg dose level
Final compared to initial body weight: body weight increase in males at the 800 mg/kg dose level; decrease of body weight in females at 800 mg/kg dose level.
No final body weights reported for the 1250 mg/kg dose level.
Gross pathology:
Necropsy of the animals dying on study: distended and/or fluid-filled stomachs and intestines, pale livers and pale kidneys.
Terminal necropsy of the remaining animals: distended fluid-filled intestines in one female rat.

Results of dose range finding study:

Signs observed included decreased activity, abnormal stance, abnormal gait, and dyspnea. None of the animals died at the 500 mg/kg dose level. Two of two animals died at both the 2500 and 5000 mg/kg dose levels. Based upon these results, a definitive LD50 study was performed.

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The Acute Oral LD50 in male and female rats for the substance was determined to be 688.1 mg/kg (95%CL of 546.9 to 865.6 mg/kg). Based on the results of this study and according to the criteria of the CLP Regulation the substance should be classified as a category 4 acute oral toxicant.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
July 1981 - August 1981
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
Acclimation period is 3-5 days, instead of at least 5 days. No information on temperature during test.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): 4236-43-15 (J-77)
- Physical state: liquid
- Density=0.88 g/ml
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington MA
- Age at study initiation: young adults
- Weight at study initiation: males group mean 194.0-212.0 g; females group mean 182.4-188.6 g
- Fasting period before study: fasted overnight (approximately 18 hours) prior to receiving a single oral dose of the test article
- Housing: individually housed in wire mesh bottom cages
- Diet (e.g. ad libitum): NIH open formula 07, certified feed (Zeigler Bros. Gardeners, PA) ad libitum.
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: approximately 3 to 5 days


ENVIRONMENTAL CONDITIONS
- Air changes (per hr): 12-15 air change per hour
- Photoperiod (hrs dark / hrs light): 12h dark/12h ligh

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Not applicable
Doses:
500, 660, 870, 1140 and 1500 mg/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: 3 times on the day of dosing, twice on the following day and once daily for the remainder of the study. Body weight: initially, day 8 and day 15
- Necropsy of survivors performed: yes
Statistics:
Method of LD50 Calculation: Finney, D. J., Statistical Methods in Biological Assay, second edition. London: Griffin Press, 1971
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
750 mg/kg bw
95% CL:
640 - 870
Remarks on result:
other: Slope= 7.75
Mortality:
1/10 animals died at the 500 mg/kg dose level (1 male)
3/10 animals died at the 660 mg/kg dose level (1 male, 2 females)
7/10 animals died at the 870 mg/kg dose level (2 males, 5 females)
9/10 animals died at the 1140 mg/kg dose level (4 males, 5 females)
10/10 animals died at the 1500 mg/kg dose level
Clinical signs:
Decreased activity, ataxia, dried blood around nose, diarrhea, salivation
Body weight:
Fasted body weights at the day 1- day 15:
Males: body weight increase for all dose levels
Females: body weight increase for the 500 mg/kg dose level; body weight decrease for the 0.66 mg/kg dose level; for other dose levels, the animals died before day 15
Gross pathology:
660 mg/kg dose level: thoracic cavity: contains tan viscous liquid; intestines: contain blood-like viscous liquid
870 mg/kg dose level: liver, spleen, stomach, & rib cage: adhered together; intestines: contain blood like fluid; abdominal cavity: contains bloodlike liquid
1140 mg/kg dose level: thoracic cavity: contains bloodlike liquid; liver, spleen, stomach, & rib cage: adhered together; stomach: contains bloodlike liquid; intestines: contain bloodlike liquid
1500 mg/kg dose level: stomach: contains bloodlike liquid; intestines: contain bloodlike liquid
Dosage level (mg/kg)  Clinical observation  Necroscopy observation
 500  activity decrease (all), deaths (1F)  no findings
 660  activity decrease (all), ataxia (1M and 3F), dried blood around nose (1M and 3F), deaths (1M and 2F)  thoracic cavity: contains tan viscous liquid (1F).Intestines: contain blood-like viscous liquid (2 F).
 870 activity decrease( all), ataxia (4M and 5F), dried blood around nose (2M and 2F), deaths (2M and 5F)   Liver, spleen, stomach, & rib cage: adhered together (1M and 1F). Intestines: contain blood-like liquid (1M and 3F). Abdominal cavity: containg.blood-like liquid (1M and 1F).
 1140 activity decrease (all), Ataxia (4M and 5F), Diarrhea (3M and 1F), Salivation (2M and 2F), Deaths (4M and 5F).   Thoracic cavity: contains blood-like liquid (1F). Liver, spleen, stomach, & rib cage: adhered together (1M). Stomach: contains bloodl-ike liquid (2M and 2F). Intestines: contain blood.-like liquid (3M and 4F).
 1500 activity decrease (all), Ataxia (5M and 4F) Salivation (1M and 3F), Deaths (5M and 5F).  Stomach: contains blood-like liquid (2M and 2F). Intestines: contain blood-like liquid (5M and 3F).
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The Acute Oral LD50 in rats was determined to be 750 mg/kg/bw (95%CL of 640 to 870 mg/kg). Based on the results of this study and according to the criteria of the CLP Regulation, the substance should be classified as acute oral toxicant category 4.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
22 July 1981 - 05 August 1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Well documented GLP study performed according to a method similar to OECD Guideline 401. One high dose was tested at which all rats died. Study is not relevant for classification purposes.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
Acclimation period 3-5 days instead of at least 5 days. No data on temperature during the study.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
- Name of test material (as cited in study report): 4236-43-15 (J-77)
- Physical state: liquid
- Other: density = 0.88 g/ml
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, HA.
- Age at study initiation: young adults
- Weight at study initiation: males mean 196.6 g; females mean 231.8 g
- Fasting period before study: overnight approximately 18h prior to dosing
- Housing: individually housed in wire mesh bottom cages in environment controlled rooms as per "Guide for the Care and Use of Laboratory
Animals"
- Diet (e.g. ad libitum): NIH open formula 07, certified feed (Ziegler Bro., Gardeners,PA), ad libitum.
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 3-5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity: no data
- Air changes (per hr): 12-15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12h dark/12h light
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Not applicable
Doses:
10000 mg/kg
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: body weigh: days 0, 8 and 15. Animals were observed on day 0 and daily through 15 days.
- Necropsy of survivors performed: yes; all animals that died during the study and those sacrificed at termination were subjected to a gross necropsy. All abnormalities were recorded
Key result
Sex:
male/female
Dose descriptor:
LD100
Effect level:
10 000 mg/kg bw
Based on:
test mat.
Mortality:
All animals died within 1 day.
Clinical signs:
- decreased activity in all animals
- ataxia: 3 animals
Body weight:
No changes in body weight were observed.
Gross pathology:
- stomach: contains blood- like liquid ( observed in 4 males and 3 females)
- intestines: contain blood-like viscous liquid (observed in all animals)
Interpretation of results:
study cannot be used for classification
Conclusions:
100% mortality was observed in rats at 10000 mg/kg bw (limit test).
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
No data
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): Methoxypropylamine (MOPA)
- Batch: FABRICATION F 6612 r (860208)
- Purity c.a. 99%
- Supplier: Atochem, La Chambre
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Iffa-Credo : Les Oncins- 69210 L'Arbresle- France.
- Fasting period before study: yes

ENVIRONMENTAL CONDITIONS
No data
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Volumes of administration: 0.79- 1.11- 1.24- 1.4- 1.57- 2.23 ml/kg of live bodyweight ot: the test article as supplieed
Doses:
0, 711, 999, 1116, 1260, 1413, 2007 mg/kg
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
Mortality and abnormal clinical signs were noted 15 minutes after administration of the test article, then 1, 2 and 4 hours later and then daily for the 14 day study period. The nature and duration of the clinical signs were recorded.
The daily observations took into account any changes to the skin, the hair, the eyes, the mucous membranes, the respiratory system, the circulatory system, the autonomous and central nervous systems, as well as motor activity and behaviour. Special attention was paid when quivering, convulsions, salivation, diarrhea, apathy, sleep and coma were observed.
- Frequency of weighing: The animals were weighed on Day -1, Day 1 (immediately before administration of the test article), Day 8 and Day 15.
- Necropsy of survivors performed: yesA necropsy was perfor'Jiled on all animal dying during the study.
After the 14 day study and the final observation (Day 15), the surviving rats were anaesthetised, sacrificed by exsanguination and necropsied. The abdominal and thoracic cavities were opened and an observation was performed on the following organs : liver, heart, kidneys, lungs.
Statistics:
Two methods will be used from amongst the many available to calculate the LD50:
• BLISS method (1938)
• LITCHFIELD & WILCOXON'S method (1949)
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
971 mg/kg bw
95% CL:
>= 863 - <= 1 093
Mortality:
Dose        Male        Female        Combined  %
(mg/kg)
0         0         0          0 0
711         1         0         1                10
999         2         3         5                50
1116         4         4         8                80
1260         3         4         7                70
1413         4         5         9                90
2007        5         5         10                100
Clinical signs:
The daily observation of animals after the administration and for the following 14 days mainly highlighted:
at 711 mg/kg signs of abatement in all rats associated for one of them with piloerection and dyspnea. On D3, all surviving animals recovered normal behavior.
at 999 mg/kg signs of abatement in all rats and some cases of polyuria, ataxia, and piloerection. On day 7, all surviving animals recovered normal behavior.
at 1116 mg/kg ,signs of abatement in all rats and some cases of salivation, polyuria, diarrhea, prostration, ataxia, ptosis, piloerection and dyspnea.
at 1260 mg/kg signs of abatement in all animals and some cases of salivation, polyuria, prostration,dyspnea, lacrimation and piloerection.
a 1413mg/kg, depression and/or prostration in all rats and some cases of coma, salivation, dyspnea, snoring and piloerection.
at 2007 mg/kg,depression and/or prostration in all animals associated for two of them with piloerection.
Body weight:
The weight change of the animals treated with doses of 711 and 999 mg/kg was in overall slightly lower than that of the control group rats. Regarding
the other treated groups (1116-1260-1413-2007 mg / kg), the mortality rate did not allow an interpretation of weight change.
Gross pathology:
Gross specific abnormalities encountered during autopsies were located in the abdomen corresponding to a beginning peritonitis with congested appearance of the digestive tract.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Considering the results obtained in these experimental conditions, the oral LD50 of methoxypropylamine administered as such, is equal to 974 mg/kg (830-1143 mg/kg) according to the method of LITCHFIELD and Wilcoxon or equal to 971 mg/kg (863-1093 mg/kg) according to the method of BLISS.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
688.1 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No data
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Specific details on test material used for the study:
- Name of test material (as cited in study report): methoxy-3-propylamine
- Batch:, 26/05/92
- Purity: 99.44%
- Supplier: Elf Atochem, La Chambre
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: lffa Crédo, 69210 L'Arbresle, France
- Age on the day of treatment: 8 weeks old
- Weight on the day of treatment: 282 ± 10 g for the males and 229 ± 8 g for the females.
- Fasting period before study: no
- Housing: individually during the study In polycarbona te cages
- Diet: ad libitum with a certified pelleted diet "Rats- Mice sustenance ref. A04 C" (U.A.R., 91360 Villemoissonsur/Orge, France)
- Water: free access to tap water filtered by a 0.22 micron filter membrane
- Acclimation period: at !east 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50 ± 20
- Air changes (per hr): The air was non-recycled and filtered
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Vehicle:
water
Details on dermal exposure:
The test substance in its original form was applied at a dose level of 2000 mg/kg at a volume of 2. 30 ml/kg taking into consideration that the specifie gravity (SG) of the test substance was 0.871 directly to the skin. The test substance in water for injections at a dose level of 400 mg/kg at a volume of 5 ml/kg was prepared on a dry hydrophilic gauze patch ) and then applied to an area of skin representing approximately 10% (5 x 6 cm for the females and 5 x 7 cm for the males) of the body surface of the animal. This was calculated according to Meeh' s formula. The test substance and the gauze patch were held in contact with the skin for 24 hours by means of an adhesive hypoallergic aerated semi-occlusive dressing attached to a restraining bandage. This dressing prevented the ingestion of the test substance by the animal. No residual test substance was observed at removal of the dressing.
Duration of exposure:
24 hours
Doses:
2000 and 400 mg/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
The animals were checked for clinical signs, mortality and body weight gain for a period of 4 days (2000 mg/kg) or 14 days (400 mg/kg) after the single application of the test substance. A necropsy was performed on each animal sacrificed at the end of the study.
Statistics:
None
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
ca. 2 000 mg/kg bw
Mortality:
At 400 mg/kg, no deaths occurred during the observation period.
At 2000 mg/kg, 4 females died between days 2 and 4.
Clinical signs:
At 400 mg/kg, no clinical signs were observed during the study.
At 2000 mg/kg, sedation or hypokinesia and dyspnea were noted between days 2 and 5. Signs of necrosis and ulceration were also observed after removal of the dressing.
Body weight:
At 400 mg/kg, the body weight gain of the animals was normal.
Gross pathology:
In all animals treated wi th the 400 mg/kg dose level, the macroscopic examination of the main organs of the animals sacrificed at the end of the
study revealed no apparent abnormalities.
In all animals treated wi th the 2000 mg/kg dose level, samples of skin were taken. Nec rosis of the skin (male Nos. 01, 03, 04, 05; female Nos. 01, 02, 03, 04, 05) and signs of ulceration affected of the whole depth skin (male No. 02) were observed at necropsy.
No histological examination was performed on cutaneous samples.
Interpretation of results:
GHS criteria not met
Conclusions:
The LD50 of the test substance methoxy-3-propylamine when administered by dermal route in rats was higher than 400 mg/kg. No signs of toxicity were observed at this dose level. The LD50 was estimated at 2000 mg/kg.
In order to comply with new ethic and scientific recommendations concerning the LD50, a more precise determination was not necessary.
Executive summary:

The acute toxicity of the test substance methoxy-3 -propylamine was evaluated in rats according to the recommendations of the OECD Guideline No. 402 (OECD, 24th February 1987) for the testing of chemicals administered by dermal route and the Principles of Good Laboratory Practice (OECD, 12th May 1981). In a first assay, the test substance was applied in its original form directly to the skin of 10 Sprague-Dawley rats (5 males and 5 females) at a dose level of 2000 mg/kg, at a volume taking into consideration that the specific gravity (SG) of the test substance was 0.871. In a second assay, the test substance was solubilised in water, prepared on a dry compress at a dose level of 400 mg/kg and then applied to the skin of 10 SpragueDawley rats {5 males and 5 females) at a volume of 5 ml/kg. After 24 hours under a semi-occlusive dressing, no residual test substance was observed at removal of the dressing. The animals were checked for clinical signs, mortality and body weight gain for a period of 4 days (2000 mg/kg) or 14 days (400 mg/kg) after the single application of the test substance. A necropsy was performed on each animal sacrificed at the end of the study. At 400 mg/kg, the general behaviour and body weight gain of the animals were not affected by the treatment. No deaths occurred at the dose level of 400 mg/kg. The macroscopic examination revealed no abnormalities in the animals sacrificed at the end of the study. At 2000 mg/kg, 4 females died between days 2 and 4. Cutaneous signs of necrosis and ulceration appeared between days 2 and 5. The animals were sacrificed for humane reasons on day 5. Under these experimental conditions, the LD50 of the test substance when administered by dermal route in rats was higher than 400 mg/kg. No signs of toxicity were observed at this dose level. The LD50 was estimated at 2000 mg/kg. In order to comply with ethic and scientific recommendations concerning the LD50, a more precise determination was not necessary.

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
No data
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: See "Remark"
Remarks:
GLP study in which one high dose (8000 mg/kg bw) was tested on the abraded skin of 4 animals per sex. All animals died.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
skin is abraded in all animals, 4 instead of 5 animals per sex were tested
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
- Name of test material (as cited in study report): 4236-43-15
- Physical state: liquid
- Analytical purity: responsibility of the Sponsor
- Lot/batch No.:
- Stability under test conditions: responsibility of the Sponsor
- Storage condition of test material: responsibility of the Sponsor
- Other: extreme flammable; density= 0. 88 g/ml
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: H.A.R.E. - Rabbits for Research, Hewitt, N.J. (a USDA approved supplier)
- Age at study initiation: no data
- Weight at study initiation: 1.77-2.39 kg (one animal below body weight range, this did not affect the integrity of the study)
- Fasting period before study: no
- Housing: housed individually in wire mesh bottom cages in an environmentally contolled room
- Diet (e.g. ad libitum): NIH Animal Feed A (certified), ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: minimum 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): in compliance with the "Guide for the care and Use of Labolatory Animals"
- Humidity (%): in compliance with the "Guide for the care and Use of Labolatory Animals"
- Air changes (per hr): 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12h dark/12h light

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: abraded dorsal trunk area (clipped free of fur)
- % coverage: approximately 10% of the body surface area
- Type of wrap if used: occlusive binder (a layer of plastic wrap, a protective cloth and a stockinette sleeve all secured in place with masking tape)


REMOVAL OF TEST SUBSTANCE
- Washing (if done): wiped with clean gauze to remove as much non-absorbed test article as possible.
- Time after start of exposure: 24 hours




Duration of exposure:
24h
Doses:
8000 mg/kg
No. of animals per sex per dose:
4
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: mortality, toxic signs observed at day 0 and once daily thereafter for 14 days (at least 5 h apart), body weight observed on day 1 and at death.
- Necropsy of survivors performed: yes
Sex:
male/female
Dose descriptor:
LD50
Effect level:
< 8 000 mg/kg bw
Based on:
test mat.
Mortality:
All animals were dead on Day 2.
Clinical signs:
decreased activity, ataxia, wobbly gait
Body weight:
slight weight loss in all animals
Gross pathology:
eschar formation on back
Interpretation of results:
study cannot be used for classification
Conclusions:
The mortality data presented above suggests that the acute dermal LD50 is less than 8000 mg/kg of body weight.
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
19 December 1990 - 2 January 1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
occlusive dressing applied (instead of non-occlusive)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
- Name of test material (as cited in study report): 6398-24-1, Project #90-018
- Substance type: clear, colorless liquid
- Physical state: liquid
- Analytical purity: responsibility of the sponsor
- Stability under test conditions: no apparent change in the physical characteristics of the test article during administration
- Storage condition of test material: no data
- Other: specific gravity=0.8725 g/ml
- Other: pH=12 (litmus paper)
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products, Denver, PA
- Age at study initiation: young adult
- Weight at study initiation: 2425-3145 g (males), 2522-2866 g (females)
- Housing: individually in cages sized in accordance with the "Guide for the Care and Use of Laboratory Animals" of the Institute of Laboratory Animal Resources, National Research Council.
- Diet (e.g. ad libitum): certified Purina Rabbit Ration H.F., ad libitum
- Water (e.g. ad libitum): fresh tap water, ad libitum
- Acclimation period: minimum 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20±3°C
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): 12h dark/12h light


IN-LIFE DATES: From: 1990-12-19 To: 1991-01-02
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: dorsal area of trunk (clipped free of fur)
- Type of wrap if used: rubber dam and an elastic bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with water and gauze
- Time after start of exposure: 24h




Duration of exposure:
24h
Doses:
3000 mg/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily clinical observations; body weights at days 0, 7 and 14
- Necropsy of survivors performed: yes
Statistics:
Not applicable.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 3 000 mg/kg bw
Based on:
test mat.
Mortality:
None of the rabbits died during the study.
Clinical signs:
Days 1 and 2: 5/10 animals decreased activity
Days 1 and 2: 10/10 animals abnormal stance, abnormal gait, loss of front end support
Days 3 up to 14 no signs in all observed animals
Necrosis of the skin at application site on Days 1 through 14.
Body weight:
d0-d7: body weight slightly decreases
d7-d14: Males: slight decrease of bodyweight; Females: slight increase of bodyweight
Gross pathology:
Terminal necropsy of the animals revealed mottled (9/10 animals), pale (1/10 animal), dark red (2/10 animals) or tan (3/10 animals) lungs and necrosis of underlying muscle tissue at the application site (10/10).
Other findings:
- Other observations: Immediate post-dose vocalization was also observed.
Interpretation of results:
GHS criteria not met
Conclusions:
Based upon the observations made in the present study in rabbits, the dermal LD50 of the substance was determined to be greater than 3000 mg/kg.
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
No data
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: See "Remarks"
Remarks:
GLP study performed according to a method similar to OECD TG 402 with the following deviations: only 2 animals per dose level per sex were used, of which one had abraded skin, and one had intact skin.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
only two animals per sex per dose of which one had abraded and one had intact skin.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): 4236-43-15
- Physical state: liquid
- Analytical purity: responsibility of the Sponsor
- Stability under test conditions: responsibility of the Sponsor
- Storage condition of test material: responsibility of the Sponsor
- Other: article density= 0.88 g/ml
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: H.A.R.E. Rabbits for Research, Hewitt, NJ
- Age at study initiation: no data
- Weight at study initiation: 1.83-2.66 kg
- Fasting period before study: no
- Housing: individually housed.in wire mesh bottom cages
- Diet (e.g. ad libitum): NIH Animal Feed A (certified) ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: minimum of 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): in compliance with the "Guide for the care and Use of Labolatory Animals"
- Humidity (%): in compliance with the "Guide for the care and Use of Labolatory Animals"
- Air changes (per hr): 12-15 air change per hour
- Photoperiod (hrs dark / hrs light): 12h dark/12h light


Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: skin of dorsal area (clipped free of fur and abraded)
- % coverage: app. 10%
- Type of wrap if used: occlusive binder (a layer of plastic wrap, a protective cloth and a stockinette sleeve)

REMOVAL OF TEST SUBSTANCE
- Twenty-four hours post-dose the binders were removed.



Duration of exposure:
24h
Doses:
1000, 1651, 2726 and 4500 mg/kg
No. of animals per sex per dose:
2
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observed once a day during 15 days (dermal readings reported after 30 min, after the binders removal). Body weight: reported initially, on days 8 and 15 , and/or at death.
- Necropsy of survivors performed: yes
Statistics:
The dermal LD50 was calculated by the method of Miller and Tainter (Proc. Soc.Biol. Med. (1944) 57, 261).
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 600 mg/kg bw
Based on:
test mat.
95% CL:
642 - 4 558
Mortality:
1/4 animals are dead at the 1000 (Day 11) and 1651 mg/kg/bw (Day 15)
2/4 animals are dead at the 2726 mg/kg/bw (Days 2 and 4)
3/4 animals are dead at the 4500 mg/kg/bw (Day 2)
Clinical signs:
Daily observations revealed that several animals experienced nasal discharge, anorexia, decreased activity and ataxia. Dermal readings revealed eschar formation in all animals that survived the 24h exposure period.
At 1000 and 1651 mg/kg doses: decreased activity and anorexia (4); nasal discharge (2)
At 1651 mg/kg dose: decreased activity (4), anorexia (4), respiration increased (3), nasal discharge (2), ataxia (2)
At 2726 mg/kg dose: decreased activity (4), respiration increased (4), anorexia (3), ataxia (2)
4500 mg/kg dose: decreased activity (4), respiration increased (4)
Body weight:
d0-d8-d15: body weight decrease
Weight loss in all dosing groups, was partially caused by the trauma experienced from the actual dosing and binding of the animals.
Gross pathology:
At 1000 and 1651 mg/kg doses: intestines inflamed
At 2726 and 4500 mg/kg doses: no noteworthy findings
Interpretation of results:
GHS criteria not met
Conclusions:
The LD50 of the substance in albino rabbits was 2600 mg/kg/bw (95% confidence limit of 642 - 4558 mg/kg).
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

Additional information

Acute toxicity: oral

Mallory VT (1991) investigated the acute oral toxicity via gavage of 500, 800, 1250 and 2000 mg/kg bw test substance in 10 Sprague-Dawley male/female rats. After 14 days of observation, mortality has been observed: 2/10 animals died at the 500 mg/kg dose; 6/10 animals died at the 800 mg/kg dose and 10/10 animals died at both the 1250 and 2000 mg/kg dose levels. The acute oral LD50 was determined to be 688.1 mg/kg bw. This study is designated as key study. In addition, three supporting studies reported higher LD50 values.

Acute toxicity: inhalation

No reliable studies were available for the inhalation route. A waiver statement was added and justified as following: next to the oral route of exposure, for substances other than gases, the information mentioned under 8.5.2 to 8.5.3 shall be provided for at least one other route (REACH Regulation, column 2 adaptation of Annex VIII). For the test substance, a key study is available for the dermal route of exposure. Therefore, an acute inhalation toxicity study should not be performed.

Acute toxicity: dermal

The acute dermal toxicity was evaluated in rats (OECD 402) by Clouzeau (1992). The test substance was applied to 10 Sprague-Dawley rats (5 males and 5 females) at a dose level of 400 and 2000 mg/kg. The animals were checked for clinical signs, mortality and body weight gain for a period of 4 days (2000 mg/kg) or 14 days (400 mg/kg) after the single application of the test substance. No deaths occurred at the dose level of 400 mg/kg. At 2000 mg/kg, 4 females died between days 2 and 4. Under these experimental conditions, the LD50 of the test substance when administered by dermal route in rats was higher than 400 mg/kg. No signs of toxicity were observed at this dose level. The LD50 was estimated at 2000 mg/kg. In order to comply with ethic and scientific recommendations concerning the LD50, a more precise determination was not necessary. At 2000 mg/kg, sedation or hypokinesia and dyspnea were noted between days 2 and 5. Signs of necrosis and ulceration were also observed after removal of the dressing.

Mallory VT (1991) investigated acute dermal toxicity of the test substance in 10 New Zealand White male/female rabbits after 24 hours of exposure. After 14 days of observation, an LD50 value of > 3000 mg/kg bw was reported. This study is designated as supporting study. In addition, two other supporting studies (K3) reported LD50 values of 2600 and <8000 mg/kg bw. The study indicating an LD50 value of 2600 mg/kg, had important deviations from the guideline: only 2 animals were tested per dose and the skin of one of those was abraded.

Justification for classification or non-classification

Based on the results of this study and according to the criteria of the CLP Regulation , the test substance should be classified as a category 4 acute oral toxicant (H302). The test substance should not be classified as acute toxic via the dermal route according to the CLP criteria.

No data were available to decide on the classification via the inhalation route.