Registration Dossier

Administrative data

Description of key information

Oral toxicity

A study was performed to assess the acute oral toxicity of the test material following a single oral administration to the Sprague-Dawley CD strain rat. The method followed that in the OECD Guidelines for Testing of Chemicals No. 423 "Acute Oral Toxicity - Acute Toxic Class Method" (adopted 22 March 1996) and Method B1 tris of Commission Directive 96/54/EC (which constitutes Annex V of Council Directive 67/548/EEC).

The acute median lethal dose, LD50, of the test material was estimated as being greater than 2000 mg/kg. No adverse effects were observed at the highest dose.

Dermal toxicity

A study was performed to assess the acute dermal toxicity of the test material in the Sprague-Dawley CD strain rat. The method used followed that described in the OECD Guidelines for Testing of Chemicals No 402 "Acute Dermal Toxicity" (adopted 24 February 1987) and Method B3 of Commission Directive 92/69/EEC (which constitutes Annex V of Council Directive 67/548/EEC).

The acute dermal median lethal dose (LD50) of the test material in the Sprague-Dawley CD strain rat was found to be greater than 2000 mg/kg bodyweight. No deaths or any other adverse effects were observed at the highest dose.

Inhalation toxicity

The inhalatory LC50,4h value of BMS-214702-01 in Wistar rats was established to exceed 5 mg/L. According to the OECD 436 test guideline, the LC50, 4h cut-off value was considered to exceed 12.5 mg/L.

Based on these results BMS-214702-01 does not have to be classified and has no obligatory labelling requirement for acute inhalation toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2011) (including all

amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments).

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:
Between 24 november and 10 December 1998
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
(adopted 22 March 1996)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
Commission Directive 96/54/EC
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Animals were supplied by Charles River (UK) Ltd, Margate, Kent, UK. At the start of the study the males weighed 220 to 227 g and the females 200 to 216 g and were eight to twelve weeks old. After an acclimatisation period of at least fice days, the animals were selected at random and given a number unique within the cage by tail marking.

The animals were housed in groups of up to three by sex in solid-floor PP cages furnished with woodflakes. With the exception of an overnight fast immediately before dosing and for approximately three to four hours after dosing, free access to mains drinking water and food (Rat and Mouse Expanded Diet No.1, Special Diets Services Limited, Witham, Essex, UK) was allowed throughout the study.
The animal room was maintained at a temperature of 19 to 21 C and relative humidity of 44 to 66%. The rate of air exchange was approximately fifteen changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light and twelve hours darkness.
Route of administration:
oral: gavage
Vehicle:
other: Arachis oil BP
Details on oral exposure:
All animals were dosed once only by gavage, using a metal cannula attached to a graduated syringe. The volume administered to each animal was calculated according to the fasted bodyweight at the dime of dosing. Treatment of animals was sequential. Sufficient time was allowed between each sex to confirm the survival of the previously dosed animals.
Doses:
Dose level: 2000 mg/kg
Concentration: 200 mg/ml
Dose volume: 10 mg/kg
No. of animals per sex per dose:
3 animals per sex per dose
Control animals:
no
Details on study design:
The animals were observed for deaths or overt signs of toxicity 0.5, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days.
Individual body weights were recorded prior to dosing and seven and fourteen days after treatment.
At the end of the observation period the animals were killed by overexposure to carbon dioxide. All animals were subjected to gross pathological examination. This consisted of an external examination and opening of the abdominal and thoracic cavities for examination of major organs. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.

The number of animals dying during the study or killed for humane reasons was determined. The nature, severity, time of onset and duration of toxic effects were also determined. Effects on bodyweights and abnormalities noted at necropsy were identified. Using the mortality data obtained, an estimate of the acute oral median lethal dose (LD50) of the test material was made.
Statistics:
Not mentioned
Preliminary study:
The animals were exposed on a single dose of 2000 mg/kg bw, selected according to the available information.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
Male: 2000 mg/kg bw; Number of animals: 3; Number of deaths: 0
Female: 2000 mg/kg bw; Number of animals: 3; Number of deaths: 0
Clinical signs:
Signs of toxicity related to dose levels:
No signs of systemic toxicity were noted during the study period.
All animals showed expected gains in bodyweight over the study period.
Body weight:
Bodyweight gain during Week 1 / Week 2
Female 1-0: 23 / 15
Female 1-1: 31 / 17
Female 1-2: 36 / 2
Male 2-0: 50 / 43
Male 2-1: 56 / 34
Male 2-2: 64 / 45
Gross pathology:
Effects on organs:
No abnormalities were noted at necropsy of animals killed at the end of the study period.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral LD50 of the test material, BMS 214702-01, in the Sprague-Dawley CD strain rat was estimated to be greater than 2000 mg/kg.
No symbol and risk phrase are required according to EU labelling regulations.
Executive summary:

Methods

A study was performed to assess the acute oral toxicity of the test material following a single oral administration to the Sprague-Dawley CD strain rat. The method followed that in the OECD Guidelines for Testing of Chemicals No. 423 "Acute Oral Toxicity - Acute Toxic Class Method" (adopted 22 March 1996) and Method B1 tris of Commission Directive 96/54/EC (which constitutes Annex V of Council Directive 67/548/EEC).

The results may be used as a basis for classification and labelling under Annex VI of Council Directive 67/548/EEC (as adapted to technical progress by Commission Directive 93/21/EEC) relating to the classification, packaging and labelling of dangerous substances.

Procedures

Using all available information, 2000 mg/kg bodyweight was selected as the starting dose.

A group of three fasted females was treated with the starting dose. This was followed by a group of three fasted animals of the other sex at the same dose level. Dosing was performed sequentially.

The test material was administered orally as a suspension in arachis oil BP. The animals were observed 0.5, 1, 2 and 4 hours after dosing and then once daily for up to fourteen days. Bodyweights were recorded on Day 0 (day of dosing) and on Days 7 and 14. At the end of the observation period all animals were killed by overexposure to carbon dioxide and were subjected to gross necropsy.

Results

The following results were obtained:

  • There were no deaths.
  • There were no signs of systemic toxicity.
  • All animals showed expected gains in bodyweight over the study period.
  • No abnormalities were noted at necropsy.
  • The acute median lethal dose, LD50, of the test material was estimated as being greater than 2000 mg/kg.

Conclusion

No symbol and risk phrase are required according to EU labelling regulations.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
Study performed according to guideline

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
Study period:
09 - 27 March 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
Version / remarks:
Organisation for Economic Co-operation and Development (OECD), OECD Guidelines for Testing of Chemicals, Section 4, Health Effects. No.436, "Acute Inhalation Toxicity - Acute Toxic Class Method", September 2009.
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Wistar
Remarks:
Crl:WI(Han) - (outbred, SPF-Quality)
Sex:
male/female
Details on test animals and environmental conditions:
Animal source: Charles River Deutschland, Sulzfeld, Germany.
Young adult animals were selected (approximately 10 weeks old). Animals used within the study were of approximately the same age and body weight variation did not exceed +/- 20% of the sex mean. At least prior to exposure animal health was inspected. It was ensured that the animals were hwalthy and without any abnormality that might affect the study integrity.

The temperature and relative humidity were measured with a humidity and temperature indicator (E+E Elektronik, Engerwitzdorf, Austria) and were recorded after the animals were placed in the experimental set-up and at 30 minute intervals after initiation of the exposure. The probe was inserted in a tube mounted in one of the free animal ports of the middle section of the exposure chamber. The temperature of the atmosphere was between 21.2 and 22.1oC and relative humidity was between 12 and 18%. These conditions were considered appropriate for this relatively short 4 hours exposure duration.

Animal Husbandry
Conditions:
Environmental controls for the animal room were set to maintain 18 to 24°C, a relative humidity of 40 to 70%, at least 10 air changes/hour, and a 12-hour light/12-hour dark cycle. Any variations to these conditions were maintained in the raw data and had no effect on the outcome of the study.

Accommodation
Group housing of three animals per sex per cage in labelled Makrolon cages (type IV; height 18 cm) containing sterilised sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom). Acclimatisation period was at least 5 days before start of treatment under laboratory conditions. During this period, animals were housed at maximally five animals per cage per sex as described above.

Diet
Free access to pelleted rodent diet (SM R/M-Z from SSNIFF Spezialdiaeten GmbH, Soest, Germany) except during exposure to the test substance.

Water
Free access to tap water except during exposure to the test substance

Animal husbandry on the day of exposure
The animals were moved to the inhalation area to in order to perform the exposure. During the exposure, there was no access to food and water. After exposure, the animals were returned to their cages which were placed in a fume cupboard for a short time period to allow test substance remnants to evaporate. A sheet of filter paper was used to cover the bedding material to prevent suffocation in case of bad health condition and in order to recover and to aid the clinical observations. The sheet was removed and before the end of the exposure day, the surviving animals were returned to the animal room.

Diet, water, bedding and cage enrichment evaluation for contaminants and/or nutrients was performed according to facility standard procedures. There were no findings that could interfere with the study.
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Mass median aerodynamic diameter (MMAD):
>= 3.3 - <= 4.9 µm
Geometric standard deviation (GSD):
>= 1.8 - <= 2
Remark on MMAD/GSD:
At 1 mg/l concentration: 4.9 μm (gsd 1.8) at both occasions
At 5 mg/l concentration: 4.9 μm (gsd 2.0) and 3.3 μm (gsd 1.8)
Details on inhalation exposure:
The design of the exposure chamber is based on the flow past nose-only inhalation chamber (Am. Ind. Hyg Assoc. J. 44(12): 923-928, 1983). The chamber (volume approximately 150 mL) consisted of three animal sections with eight animal ports each. Each animal port had its own atmosphere inlet and exhaust outlet. The animals were placed in restraining tubes and connected to the animal ports. The number of animal sections and number of open inlets were adapted to the air flow in such a way that at each animal port the theoretical air flow was at least 1 L/min, which ensures an adequate oxygen supply to the animals. The main inlet of the test atmosphere was located at the top section and the main outlet was located at the bottom section. The direction of the flow of the test atmosphere guaranteed a freshly generated atmosphere for each individual animal. All components of the exposure chamber in contact with the test material were made of stainless steel, glass, rubber or plastic. To avoid exposure of the personnel and contamination of the laboratory the exposure chamber was placed in a fume hood, which maintained at a slight negative pressure.

The test atmosphere generation was based on the method developed during extensive trial generations. Trial generation results showed that the test substance was not volatile and the test atmosphere consisted mainly of aerosol with a negligibly small (if any) vapor part. The generation was performed at the technically maximum attainable concentration.

The test substance formulation was placed on a magnetic stirrer and was transferred to a stainless steel nebulizer (type 156.000.16.16, Lechler, Metzinger, Germany) by means of a rotating pump (type VL500 digit, VERDER Lab Tec GmbH & Co. KG, Haan, Germany). The nebulizer was mounted under a vertical elutriator in which large droplets were allowed to settle. The formulation was nebulized with the use of pressurized air with a mean total airflow of 17.3 L/min. From the elutriator the test atmosphere was passed through the exposure chamber.

For the exposure to 1 mg/L, the primary aerosol was diluted with pressurized air before it entered the exposure chamber and the resulting mean total airflow was 40 L/min.
For the exposure to 5 mg/L, the mean total airflow was 15 L/min. From the exposure chamber the test atmosphere was passed through a filter before it was released to the exhaust of the fume hood.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
gravimetric determination
Duration of exposure:
ca. 4 h
Concentrations:
Target concentrations were based on the cut off concentration values specified in the UN and EC classification guidelines. The study started with the exposure of three animals of each sex for 4 hours to a target concentration of the test substance of 1 mg/L. Based on the results, three animals of each sex were exposed to the highest target concentration of 5 mg/L.

For the 1 mg/L exposure group, the time-weighted mean actual concentration was 1.2 ± 0.04mg/L. The nominal concentration (amount of test substance used divided by the volume of pressurized air used) was 20 mg/L. The generation efficiency (ratio of actual and nominal concentration) was 6%. The concentration measurements equally distributed over time showed that the substance was sufficiently stable. The variations in concentration were caused by adjustments to the generation equipment and were considered not to have affected the exposure level. By calculating the time-weighted mean concentration, the effects of these variations were taken into account resulting in an actual reflection of the mean exposure concentration over time.

For the 5 mg/L exposure group, the time-weighted mean actual concentration was 5.6 ± 0.15mg/L. The nominal concentration (amount of test substance used divided by the volume of pressurized air used) was 158 mg/L. The generation efficiency (ratio of actual and nominalconcentration) was 0.6%. The concentration measurements equally distributed over time showed that the substance was sufficiently stable. The variations in concentration were caused by adjustments to the generation equipment and were considered not to have affected the exposure level. The generation was interrupted at three occasions in order to remove test substance deposits from the system or to refill the dust feeder with test substance. The generation time was elongated with 13 minutes in order to achieve an actual exposure time of 240 minutes.
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
Observations
Mortality / Viability: Twice daily
Clinical signs during exposure: Three times during exposure for mortality, behavioural signs of distress and effects on respiration
Clinical signs after exposure: On Day 1, one and three hours after exposure and once daily thereafter until Day 15. The clinical signs were graded according to fixed scales and the time of onset, degree and duration were recorded.
Body weights: Days 1 (pre-administration), 2, 4, 8 and 15
Necropsy: All animals were euthanatized at the end of the observation period by an intraperitoneal injection with Euthasol ® (AST Farma BV, Oudewater, The Netherlands). All animals assigned to the study were subjected to necropsy and descriptions of all internal macroscopic abnormalities were recorded. Particular attention was given to any changes in the respiratory tract.
Preliminary study:
No
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5 mg/L air (nominal)
Based on:
test mat. (total fraction)
Exp. duration:
4 h
Key result
Sex:
male/female
Dose descriptor:
LC50 cut-off
Effect level:
> 12.5 mg/L air (nominal)
Based on:
test mat. (total fraction)
Exp. duration:
4 h
Mortality:
No mortality occurred at 1 and 5 mg/l.
Clinical signs:
other: At 1 mg/L, no clinical signs of systemic toxicity were noted. At 5 mg/L, no clinical signs were seen during exposure (not presented in the table). After exposure, lethargy, hunched posture, and piloerection were observed in the animals. Laboured respirati
Body weight:
Overall mean body weight gain in males and females was within the range expected for rats of this strain and age used in this type of study and were therefore considered not indicative of toxicity.
Gross pathology:
No test substance related abnormalities were found at macroscopic post mortem examination of the animals.

Pelvic dilation of the kidney, as found in one male exposed to 5 mg/L, is occasionally seen among rats of this age and strain and was therefore considered not related to treatment.

See attached pdf document.

Interpretation of results:
GHS criteria not met
Conclusions:
The inhalatory LC50, 4h value of BMS-214702-01 in Wistar rats was established to exceed 5mg/L. According to the OECD 436 test guideline, the LC50, 4h cut-off value was considered to exceed 12.5 mg/L.

Based on these results BMS-214702-01 does not have to be classified and has no obligatory labelling requirement for acute inhalation toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2011) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments).
Executive summary:

Assessment of acute inhalation toxicity with BMS-214702-01 in the rat (acute toxic class method) (nose-only).

The study was carried out based on the guideline described in Organisation for Economic Cooperation and Development (OECD), OECD Guidelines for Testing of Chemicals, Section 4, Health Effects. No.436, "Acute Inhalation Toxicity - Acute Toxic Class Method", September 2009.

BMS-214702-01 was administered as a dust by nose-only inhalation for 4 hours to two groups of three males and three females. Mortality and clinical signs were observed daily during the observation period and body weights were determined on Days 1, 2, 4, 8 and 15. Macroscopic

examination was performed after terminal (Day 15).

For the 1 mg/L exposure group, the time-weighted mean actual concentration was 1.2 ± 0.04 mg/L. The nominal concentration (amount of test substance used divided by the volume of pressurized air used) was 20 mg/L. The generation efficiency (ratio of actual and nominal concentration) was 6%. The concentration measurements equally distributed over time showed that the substance was sufficiently stable.

For the 5 mg/L exposure group, the time-weighted mean actual concentration was 5.6 ± 0.15 mg/L. The nominal concentration (amount of test substance used divided by the volume of pressurized air used) was 158 mg/L. The generation efficiency (ratio of actual and nominal concentration) was 0.6%. The concentration measurements equally distributed over time showed that the substance was sufficiently stable.

The Mass Median Aerodynamic Diameter (MMAD) and geometric standard deviation (gsd) were determined twice during the each exposure period. At 1 mg/L, the MMAD was 4.9 µm (gsd 1.8) at both occasions. At 5 mg/L, the MMAD was 4.9 µm (gsd 2.0) and 3.3 µm (gsd 1.8).

The MMAD just exceeded the recommended range of 1 - 4 µm at three occasions. There was no evidence for substance deposition in the upper airways due to the larger size. Since it is generally known that good distribution throughout the lung requires particles with an aerodynamic diameter between 1 and 5 μm, it can be assumed that sufficient deposition in the lower respiratory tract occurred during the exposure. At 5 mg/L, the MMAD became smaller during the exposure since the test material had to be retrieved from the cyclone, grinded and used again due to the limited availability of fresh test substance. It was considered that the study outcome was not affected.

No mortality occurred at 1 and 5 mg/L. At 1 mg/L, no clinical signs of systemic toxicity were noted. At 5 mg/L, no clinical signs were seen during exposure (not presented in the table). After exposure, lethargy, hunched posture, and piloerection were observed in the animals. Laboured respiration and ptosis were seen for the males and watery discharge and chromodacryorrhoea was seen for the females. The animals had recovered from the signs by Day 6.

Overall mean body weight gain in males and females was within the range expected for rats of this strain and age used in this type of study and were therefore considered not indicative of toxicity.

No test substance related abnormalities were found at macroscopic post mortem examination of the animals.

The inhalatory LC50, 4h value of BMS-214702 -01 in Wistar rats was established to exceed 5 mg/L According to the OECD 436 test guideline, the LC50,4h cut-off value was considered to exceed 12.5 mg/L.

Based on these results BMS-214702-01 does not have to be classified and has no obligatory labelling requirement for acute inhalation toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2011) (including all

amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating conc.
Value:
5 000 mg/m³
Quality of whole database:
Study was carried out according to OECD Test Guideline 436

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
Study period:
Between 21 july 1999 and 4 August 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
adopted 24 February 1987
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
Commission Directive 92/69/EEC
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Remarks:
CD (Crl: CE (SD) IGS BR)
Sex:
male/female
Details on test animals and environmental conditions:
Test animals were supplied by Charles River (UK) Ltd, Margate, Kent, UK. At the start of the study the males weighed 202 to 252 g and the females 212 to 227 g and were approximately eight to twelve weeks old. After an acclimatisation period of at least five days, the animals were selected at random and given a number unique within the cage by indelible ink-marking on the tail and a number written on a cage card.

The animals were housed in suspended PP cages furnished with woodflakes. They were housed individually during the 24-hour exposure period and in groups of five, by sex, for the remainder of the study. Free access to mains drinking water and food (Rat and Mouse Expanded Diet No.1, Special Diets Services Limited, Witham, Essex, UK) was allowed throughout the study.

The temperature and relative humidity were controlled to remain within target ranges of 19 to 25 C and 30 to 70% respectively. Occasional deviations from these targets were considered not to have affected the purpose or integrity of the study. The rate of air exchange was approximately fifteen changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light and twelve hours darkness.
Type of coverage:
semiocclusive
Vehicle:
other: Arachis oil BP
Details on dermal exposure:
On the day before treatment the back and flanks of each animal were clipped free of hair using veterinary clippers.
Duration of exposure:
24 h
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 animals per sex per dose
Control animals:
no
Details on study design:
The appropriate amount of the test material, moistened with arachis oil BP to form a paste, was pplied uniformly to an area of shorn skin (approximating to 10% of the total body surface area). A piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage. The animals were caged individually for the 24-hour exposure period. Shortly after dosing the dressings were examined to ensure that they were securely in place.

The animals were observed for deaths or overt signs of toxicity 0.5, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days.

After the 24-hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with distilled water to remove any residual test material. The animals were returned to group housing for the remainder of the study period.

After removal of the dressings and subsequently once daily for fourteen days, the test sites were examined for evidence of primary irritation and scored according to the scale from Draize J H (1977) "Dermal and Eye Toxicity Tests" In: Principles and Procedures for Evaluating the Toxicity of Household Substances, National Academy of Sciences, Washington DC p.31.

Any other skin reactions, if present, were also reported.

Individual bodyweights were recorded prior ro application of the test material on Day 0 and Days 7 and 14.

At the end of the study, the animals were killed by cervical dislocation and subjected to gross pathological examination. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.

Data evaluations included the relationship, if any, between the animal's exposure to the test material and the incidence and severity of all abnormalities including behavioural and clinical observations, gross lesions, bodyweight changes, mortality and any other toxicological effects. Using the mortality data obtained, an estimate of the acute dermal median lethal dose (LD50) of the test material was made.
Statistics:
Not mentioned
Preliminary study:
Study was a limit test
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
Male: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Clinical signs:
Signs of toxicity related to dose levels:
No signs of systemic toxicity were noted during the study period. No toxicologically significant effects on bodyweight were noted during the study.
Body weight:
All animals showed an expected gain in bodyweight during the study.
Gross pathology:
Effects on organs:
No abnormalities were noted at necropsy of animals killed at the end of the study.
Other findings:
Signs of toxicity (local):
No signs of dermal irritation were noted during the study period.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute dermal median lethal dose (LD50) of the test material, BMS 214702-01, in the Sprague-Dawley CD strain rat was found to be greater than 2000 mg/kg bodyweight. No symbol and risk phrase are required according to EU labelling regulations.
Executive summary:

Methods

A study was performed to assess the acute dermal toxicity of the test material in the Sprague-Dawley CD strain rat. The method used followed that described in the OECD Guidelines for Testing of Chemicals No 402 "Acute Dermal Toxicity" (adopted 24 February 1987) and Method B3 of Commission Directive 92/69/EEC (which constitutes Annex V of Council Directive 67/548/EEC).

The results may be used as a basis for classification and labelling under Annex VI of Council Directive 67/548/EEC (as adapted to technical progress by Commission Directive 93/21/EEC) relating to the classification, packaging and labelling of dangerous substances.

Procedures

A group of ten animals (five males and five females) was given a single 24-hour, semi-occluded dermal application to intact skin at a dose level of 2000 mg/kg bodyweight. The animals were observed for fourteen days after the day of treatment and were then killed for gross pathological examination.

Results

There were no deaths. No signs of systemic toxicity or dermal irritation were noted during the study.

All animals showed an expected gain in bodyweight during the study.

No abnormalities were noted at necropsy.

Conclusions

The acute dermal median lethal dose (LD50) of the test material in the Sprague-Dawley CD strain rat was found to be greater than 2000 mg/kg bodyweight. No symbol and risk phrase are required according to EU labelling regulations.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
Study was carried out according to guideline

Additional information

Justification for classification or non-classification

An acute oral study and acute dermal toxicity study did not show any toxicity or any other adverse effects at the highest testing dose of 2000 mg/kg bw. The LD50 was >2000 mg/kg bw in both studies, which is above the limit for classification as acute toxic. An acute inhalation toxicity study did not show any toxicity after a 4h exposure to 5 mg/l of the test substance.