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Description of key information

Acute Oral Toxicity:

The test substance (SiMAA2) was assessed for acute oral toxicity using a test method equivalent/similar to OECD 423.

The test substance was administered once orally to male and female rats at 2000 mg/kg and its toxicity was evaluated.

No animals died in each group of males and females, and the LD50 was assessed to be higher than 2000 mg/kg.

In addition, no treatment-related effects were observed in general conditions, body weight, and anatomy findings.

Under the conditions of the study, no animals died after single administration of SiMAA2 at 2000 mg/kg, and no other toxicological effects were detected.

Acute Dermal Toxicity:

The test substance (SiMAA2) was assessed for acute dermal toxicity using a test method equivalent/similar to OECD 402.

The test substance was administered once dermally to male and female rats at 2000 mg/kg and its toxicity was evaluated.

 

No animals died in each group of males and females, and the LD50 was assessed to be higher than 2000 mg/kg.

In addition, no treatment-related effects were observed in general conditions, body weight, and anatomy findings.

 

Under the conditions of the study, no animals died after single administration of SiMAA2 at 2000 mg/kg, and no other toxicological effects were detected.

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 October 2002 to 25th October 2002
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted in accordance with generally accepted scientific principles, possibly with incomplete reporting or methodological deficiencies, which do not affect the quality of relevant results.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Principles of method if other than guideline:
The test material was evaluated following a single oral administration to male and female Slc:SD rats. The oral route and a single dose of 2000 mg/kg were selected. According to the OECD Guidelines for acute toxicity studies, no further dose levels are necessary when there are no toxic signs at 2000 mg/kg.
GLP compliance:
not specified
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
other: Slc:SD
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Animals bred at Japan SLC, Inc
- Age at study initiation: 4 weeks old
- Weight at study initiation: Mean body weight of 124.65-126.12g for males and 109.54-110.90g for females
- Fasting period before study: 16 hours of fasting
- Housing: Animal room 2207 in the animal building II, in the barrier-sustained facility. Animals were housed in Stainless steel, wire mesh cages (W37cm x D47cm x H19cm) equipped with urinary trays and a wire mesh bottom were used throughout the acclimatisation and study periods. Five animals were housed in a cage
- Diet: Radiation-sterilized pellet diet Labo stock (Nosan Corporation) was fed ad libitum
- Water: Chlorinated well water supplied using water bottles ad libitum
- Acclimation period: 7 days, 5 animals per cage.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-27 deg C
- Humidity (%): 30-70
- Air changes (per hr): Ca 16 times per hour
- Photoperiod (hrs dark / hrs light): 12 hours per day (7:00 am - 7:00 pm)
- Urinary trays were exchanged twice a week, with new trays containing autoclaved bedding
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
VEHICLE
- Concentration in vehicle: No verchile was used. the substance is a liquid, hence was used as a dosing soultion


DOSAGE PREPARATION (if unusual): 2000 mg/kg of neat substance


Doses:
2000 mg/kg
No. of animals per sex per dose:
2000 mg/kg dose: 5 males/5 females
Control (group given water for injection only): 5 males/5 females
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed for general condition continuously until 6 hours after administration and once every day thereafter until Day 14. Body weight was measured just prior to administration and on Days 7 and 14 after administration. Day 0 was defined as the day of administration.
- Necropsy of survivors performed: yes - After 14 days of administration, animals were euthanized by exsanguination under ether anesthesia, and organs and tissues were observed grossly for any abnormalities.
Statistics:
Group means and standard deviations of body weight were calculated for each group. At statistical analysis, the homogeneity of variance was evaluated using F-test, and then student's t-test was applied when the variance was homogeneous; when the variance was heterogeneous, Aspin-Wlch t-test was used. Statistical significance of the difference between control and treated groups was analyzed at the significance level of 5%, and the results were shown as either P<0.05 (lower than 5%) or P<0.01 (lower than 1%).
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No animals died in any group of either sex.
Clinical signs:
There were no abnormalities in general condition.
Body weight:
The body weight changes of males and females in the SiMAA2 treated group were comparable to those in the control group and there were no statistically significant differences compared to the controls on any days of measurement.
Gross pathology:
No abnormalities were detected in any group at anatomy conducted at termination of the study.

Results of motality and LD50. Administration of test material via oral route:

Sex  Dose (mg/kg)  Mortality  LD50 (mg/kg) 
Male  Contol  0/5   
Male  2000  0/5  >2000 
 Female  Control  0/5  
 Female  2000  0/5  >2000

Mortality: Number of dead rats/number of treated rats

Interpretation of results:
GHS criteria not met
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the study, no animals died after single administration of SiMAA2 at 2000 mg/kg and no other toxicological effects were detected.
Executive summary:

According to the OECD guidelines for acute toxicity studies, no further dose levels are necessary when there are no toxic signs at 2000 mg/kg after single oral administration.

Therefore, SiMAA2 was administered once orally to male and female rats at 2000 mg/kg and its toxicity was evaluated.

No animals died in each group of males and females, and LD50 was higher than 2000 mg/kg.

In addition, no treatment-related effects were observed in general conditions, body weight, and anatomy findings.

Under the conditions of the present study, no animals died after single administration of SiMAA2 at 2000 mg/kg, and no other toxicological effects were detected.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 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
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
October 4 2002 to October 25, 2002
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted in accordance with generally accepted scientific principles, possibly with incomplete reporting or methodological deficiencies, which do not affect the quality of relevant results.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Slc:SD
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Rats bred at Japan SPLC, Inc.
- Age at study initiation: 6 weeks old.
- Weight at study initiation: Males: Mean weight of test group = 232.85 g. Females: Mean weight of test group = 166.28 g
- Fasting period before study: None.
- Housing: Stainless steel wire mesh cages (W37 × D47 × H19 cm) equipped with urinary trays and wire mesh bottom were used during the
acclimatization period. Urinary trays were exchanged twice a week with new trays containing autoclaved bedding (Softchip of fir). Aluminum cages (W25 × D40 × H18 cm) were used during the study period. Cages were exchanged twice a week with new ones containing autoclaved fresh and clean bedding. Five animals were housed in a cage during the acclimatization period and one animal after grouping.
- Diet (e.g. ad libitum): Radiation-sterilized pellet diet was fed ad libitum
- Water (e.g. ad libitum): Chlorinated well water was supplied using water bottles ad libitum
- Acclimation period: 7 days prior to study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 27°C
- Humidity (%): 30 - 70%
- Air changes (per hr): approximately 16 times per hour
- Photoperiod (hrs dark / hrs light): illumination for 12 hours/day

Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: Approximately 24 hours prior to administration, fur was clipped from the dorsal area of the trunk with an electric clipper.
- % coverage: The test article was applied evenly over an area approximately 10% of the body surface area.
- Type of wrap if used: The area was covered with a porous gauze dressing throughout the exposure period of 24 hours and the attachment between the test article and the skin was further secured with non-irritating tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Not stated.
- Time after start of exposure: 24 hours.

TEST MATERIAL
Dose concentration: 2000 mg/kg.
The administration volume was calculated individually based on the body weight on the day of administration.

VEHICLE
Not applicable. Since the test article was liquid, it was used as a dosing solution as it was.





Duration of exposure:
24 hours.
Doses:
2000 mg/kg.
No. of animals per sex per dose:
5 males and 5 females at 2000 mg/kg.
Control animals:
other: A group of 5 males and 5 females were given water for injection only as a control.
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed for general condition continuously until 6 hours after administration and once every day thereafter until Day 14. Body weight was measured just prior to administration and on Days 7 and 14 after administration. Day 0 was
defined as the day of administration.
- Necropsy of survivors performed: yes - After 14 days of administration, animals were euthanized by exsanguination under ether anesthesia, and organs and tissues were observed grossly for any abnormalities.
Statistics:
Group means and standard deviations of body weight were calculated for each group. At statistical analysis, the homogeneity of variance was evaluated using F-test, and then Student’s t-test was applied when the variance was homogeneous; when the variance was heterogeneous, Aspin-Welch t-test was used. Statistical significance of the difference between the control and treated groups was analyzed at the significance level of 5%, and the results were shown as either P < 0.05 (lower than 5%) or P < 0.01 (lower than 1%).
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No animals died in any group of either sex.

Clinical signs:
There were no abnormalities in general condition.

Body weight:
The body weight changes of males and females in the SiMAA2-treated group were comparable to those in the control group, and there were no statistically significant differences compared to the controls on any days of measurement.

Gross pathology:
At necropsy conducted at termination of the study, a hepatodiaphragmatic nodule was observed in one male in the 2000 mg/kg group. The lesion was, however, considered incidental because of its severity as well as the fact that the change is frequently observed in the untreated control group. There were no other abnormalities in any group.

Table 1: Mortality and LD50

 

Route

Sex

Dose (mg/kg)

Mortality

LD50 (mg/kg)

Dermal

Male

Control

0/5

>2000

2000

0/5

Female

Control

0/5

>2000

2000

0/5

Table 2: Group mean body weight

 

Sex

Dose (mg/kg)

Days after administration

 

-1

7

14

Male

Control

N

5

5

5

Mean

230.98

278.27

315.70

S.D.

4.55

8.90

11.65

2000

N

5

5

5

Mean

232.85

286.64

329.42

S.D.

5.25

14.26

19.37

Female

Control

N

5

5

5

Mean

163.17

184.00

198.13

S.D.

4.59

8.76

7.68

2000

N

5

5

5

Mean

166.28

187.70

200.74

S.D.

7.22

10.24

11.65

Interpretation of results:
GHS criteria not met
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
SiMAA2 was administered once dermally to male and female rats at 2000 mg/kg and its toxicity was evaluated.
No animals died in each group of males and females, and the LD50 was higher than 2000 mg/kg.

Executive summary:

According to the OECD guidelines for acute toxicity studies, no further dose levels are necessary when there are no toxic signs at 2000 mg/kg after single dermal administration.

 

Therefore, SiMAA2 was administered once dermally to male and female rats at 2000 mg/kg and its toxicity was evaluated.

 

No animals died in each group of males and females, and LD50 was higher than 2000 mg/kg.

In addition, no treatment-related effects were observed in general conditions, body weight, and anatomy findings.

 

Under the conditions of the present study, no animals died after single administration of SiMAA2 at 2000 mg/kg, and no other toxicological effects were detected.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

The acute oral and acute dermal LD50 values of the test substance were >2000 mg/kg bw.

Justification for classification or non-classification

In the CLP regulation acute toxicity means those adverse effects occurring following oral or dermal administration of a sinlge dose of a substance or a mixture, or multiple doses given within 24 hours, or an inhalation exposure of 4 hours.

The substance does not meet the criteria for classification under the CLP regulations for acute toxicity via the oral based on the result of an acute oral toxicity study, which gave a LD50 of greater than 2000 mg/kg bodyweight, which is above the classification cut-off value ( ≤2000 mg/kg bodyweight) for acute oral toxicity.

The substance does not meet the criteria for classification under the CLP regulations for acute toxicity via the dermal based on the result of an acute dermal toxicity study, which gave a LD50 of greater than 2000 mg/kg bodyweight, which is above the classification cut-off value ( ≤2000 mg/kg bodyweight) for acute dermal toxicity.