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EC number: 276-538-7 | CAS number: 72252-58-5
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Endpoint summary
Administrative data
Description of key information
The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2500 mg/kg body weight.
The acute dermal LD50of the test item is more than 2000 mg/kg body weight in male and female Wistar rats.
Key value for chemical safety assessment
Acute toxicity: via oral route
Link to relevant study records
- Endpoint:
- acute toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Betwen 26 May 2016 and 15 June 2016
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Test type:
- acute toxic class method
- Limit test:
- yes
- Species:
- rat
- Strain:
- Wistar
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- Female Wistar (RccHan™:WIST) strain rats were supplied by Envigo RMS (UK) Limited, Oxon, UK. On receipt the animals were randomly allocated to cages. The females were nulliparous and non pregnant. After an acclimatization period of at least 5 days the animals were selected at random and given a number unique within the study by indelible ink marking on the tail and a number written on a cage card. At the start of the study the animals were 8 to 12 weeks of age. The body weight variation did not exceed ±20% of the mean body weight of any previously dosed animals.
Animal Care and Husbandry
The animals were housed in groups three in suspended solid floor polypropylene cages furnished with woodflakes. With the exception of an overnight fast immediately before dosing and for approximately 3 to 4 hours after dosing, free access to mains drinking water and food (2014C Teklad Global Rodent diet supplied by Envigo RMS (UK) Limited, Oxon, UK) was allowed throughout the study. The diet, drinking water and bedding were routinely analyzed and were considered not to contain any contaminants that would reasonably be expected to affect the purpose or integrity of the study.
The temperature and relative humidity were set to achieve limits of 19 to 25 °C and 30 to 70% respectively. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give 12 hours continuous light and 12 hours darkness.
The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study. - Route of administration:
- oral: gavage
- Vehicle:
- arachis oil
- Details on oral exposure:
- All animals were dosed once only by gavage
- Doses:
- Using available information on the toxicity of the test item, 2000 mg/kg was chosen as the starting dose.
Groups of fasted animals were treated as follows:
Dose Level(mg/kg) Concentration(mg/mL) Dose Volume(mL/kg) Number of Rats(Female)
2000 200 10 3
2000 200 10 3 - No. of animals per sex per dose:
- 3 animals per dose, 2 dose groups.
- Control animals:
- no
- Details on study design:
- Using available information on the toxicity of the test item, 2000 mg/kg was chosen as the starting dose.
Groups of fasted animals were treated as follows:
Dose Level(mg/kg) Concentration(mg/mL) Dose Volume(mL/kg) Number of Rats(Female)
2000 200 10 3
2000 200 10 3
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 body weight at the time of dosing. Treatment of animals was sequential. Sufficient time was allowed between each group to confirm the survival of the previously dosed animals.
The animals were observed for deaths or overt signs of toxicity 30 minutes, 1, 2 and 4 hours after dosing and subsequently once daily for 14 days.
Individual body weights were recorded prior to dosing and 7 and 14 days after treatment.
At the end of the observation period the animals were killed by cervical dislocation. 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. - Statistics:
- None recorded
- Preliminary study:
- Not applicable.
- Key result
- Sex:
- female
- Dose descriptor:
- LD50
- Effect level:
- > 2 000 mg/kg bw
- Based on:
- test mat.
- Remarks on result:
- other: 95% CL not reported
- Mortality:
- Individual mortality data are given in Table 1
There were no deaths - Clinical signs:
- other: Individual clinical observations are given in Appendix 1. Noisy respiration and/or hunched posture were noted in the first group of three treated animals. These animals appeared normal 4 hours or 2 days after dosing. No signs of systemic toxicity were no
- Gross pathology:
- Individual necropsy findings are given in Table 3.
Black stained kidneys and stomach were noted at necropsy of the first group of three treated animals. No abnormalities were noted at necropsy of the second group of three treated animals. - Other findings:
- None
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2500 mg/kg body weight (Globally Harmonized Classification System - Unclassified).
- Executive summary:
Introduction
The study was performed to assess the acute oral toxicity of the test item in the Wistar strain rat.
Methods
A group of three fasted females was treated with the test item at a dose level of 2000 mg/kg body weight. This was followed by a further group of three fasted females at the same dose level. Dosing was performed sequentially.
The test item was administered orally as a suspension in arachis oil BP. During the observation period of 14 days clinical signs and body weight development were monitored. Thereafter all animals were subjected to gross necropsy.
Results
Mortality. There were no deaths.
Clinical Observations. Noisy respiration and/or hunched posture were noted in the first group of three treated animals. There were no signs of systemic toxicity noted in the second group of three treated animals. Black staining of the feces and urine was noted in the cages of all animals.
Body Weight. All animals showed expected gains in body weight.
Necropsy. Black stained kidneys and stomach were noted at necropsy of the first group of three treated animals. No abnormalities were noted at necropsy of thesecond group of three treated animals.
Conclusion
The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2500 mg/kg body weight (Globally Harmonized Classification System - Unclassified).
Reference
Table1 Individual Clinical Observations and Mortality Data
Dose Level mg/kg |
Animal Number and Sex |
Effects Noted After Dosing |
Effects Noted During Period After Dosing |
||||||||||||||||
½ |
1 |
2 |
4 |
1UF |
2U*F |
3U*F |
4U*F |
5F· |
6 |
7 |
8 |
9 |
10 |
11 |
12 |
13 |
14 |
||
2000 |
1-0 Female |
H |
H |
H |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1-1 Female |
HRn |
HRn |
HRn |
Rn |
Rn |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
1-2 Female |
HRn |
HRn |
HRn |
Rn |
Rn |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2-0 Female |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2-1 Female |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2-2 Female |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0= No signs of systemic toxicity
H = Hunched posture
Rn =Noisy respiration
F = Black colored staining of the feces
F·= Black colored staining of the feces of animal numbers 1-0, 1-1 and 1-2
U = Black staining of the urine
U* =Black staining of the urine in the cages of animal numbers 2-0, 2-1 and 2-2
Table 2 Individual Body Weights and Body Weight Changes
Dose Level |
Animal Number |
Body Weight (g) at Day |
Body Weight Gain (g) During Week |
|||
0 |
7 |
14 |
1 |
2 |
||
2000 |
1-0 Female |
176 |
186 |
199 |
10 |
13 |
1-1 Female |
173 |
184 |
192 |
11 |
8 |
|
1-2 Female |
188 |
213 |
220 |
25 |
7 |
|
2-0 Female |
184 |
194 |
217 |
10 |
23 |
|
2-1 Female |
202 |
207 |
220 |
5 |
13 |
|
2-2 Female |
198 |
205 |
221 |
7 |
16 |
Table 3 Individual Necropsy Findings
Dose Level |
Animal Number |
Time of Death |
Macroscopic Observations |
2000 |
1-0 Female |
Killed Day 14 |
Kidneys: stained black Stomach: stained black |
1-1 Female |
Killed Day 14 |
Kidneys: stained black Stomach: stained black |
|
1-2 Female |
Killed Day 14 |
Kidneys: stained black Stomach: stained black |
|
2-0 Female |
Killed Day 14 |
No abnormalities detected |
|
2-1 Female |
Killed Day 14 |
No abnormalities detected |
|
2-2 Female |
Killed Day 14 |
No abnormalities detected |
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- LD50
- Value:
- 2 500 mg/kg bw
- Quality of whole database:
- 1 reliable without restriction
Acute toxicity: via inhalation route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Acute toxicity: via dermal route
Link to relevant study records
- Endpoint:
- acute toxicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2016
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- According to OECD and GLP
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 402 (Acute Dermal Toxicity)
- GLP compliance:
- yes
- Test type:
- standard acute method
- Limit test:
- yes
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Geniron Biolabs Pvt. Ltd., No.93, Solur, Thally Road, Anekal, Bengaluru - 562106, India
- Age at study initiation: 11 to 12 weeks
- Weight at study initiation: Males : 229.4 to 234.3 g; Females: 215.3 to 225.8 g
- Housing: Animals were housed individually in standard polysulfone cages (Size: approximately L 425 x B 266 x H 185 mm), with stainless steel top grill having facilities for pelleted food and drinking water in polycarbonate bottle. Additionally, polycarbonate rat huts were placed inside the cage as an enrichment object and were changed along with the cage at once a week.
Bedding: Steam sterilized corn cob was used and changed once a week along with the cage.
- Diet (e.g. ad libitum): Hypro rat & mice pellet feed, manufactured by Pranav Agro Industries Ltd., Pune 411 030, Maharashtra, India, was provided to animals
- Water (e.g. ad libitum): Deep bore-well water passed through activated charcoal filter and exposed to UV rays in Aquaguard on-line water filter-cum-purifier manufactured by Eureka Forbes Ltd, Mumbai 400 001, India, was provided to animals in polycarbonate bottles with stainless steel sipper tubes.
- Acclimation period: After physical examination for good health and suitability for experiment, the rats were acclimatized for six days before treatment under standard laboratory conditions. Animals were observed once daily during acclimatization period. Females were nulliparous and non-pregnant
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 to 23°C
- Humidity (%): 65 to 67 %
- Air changes (per hr): 14.1 to 14.3 air changes/hour
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark cycle
IN-LIFE DATES: From : 29 September 2016 To : 19 October 2016 - Type of coverage:
- semiocclusive
- Vehicle:
- other: milli-Q water
- Details on dermal exposure:
- TEST SITE
- Area of exposure: Approximately 24 hours before treatment, the hair on the dorsolateral thoracic surface of the skin was clipped (approximately 10 x 8 cm) with an electric clipper (Aesculap- Germany).
Based on the individual body weight, the finely ground test item at the dose of 2000 mg/kg body weight was weighed on an aluminium foil and made into a paste by adding sufficient volume of Milli-Q water (approximately 1.4 mL) and completely transferred on to the cotton gauze (size: Males: 9 x 6 cm; Females: 8 x 5 cm of 6 ply) and applied (semi-occlusive) directly to the clipped skin of the rat to cover about 10% of body surface of the rat. Then the cotton was secured in position by adhesive tape wound around the torso. The test item contact period with the skin was for 24 hours.
REMOVAL OF TEST SUBSTANCE
- Washing (if done): After the 24 hour contact period, the dressing was removed and the applied area was washed with water and wiped dry using a clean towel.
- Time after start of exposure:10:27 AM to 10:34 AM
TEST MATERIAL
- Amount(s) applied (volume or weight with unit):
Refer Appendix 1
- Constant volume or concentration used: no
- For solids, paste formed: yes
VEHICLE
- Amount(s) applied (volume or weight with unit): Approxmately 1.4 mL - Duration of exposure:
- 24 hours
- Doses:
- limit dose: 2000 mg/kg
- 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
- Frequency of observations and weighing: The animals were observed for clinical signs and pre-terminal deaths (mortality) four times (at hourly intervals after application) during day 1 and twice daily on day 2 and 3 and once daily during Days 4 to 15. Individual body weights of animals were recorded on test days 1 (Pre-application), 8 (7 days post application), and 15 (14 days post application).
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathology. - Statistics:
- The statistical analysis was not performed as the test was completed with the limit dose.
- Preliminary study:
- No priliminary study
- Sex:
- male/female
- Dose descriptor:
- approximate LD50
- Effect level:
- > 2 000 mg/kg bw
- Based on:
- test mat.
- Mortality:
- No mortality
- Clinical signs:
- other: There were no clinical signs observed during the study. However, black colour stain was observed on test item applied area in all rats on day 2 and 3 post dose observation
- Gross pathology:
- No abnormality was detected at necropsy
- Interpretation of results:
- not classified
- Remarks:
- Migrated information Criteria used for interpretation of results: not specified
- Conclusions:
- The acute dermal LD50 of the test item is more than 2000 mg/kg body weight in male and female Wistar rats.
- Executive summary:
The acute dermal toxicity of the test item was tested in 5 male and 5 female Wistar rats with the limit dose of 2000 mg/kg body weight.
All the rats were observed for clinical signs of toxicity and mortality for 14 days post application. There were no clinical signs of toxicity and mortality. However, black colour stain was observed on test item applied area in all rats on day 2 and 3 post dose observation. All rats gained weight during experimental period. At the end of observation period, all surviving animals were euthanized and subjected to necropsy. There were no abnormalities detected at the necropsy.
Based on the present study results, the acute dermal LD50of the test item is more than 2000 mg/kg body weight in male and female Wistar rats.
Reference
Table 1. Individual body weight, body weight changes and pre-terminal deaths
Group and Dose (mg/kg body weight) |
Rat No. |
S e x |
Body weight (g) |
No.dead / No.tested |
Pre- terminal deaths (%) |
||||
Initial (at treatment) |
8th day |
Weight change (day 8 – Initial) |
15th day |
Weight change (day 15 – Initial) |
|||||
G1 and 2000 Limit test
|
Rm5211 |
M |
234.3 |
251.6 |
17.3 |
264.6 |
30.3 |
0/10 |
0 |
Rm5212 |
M |
230.8 |
246.8 |
16.0 |
258.9 |
28.1 |
|||
Rm5213 |
M |
231.4 |
242.9 |
11.5 |
255.6 |
24.2 |
|||
Rm5214 |
M |
229.4 |
245.1 |
15.7 |
257.3 |
27.9 |
|||
Rm5215 |
M |
232.9 |
250.0 |
17.1 |
262.2 |
29.3 |
|||
Rm5216 |
F |
220.8 |
232.6 |
11.8 |
245.6 |
24.8 |
|||
Rm5217 |
F |
215.3 |
227.2 |
11.9 |
229.8 |
14.5 |
|||
Rm5218 |
F |
223.8 |
234.8 |
11.0 |
245.1 |
21.3 |
|||
Rm5219 |
F |
225.8 |
238.7 |
12.9 |
251.6 |
25.8 |
|||
Rm5220 |
F |
218.9 |
231.3 |
12.4 |
243.4 |
24.5 |
F: Female M: Male
Table 2. Individual test item application, clinical signs and necropsy findings
Group and Dose (mg/kg body weight) |
Date & Time of Application |
Rat No. |
Sex |
Body weight initial (g) |
Quantity applied (mg)
|
Day of Observations |
|||||||
Day 1 |
2 |
3 |
|||||||||||
1 hour |
2 hours |
3 hours |
4 hours |
|
|
||||||||
AM |
PM |
AM |
PM |
||||||||||
G1 and 2000 Limit test |
05 October 2016 and 10:27 AM to 10:34 AM |
Rm5211 |
M |
234.3 |
469 |
N |
N |
N |
N |
N* |
N* |
N* |
N* |
Rm5212 |
M |
230.8 |
462 |
N |
N |
N |
N |
N* |
N* |
N* |
N* |
||
Rm5213 |
M |
231.4 |
463 |
N |
N |
N |
N |
N* |
N* |
N* |
N* |
||
Rm5214 |
M |
229.4 |
459 |
N |
N |
N |
N |
N* |
N* |
N* |
N* |
||
Rm5215 |
M |
232.9 |
466 |
N |
N |
N |
N |
N* |
N* |
N* |
N* |
||
Rm5216 |
F |
220.8 |
442 |
N |
N |
N |
N |
N* |
N* |
N* |
N* |
||
Rm5217 |
F |
215.3 |
431 |
N |
N |
N |
N |
N* |
N* |
N* |
N* |
||
Rm5218 |
F |
223.8 |
448 |
N |
N |
N |
N |
N* |
N* |
N* |
N* |
||
Rm5219 |
F |
225.8 |
452 |
N |
N |
N |
N |
N* |
N* |
N* |
N* |
||
Rm5220 |
F |
218.9 |
438 |
N |
N |
N |
N |
N* |
N* |
N* |
N* |
F: Female M: Male N: AM: Ante Meridian PM: Post *:Black colour stain on test item applied area.
Table 2 contd. Individual test item application, clinical signs and necropsy findings
Group and Dose (mg/kg body weight) |
Rat No. |
Sex |
Day of Observations |
Necropsy Findings |
|||||||||||
4 |
5 |
6 |
7 |
8 |
9 |
10 |
11 |
12 |
13 |
14 |
15 |
||||
G1 and 2000 Limit test |
Rm5211 |
M |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
NAD |
Rm5212 |
M |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
NAD |
|
Rm5213 |
M |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
NAD |
|
Rm5214 |
M |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
NAD |
|
Rm5215 |
M |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
NAD |
|
Rm5216 |
F |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
NAD |
|
Rm5217 |
F |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
NAD |
|
Rm5218 |
F |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
NAD |
|
Rm5219 |
F |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
NAD |
|
Rm5220 |
F |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
N |
NAD |
F: Female M: Male NAD: No Abnormality Detected N: AM: Ante Meridian PM: Post
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- LD50
- Value:
- 2 000 mg/kg bw
Additional information
Justification for classification or non-classification
No classification
The criteria for classification are not met.
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Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
