Registration Dossier

Acute oral toxicity:

The acute oral toxicity dose (LD50) was considered based on different studies conducted on rats for the test chemical. The LD50 value is >2000 mg/kg bw, for acute oral toxicity. Thus, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified for acute oral toxicity.

Acute Inhalation Toxicity:

The acute inhalation toxicity study need not be conducted because exposure to humans via inhalation route is not likely taking into account due to the low vapour pressure of the test chemical, which is reported to be 0.0089 mm Hg. Thus, exposure to inhalable dust, mist and vapour of the chemical is highly unlikely. Therefore this study is considered for waiver.

Acute Dermal toxicity:

The acute dermal toxicity dose (LD50) was considered based on different studies conducted on rats and rabbits for the test chemical. The studies concluded that LD50 value is >2000 mg/kg bw, for acute dermal toxicity. Thus, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified for acute dermal toxicity.

Reference

Endpoint:: acute toxicity: oral
Type of information:: experimental study
Adequacy of study:: key study
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: data from handbook or collection of data
Justification for type of information:: Data is from Authoritative database
Qualifier:: according to guideline
Guideline:: other: As mentioned below
Principles of method if other than guideline:: Acute oral toxicity of test chemical in rats
GLP compliance:: not specified
Test type:: other: not specified
Species:: rat
Strain:: not specified
Sex:: not specified
Details on test animals or test system and environmental conditions:: not specified
Route of administration:: oral: unspecified
Vehicle:: not specified
Details on oral exposure:: not specified
Doses:: >60000 mg /kg bw
No. of animals per sex per dose:: not specified
Control animals:: not specified
Details on study design:: not specified
Statistics:: not specified
Preliminary study:: not specified
: Key result
Sex:: not specified
Dose descriptor:: LD50
Effect level:: > 60 000 mg/kg bw
Based on:: test mat.
Remarks on result:: other:
Remarks:: No mortality observed
Mortality:: No mortality observed at 60000 mg/kg bw dose
Clinical signs:: other: not specified
Gross pathology:: not specified
Other findings:: not specified
Interpretation of results:: other: Not classified
Conclusions:: The acute oral LD50 value was considered to be >60000 mg/kg bw when rats were treated with test chemical via oral route.
Executive summary:: Acute oral toxicity study of test chemical was conducted on rats at the dose concentration of 60000 mg/kg bw. The test chemical was administered via oral unspecified route. All animals were maintained under close observation for recording toxic signs and time of death for 14 days. No mortality and clinical signs were observed during 14 days observation period. Therefore, LD50 value was considered to be >60000 mg/kg bw, when rats were treated with test chemical via oral route.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

60 000 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and from publication

Reference

Endpoint:: acute toxicity: inhalation
Data waiving:: other justification
Justification for data waiving:: other:

Quality of whole database:

Waiver

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

Data is from study report

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Principles of method if other than guideline:

Acute dermal toxicity of test chemical in Wistar Albino rats

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

other: Wistar albino

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Institute for Industrial Research and Toxicology
Ghaziabad
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 8 to 10 weeks
- Weight at study initiation: 180±40 g
- Fasting period before study:
- Housing:
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-25oC
- Humidity (%): humidity 40-
60%
- Air changes (per hr): Air conditioned rooms with 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours artificial
fluorescent light and 12 hours dark

IN-LIFE DATES: From: To:

Type of coverage:

occlusive

Vehicle:

other: Distilled water

Details on dermal exposure:

TEST SITE
- Area of exposure: Back skin
- % coverage: 10%
- Type of wrap if used: Impervious dressing secured with adhesive tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Washing done with lukewarm water
- Time after start of exposure:24 hrs

TEST MATERIAL
- Amount(s) applied : 2000 mg/kg bw:
- Constant volume or concentration used: yes
- For solids, paste formed: yes

Duration of exposure:

24 hrs

Doses:

Group-I 2000 mg/kg b. wt : limit test
Group-II 2000 mg/kg b. wt: Confirmatory test

No. of animals per sex per dose:

10(5/sex)

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:all the animals was observed weekly on day 0 (pre
treatment), 7th and 14th (post treatment).
- Necropsy of survivors performed: yes
- Other examinations performed:
clinical signs:The treated animals were closely observed for clinical signs of intoxication, first
4 hours and thereafter for every 1 hrs interval for 24 hrs after dosing and twice
a day for 14 days
body weight:The body weight of all the animals was observed weekly on day 0 (pre
treatment), 7th and 14th (post treatment).
histopathology:Necropsy was carried out on all the animals that died during the study or
surviving animals were sacrificed at the end of the study to observe any gross
pathological changes.

Statistics:

not specified

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other:

Remarks:

No mortality observed

Mortality:

No mortality was recorded in Wistar albino rats after administration of test compound at the dose level of 2000 mg/kg b.wt. throughout the observation period of 14 days

Clinical signs:

other: Wistar albino rats treated with the test compound at the dose level of 2000 mg/kg b.wt. did not elicit any clinical sign of toxicity throughout the observation period of 14 days.

Gross pathology:

No gross pathological changes obsered during necropsy of the test animal.

Other findings:

No abnormality observed

TABLE 1:SUMMARY OF BODY WEIGHT (GM)

Group	Animal ID	Day 0	Day 7	% Gain/loss	Day 14	% Gain/loss
Group-I 2000 mg/kg bw	201315-1	200.7	205.02	2.12	213.21	6.20
	201315-2	199.36	204.98	2.81	212.05	6.36
	201315-3	182.13	191.8	5.30	202.3	11.07
	201315-4	204.9	209.6	2.29	217.5	6.14
	201315-5	202.2	208.4	3.06	215.6	6.62
	201315-6	201.4	206.2	2.38	211.4	4.96
	201315-7	190.8	197.2	3.35	212.3	11.2
	201315-8	204.9	209.6	2.29	217.5	6.14
	201315-9	202.2	208.4	3.06	215.6	6.62
	201315-10	201.39	206.56	2.56	215.89	7.19
Group-II 2000 mg/kg bw	201315-11	202.89	207.25	2.14	215.99	6.45
	201315-12	195.34	201.00	2.98	208.99	6.98
	201315-13	200.56	205.66	.54	213.45	6.42
	201315-14	199.86	204.52	2.33	212.71	6.42
	201315-15	203.58	207.81	2.07	215.27	5.74
	201315-16	201.69	206.54	2.40	214.63	6.41
	201315-17	202.84	208.11	2.59	215.69	6.33
	201315-18	199.64	205.43	2.95	213.73	7.05
	201315-19	203.64	207.39	1.84	216.57	6.34
	201315-20	200.56	205.66	2.54	213.45	6.42

TABLE 2: CLINICAL SIGNS AND MORTALITY

Group-I Limit test 2000 mg/kg

Parameters	Incidence of clinical signs observed after dosing on																			Mortality
	Day 0					DAY
	Min	Hour				DAY
	30	1	2	4	6	1	2	3	4	5	6	7	8	9	10	11	12	13	14	Total	%
Mortality (total)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0/10	0
Clinical signs-local	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Redness	-	-	-	-	-	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Pain	-	-	-	-	-	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Swelling	-	-	-	-	-	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Systemic signs	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

- = OBSERVED AFTER 24 HOURS

0 = NO CLINICAL SIGNS

+ =MILD

++ = MODERATE

+++ =HIGH

++++=SEVERE

TABLE 3:

GROUP :II CONFIRMATORY TEST Dose: 2000 mg/kg b.wt

Parameters	Incidence of clinical signs observed after dosing on																			Mortality
	Day 0					DAY
	Min	Hour				DAY
	30	1	2	4	6	1	2	3	4	5	6	7	8	9	10	11	12	13	14	Total	%
Mortality (total)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0/10	0
Clinical signs-local	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Redness	-	-	-	-	-	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Pain	-	-	-	-	-	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Swelling	-	-	-	-	-	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Systemic signs	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

- = OBSERVED AFTER 24 HOURS

0 = NO CLINICAL SIGNS

+ =MILD

++ = MODERATE

+++ =HIGH

++++=SEVERE

Table 4 :SUMMARY OF NECROPSY FINDINGS

S. NO.	FATE	WISTAR ALBINO RATS
		DOSE (mg/kg b.wt)
		2000 (limit test)	2000 (confirmatory test)
1.	Terminal ssacrifice	10/10	10/10
2.	Found dead	0/10	0/10
3.	Abnormalities detected	0/10	0/10

Interpretation of results:

other: Not classified

Conclusions:

The LD50 value is reported to be 2000 mg/kg bw.Based on the results obtained from present investigation, it can be concluded that the test compound is non toxic to Wistar albino rats under test condition.

Executive summary:

Acute dermal toxicity test was performed on 10 wistar male and female rats to determine the LD50 value of test chemical. Ten healthy Wistar albino rats of both sex (ranging bw 180±40 gm) were selected for study after acclimatization. Approximate 10 percent back skin of total body surface area was prepared 24 hrs prior to application of test compound. The test chemical was applied dermally at the dose level of 2000 mg/kg b.wt for each animal. The treated animals were closely observed for clinical signs of intoxication during first four hours of test compound administration. Thereafter, all the animals were observed periodically at one hour interval for 24 hrs and twice daily for a period of 14 days. The body weight of each rat was observed on day 0 (pre treatment), 7th and 14th (post treatment). The necropsy was performed on all animals at the termination of the study. Rats were free from any systematic and local clinical signs when observed after 24 hours of patch removal. After 14 days observation no mortality was observed. No body weight change was observed.

Necropsy was conducted at the end of the observation on all the animals (day 15th), did not reveal any significant gross pathological changes related to compound toxicity. Skin- Skin and hair coat was observed wet, All external and internal orifices were observed to be normal.

The LD50 value is reported to be >2000 mg/kg bw. Based on the results obtained from present investigation, it can be concluded that the test compound is non toxic to Wistar albino rats under test condition.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and from study report

Acute oral toxicity:

In different studies, the given test chemical has been investigated for acute oral toxicity to a greater or lesser extent. Often are the studies based on in-vivo experiments in rodents, i.e. most commonly in rats for test chemical. The studies are summarized as below –

Acute oral toxicity study of test chemical was conducted on rats at the dose concentration of 60000, 38000, 33800, 20000 and 5000 mg/kg bw. The test chemical was administered via oral unspecified route. All animals were maintained under close observation for recording toxic signs and time of death for 14 days. No mortality and clinical signs were observed during 14 days observation period. Therefore, LD50 value was considered to be >60000 mg/kg bw, when rats were treated with test chemical via oral route.

Thus, based on the above summarised studies on test chemical, it can be concluded that LD50 value is >2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified for acute oral toxicity.

Acute Inhalation Toxicity:

The acute inhalation toxicity study need not be conducted because exposure to humans via inhalation route is not likely taking into account due to the low vapour pressure of the test chemical, which is reported to be 0.0089 mm Hg. Thus, exposure to inhalable dust, mist and vapour of the chemical is highly unlikely. Therefore this study is considered for waiver.

Acute Dermal Toxicity:

In study report, the given test chemical has been investigated for acute dermal toxicity to a greater or lesser extent. Often are the studies based on in-vivo experiments in rodents, i.e. most commonly in rats for test chemical. The study is summarized as below –

Acute dermal toxicity test was performed on 10 wistar male and female rats to determine the LD50 value of test chemical. Ten healthy Wistar albino rats of both sex (ranging bw 180±40 gm) were selected for study after acclimatization. Approximate 10 percent back skin of total body surface area was prepared 24 hrs prior to application of test compound. The test chemical was applied dermally at the dose level of 2000 mg/kg b.wt for each animal. The treated animals were closely observed for clinical signs of intoxication during first four hours of test compound administration. Thereafter, all the animals were observed periodically at one hour interval for 24 hrs and twice daily for a period of 14 days. The body weight of each rat was observed on day 0 (pre treatment), 7th and 14th (post treatment). The necropsy was performed on all animals at the termination of the study. Rats were free from any systematic and local clinical signs when observed after 24 hours of patch removal. After 14 days observation no mortality was observed. No body weight change was observed.

Necropsy was conducted at the end of the observation on all the animals (day 15th), did not reveal any significant gross pathological changes related to compound toxicity. Skin- Skin and hair coat was observed wet, All external and internal orifices were observed to be normal.

The LD50 value is reported to be >2000 mg/kg bw. Based on the results obtained from present investigation, it can be concluded that the test compound is non toxic to Wistar albino rats under test condition.

Thus, based on the above summarized studies on test chemical, it can be concluded that LD50 value is >2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified for acute dermal toxicity.

Based on the above studies on test chemical, it can be concluded that LD50 value is >2000 mg/kg bw, for acute oral and acute dermal toxicity. Thus, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified for acute oral and acute dermal toxicity. For acute inhalation toxicity wavier was added so, not possible to classify.