2-(4-tert-butylphenyl)-6-cyano-5-[bis(ethoxycarbonylmethyl)carbamoyloxy]-1H-pyrrolo[1,2-b][1,2,4] triazole-7-carboxylic acid 2,6-di-tert-butyl-4-methylcyclohexylester

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

21 Jan - 04 Feb 2004

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP-guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2004

Report date:

2004

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000, including the most recent partial revisions

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

448-050-6

EC Name:

-

Cas Number:

444065-11-6

Molecular formula:

C41 H57 N5 O8

IUPAC Name:

2,6-di-tert-butyl-4-methylcyclohexyl 5-{[bis(2-ethoxy-2-oxoethyl)carbamoyl]oxy}-2-(4-tert-butylphenyl)-6-cyano-1H-pyrrolo[1,2-b][1,2,4]triazole-7-carboxylate

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Name of test material (as cited in study report): UC-141
- Physical state: white powder
- Lot/batch No.: CE-203
- Expiration date of the lot/batch: 1 Jan 2005
- Storage condition of test material: at room temperature in the dark

Test animals

Species:

rat

Strain:

other: Wistar Crl:(Wl) BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approximately 10 weeks
- Weight at study initiation: 347 ± 18 g (males, mean ± SD), 246 ± 15 g (females, mean ± SD)
- Housing: animals were individually housed in labelled Macrolon cages (type lII, height 15 cm) containing purified sawdust as bedding material (Woody-Clean type 3/4, Tecnilab-BMI B.V., Someren, the Netherlands)
- Diet: standard pelleted laboratory animal diet (Altromin (code VRF 1), Lage, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.6-22.9 (actual range)
- Humidity (%): 38-80 (actual range)
- Air changes (per hr): approximately 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 21 Jan 2004 To: 04 Feb 2004

Administration / exposure

Type of coverage:

occlusive

Vehicle:

propylene glycol

Details on dermal exposure:

TEST SITE
- Area of exposure: approximately 25 cm² in males and approximately 18 cm² in females
- % coverage: 10
- Type of wrap if used: the test substace was held in contact with the skin with a surgical gauze patch (Surgy 1 D), which was covered with aluminium foil and Coban elastic bandage. A piece of Micropore tape was used to secure the bandages in females only.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): residual test substance was cleaned from the skin using water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10 mL/kg bw
- Constant volume or concentration used: yes
- Concentration (if solution): 200 mg/mL (w/w) (calculated from 10 mL/kg bw amount and 2000 mg/kg bw)


VEHICLE
- Amount(s) applied (volume or weight with unit): 10 mL/kg bw

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

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: observations of mortality were made twice daily; observations of clinical signs were made several times on Day 1 and daily thereafter, graded according to a severity scale of 1-4; weighing was performed weekly on Day 1 (pre-administration), 8 and 15
- Necropsy of survivors performed: yes, all gross pathological changes were recorded

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 000 mg/kg bw

Based on:

test mat.

Mortality:

There was no mortality during the study period.

Clinical signs:

other: Systemic effects were observed on Day 1 from 2 hrs after administration until Day 6. Flat posture was observed in 3/5 males and 3/5 females from 2-4 hrs after dosing, while hunched posture was noted in 4/5 males and 5/5 females, generally with a later ons

Gross pathology:

Ther were no substance-related findings during necropsy and the gross pathological examination.

Other findings:

- Other observations: Mild local effects on the treated skin were seen throughout the study period. Erythema or erythema maculata was observed in 3/5 females on Day 3-5 and 3-4, respectively. Scales and/or scabs were seen in 1/5 males and 4/5 females for a total of 1-10 days between Day 5 and 15.

Any other information on results incl. tables

Table 1: Mortality and clinical signs

Dose [mg/kg bw]	Toxicological results*	Duration of clinical signs	Time of death	Mortality (%)
Males
2000	0/5/5	2 hrs on Day 1 – Day 13	-	0
Females
2000	0/5/5	2 hrs on Day 1 – Day 15	-	0
Overall LD50 > 2000 mg/kg bw

* first number = number of dead animals                                 

 second number = number of animals with systemic clinical signs         

 third number = number of animals used                               

           

Table 2: Overview of clinical signs

Observations	Males (reading time points)					Females (Reading time points)
No.	1	2	3	4	5	1	2	3	4	5
Systemic
Hunched posture	4 hrs, Day 1–Day 2		Day 2-3	Day 2-3	2 hrs, Day 1–Day 2	Day 2-5	4 hrs, Day 1–Day 6	Day 2-4	4 hrs, Day 1–Day 2	Day 2-3
Flat posture		2-4 hrs, Day 1	2-4 hrs, Day 1	2-4 hrs, Day 1				2-4 hrs, Day 1	2 hrs, Day 1	4 hrs, Day 1
Chromodacryorrhoea (snout)	2 hrs, Day 1		2 hrs, Day 1–Day 2				2 hrs, Day 1–Day 2	2 hrs, Day 1–Day 2		2-4 hrs, Day 1
Ptosis			4 hrs, Day 1
Treated skin
Scales				Day 7-13			Day 7-8	Day 5-14	Day 6-8	Day 6-8
Scabs								Day 9, 12-13	Day 15
General erythema (grade 1-4)							Day 3 -5 (grade 1)	Day 3-5 (grade 1)
Erythema maculata (grade 1-4)										Day 3-4 (grade 1)

 

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

CLP: not classified
DSD: not classified