N-[2,5-dichloro-4-(1,1,2,3,3,3-hexafluoropropoxy)-phenyl-aminocarbonyl]-2,6-difluorobenzamide

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

30 Jan 1989 to 27 Feb 1989

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1990

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)

Version / remarks:

Nov 1982

Test guideline 3

Qualifier:

according to guideline

Guideline:

EU Method B.9 (Repeated Dose (28 Days) Toxicity (Dermal))

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

N-[2,5-dichloro-4-(1,1,2,3,3,3-hexafluoropropoxy)-phenyl-aminocarbonyl]-2,6-difluorobenzamide

EC Number:

410-690-9

EC Name:

N-[2,5-dichloro-4-(1,1,2,3,3,3-hexafluoropropoxy)-phenyl-aminocarbonyl]-2,6-difluorobenzamide

Cas Number:

103055-07-8

Molecular formula:

C17 H8 Cl2 F8 N2 O3

IUPAC Name:

1-[2,5-dichloro-4-(1,1,2,3,3,3-hexafluoropropoxy)phenyl]-3-(2,6-difluorobenzoyl)urea

Test animals

Species:

rat

Strain:

other: Tif: RAIf (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: approx. 8 weeks.
- Weight at study initiation: 237 - 281 g and 205 - 241 g in males and females, respectively.
- Housing: animals were housed individually in Macrolon cages type 3, with wire mesh tops and granulated soft wood bedding.
- Diet: Pelleted, certified standard diet (assayed for composition and contaminant levels).
- Water: Tap water, ad libitum. The drinking water quality fulfilled the critical parameters in the specifications of the "Schweizerisches Lebensmittelbuch".
- Acclimation period: 10 days prior to dosing

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 3
- Humidity (%): 55 ± 15
- Air changes (per hr): approximately 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 30 Jan1989 To: 27 Feb 1989

Administration / exposure

Type of coverage:

occlusive

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

0.5 % (w/v)

Duration of treatment / exposure:

28 days

Frequency of treatment:

5 day per week during 4 weeks

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

100 mg/kg bw/day

Remarks:

Group 2, low dose.

Doses / concentrations 2

Dose / conc.:

300 mg/kg bw/day

Remarks:

Group 3, mid-dose.

Doses / concentrations 3

Dose / conc.:

1 000 mg/kg bw/day

Remarks:

Group 4, high dose.

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Results and discussion

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

> 1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Target system / organ toxicity

Key result

Critical effects observed:

no

Any other information on results incl. tables

MORTALITY AND ANTEMORTEM FINDINGS

No symptoms or signs of systemic toxicity were seen that could be attributed to application of test substance throughout the study. No animal died or had to be killed during the study.

DERMAL IRRITATION

No signs of skin irritation were observed in any animal of the four dose groups throughout the study. All scores evaluated according to Draize et al (1944) were zero.

BODY WEIGHT

Mean body weight gain of treated animals was similar to that of the respective control animals.

FOOD CONSUMPTION

No treatment-related differences in mean food consumption were observed between control animals and those exposed to the test article.

HAEMATOLOGY

The haematological investigations revealed no changes attributable to the treatment

with test substance.

CLINICAL CHEMISTRY

No relevant differences between treated and control groups were observed.

ORGAN WEIGHTS AND RATIOS

There were only minor differences in mean absolute and relative organ weights between animals exposed to the test article and the respective control group, all of which are considered to be within the normal biological variation and not to be related to treatment with the test article.

GROSS PATHOLOGY AND HISTOPATHOLOGY

Macroscopical and microscopical examination of control and treated animals did not reveal any treatment related systemic effects or local pathological changes which could be attributed to the test article.

Applicant's summary and conclusion

Conclusions:

A dose level of 1000 mg/kg is recommended as the upper dose which needs not to be exceeded.

Executive summary:

This OECD TG 410 study was conducted in order to determine the dermal toxicity of test substance upon repeated dermal application for 4 weeks (5 exposures per week) and to estimate a no-observable effect level of exposure according to GLP principles. In the present study a total of 40 albino Tif: RAIf (SPF) rats, distributed in 5 animals/sex/group. The test substance. was moistened and applied under occlusive dressing to the shaved back skin for a period of 4 weeks on a 5 day/week basis. The exposure period was 6 hours per day. The doses were 0, 100, 300 and 1000 mg/kg body weight per exposure (groups 1, 2, 3, and 4, respectively). The applied quantities of test article were adjusted weekly to individual animal body weight. The control animals (group 1) were treated with the vehicle only. The results of this study are summarised as follows:

No clinical symptoms or signs of systemic toxicity that could be attributed to treatment with test substance were observed. No signs of local irritation were seen in any animal throughout the study. No animal died or had to be killed during the study. Mean body weight gain in all treated groups did not differ from that of the respective control groups. No treatment-related differences in mean food consumption were observed between control animals and those exposed to the test article. No differences in food consumption relative to body weight that could be attributed to treatment with the test article were seen between control animals and those treated with the test article. The haematological investigations revealed no changes attributable to the treatment with the test article. No relevant differences between treated and control groups were observed. Analysis of the organ weights did not reveal any treatment-related differences between the animals of the control groups and those exposed to the test substance. Macroscopical and microscopical examination of control and treated animals did not reveal any treatment related systemic effects or local pathological changes which could be attributed to the test

substance.

It can be concluded from the above, that the no-observable effect level for test substance when applied dermally on a 5 day/week basis over a period of 4 weeks to rats is above 1000 mg/kg body weight. Since in OECD TG 410 and in EPA Guideline 82-2 a dose level of 1000 mg/kg is recommended as the upper dose which needs not to be exceeded, no further testing is envisaged. Hence, the NOAEL was set at > 1000 mg/kg bw/day.