Reaction mass of m-cresol and 2-chloro-m-cresol and 6-chloro-m-cresol

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP compliant study which was stated to be according to OECD guideline 402. However, only males were tested at the limit dose of 2000 mg/kg bw while females were tested at 1000 mg/kg bw.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2011

Report date:

2011

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

(1987)

Deviations:

yes

Remarks:

In males the limit dose of 2000 mg/kg bw was tested. Females were tested with 1000 mg/kg bw. Either females should have been tested at the limit dose as well or a complete study design should have been performed to be in compliance with OECD 402.

GLP compliance:

yes (incl. QA statement)

Remarks:

2009-02-09, North Rhine-westphalia

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Preventol KMX

IUPAC Name:

Preventol KMX

Details on test material:

- Name of test material (as cited in study report): Preventol KMX (confirmation of the identity of the test item was performed)
- Physical state: Colorless liquid
- Analytical purity: 100%
- Lot/batch No.: CHK 2109
- Expiration date of the lot/batch: 2011-09-21
- Storage condition of test material: At room temperature due to product information by the sponsor

Test animals

Species:

rat

Strain:

other: Wistar HsdCpb:Wu

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan GmbH, 5960 AD Horts, Netherlands
- Age at study initiation: approx. 9 - 13 weeks (assumed by the body weight)
- Weight at study initiation: 290 g - 300 g (males), 203 - 213 g (females)
- Housing: individually
- Diet: Provimi Kliba 3883 PM S15 Maus/Ratte Haltung, Kaiseraugust Switzerland; ad libitum
- Water: tap water; ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 55 ± 5%
- Air changes (per hr): approx. 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: 30 cm^2 on the hair free back (approx. 10% of body surface)
- % coverage: 100%, (semiocclusive)

REMOVAL OF TEST SUBSTANCE
- Washing: The dressings were removed and the test site was rinsed with tepid water using soap and gently patting the area dry.
- Time after start of exposure: After 24 hours

TEST MATERIAL
- Amounts applied: The amount of applied pure test substance was calculated on basis of the actual body weight.
- Constant volume: No

Duration of exposure:

24 hours

Doses:

1000 mg/kg bw (female)
2000 mg/kg bw (males)

No. of animals per sex per dose:

5 males at 2000 mg/kg bw (dose range 19.3 - 20.0 mg/cm^2)
5 females at 1000 mg/kg bw (dose range 6.8 - 7.1 mg/cm^2)

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 22 days
- Frequency of observations and weighing: Clinical signs and mortality were determined several times at the day of application (defined as day 1) and at least once daily thereafter. The weight gain was checked weekly.
Animals which died or were sacrificed in a moribund state were weighed and subjected to gross pathology
- Necropsy of survivors performed: yes

Statistics:

A validated LAN-linked computer system was used for data collection, processing and evaluation.

Results and discussion

Effect levels

Effect levels 1

Sex:

male

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Effect levels 2

Sex:

female

Dose descriptor:

LD50

Effect level:

> 1 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: top dose used in females

Mortality:

1/5 males died during the observation period.
No death occured in females.

Clinical signs:

Clinical signs at 1000 mg/kg bw (females) and 2000 mg/kg (males) bw comprised of: decreased motility, bloody urine, narrowed palpebral fissure and piloerection.
Local signs at site of application at 2000 mg/kg bw (males) were: dark discoloration, thickening, a partial induration, swelling, encrustation and formation of scale skin.
Local signs at site of application at 1000 mg/kg bw (females) were: dark discoloration, thickening, a partial induration, encrustation and formation of scale skin.
For details see table 1 in section "Any other information on results"

Body weight:

The body weight and the body weight gain were decreased on day 8 of the study in males and females. For details see Table 2 in section "Any other information on results"

Gross pathology:

Gross pathology of the males which died during the observation period revealed dilated intestine (gas filled) and brownish-black discolored kidneys.The males and females sacrificed at study termination showed a partial formation of scale on the site of application.

Any other information on results incl. tables

Table 1: Incidence and duration of clinical signs

Parameter	Incidence	Duration of parameter
Males
decreased motility	5/5	2 h – 2 d
bloody urine	5/5	2 h – 7 h
narrowed palpebral fissure	5/5	3 h – 2 d
piloerection	1/5	2 d
Local effects
partial induration	4/5	2 d – 7 d
swelling	4/5	2 d
dark discoloration	3/5	2 d – 8 d
thickening	4/5	3 d – 7 d
scale skin	4/5	7 d – 22 d
encrustation	4/5	8 d – 21 d
Females
decreased motility	5/5	40 min – 2 d
bloody urine	5/5	40 min – 5 h
narrowed palpebral fissure	5/5	2 h – 5 h
piloerection	5/5	2 h – 2 d
Local effects
partial induration	5/5	3 d – 10 d
dark discoloration	5/5	2 d – 10 d
thickening	5/5	2 d
scale skin	5/5	11 d – 22 d
encrustation	5/5	3 d – 20 d

Table 2: Body weight and body weight gain

Day	1	8	15	22
Males
Mean body weight (g±SD)	296± 3.9	287± 6.5	327± 7.7	351± 6.2
Mean body weight gain (g±SD)	-	- 8± 6.7	41± 6.1	24± 2.3
Females
Mean body weight (g±SD)	207± 3.7	203± 3.6	215± 5.4	235± 9.2
Mean body weight gain (g±SD)	-	- 4± 1.2	12± 5.2	20± 10.6

SD = Standard deviation

Table 3: Table for acute dermal toxicity

Dose [mg/kg bw]	Toxicological results*	Duration of clinical signs	Time of death	Mortality (%)
Males
2000	1/5/5	2 h – 22 d	2d	20
Females
1000	0/5/5	40 min – 22 d	---	0
LD50 males >2000 mg/kg bw LD50 females >1000 mg/kg bw

* first number = number of dead animals                                 

second number = number of animals with clinical signs         

 third number = number of animals used     

Applicant's summary and conclusion

Interpretation of results:

harmful

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

CLP: acute dermal Cat 4, H312
DSD: Xn, R21