Climbazole

Endpoint summary

Description of key information

Acute toxicity studies with crinipan were performed in rats (study report: Bayer/Symrise 1975039), mice (study report: Bayer/Symrise 1975038), rabbits (study report: Bayer/Symrise 1975040), and dogs (study report: Bayer/Symrise 1975039). The results clearly classify crinipan as moderately toxic with oral LD50 of 400 mg/kg bw in rats. Accordingly, the compound is classified into ‘Category 4’ according to the current EU-CLP.
No study on the acute toxicity of crinipan upon dermal application was conducted. This is considered justified, since no local corrosive or irritant effects on the skin were observed after topical application of crinipan (see the corrosion/irritation section of this Technical Dossier for details), the dermal absorption of crinipan is low (see the corrosion/irritation section of this Technical Dossier for details), and crinipan is only moderately toxic following oral application (e.g., the LD50 value of crinipan in rats was determined at 400 mg/kg; see the studies on acute oral toxicity documented in this Technical Dossier for details). Accordingly, it is considered unlikely that crinipan might elicit any noteworthy degree of local or systemic toxicity following dermal application, in particular as pharmacokinetic studies showed only limited dermal penetration.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

No study period specified, but the study report was finalized on 1975-01-08.

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to a method that is largely comparable to the current OECD guideline 401. However, it was not conducted according to the principles of GLP, as GLP had not yet been implemented at the time the study was performed.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Principles of method if other than guideline:

The test item was administered orally to groups of 10 male and female Wistar rats at dose levels of 160, 200, 250, 320, 400, 500, 630, 800, and 1000 mg/kg. Toxicity symptoms and mortality rates were recorded for a 14-d observation period. Animals that died were, whenever possible, autopsied and examined for pathological changes. The surviving rats were killed at the end of the trial and also autopsied. Computation of the LD50 values, with a confidence range of p = 0.05 was carried out by means of programmed probit analysis.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: breeder Winkelmann (Kirchborchen, Germany)
- Weight at study initiation: 170-253 g
- Housing: Animals were kept in Makrolon cages type I or type III in groups of 5 animals per cage.
- Diet: standard diet (Altromin GmbH, Lage/Lippe, Germany), ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature: about 24°C

Route of administration:

oral: gavage

Vehicle:

other: aqueous solution with 5% cremophor

Details on oral exposure:

The test item was suspended in tap water with the addition of 5% cremophor and was administered to the animals in a volume of 10 mL/kg via a stomach tube.

Doses:

The test item was administered at dose levels of 160, 200, 250, 320, 400, 500, 630, 800, and 1000 mg/kg.

No. of animals per sex per dose:

10 animals were used per dose (no data on animals per sex given).

Control animals:

not specified

Details on study design:

Toxicity symptoms and mortality rates were recorded for a 14-d observation period. Animals that died were, whenever possible, autopsied and examined for pathological changes. The surviving rats were killed at the end of the trial and also autopsied.

Statistics:

Computation of the LD50 values, with a confidence range of p=0.05 was carried out by means of the programmed probit analysis according to Fink and Hund [Fink H, Hund G (1965) Probitanalyse mittels programmgesteuerter Rechenanlagen. Arzneim-Forsch / Drug Res 15:624-630].

Preliminary study:

not applicable

Sex:

male/female

Dose descriptor:

LD50

Effect level:

400 mg/kg bw

Based on:

test mat.

95% CL:

334 - 481

Mortality:

See table 1 in section "Any other information on results incl. tables".

Clinical signs:

other: Except for the dose of 160 mg/kg, which was symptom-free tolerated, all animals showed coordination disturbances and tonic-clonic convulsions about 1 h after administration. After 2 h, motility was reduced and the animals were temporarily laying on their

Gross pathology:

The autopsies did not provide any pathological findings.

Other findings:

no data

Table 1: Acute oral toxicty of crinipan in rats

Dose (mg/kg)	Number of animals used	Toxicological result
		Number of animals that died	Number of animals showing toxic symptoms
160	10	0	0
200	10	1	10
250	10	2	10
320	10	5	10
400	10	5	10
500	10	7	10
630	10	6	10
800	10	9	10
1000	10	10	10

Interpretation of results:

moderately toxic

Remarks:

Migrated information Criteria used for interpretation of results: not specified

Conclusions:

Crinipan was found to be moderately toxic upon a single oral administration to male and female rats.

Executive summary:

The acute toxicity of crinipan upon oral administration was studied in male and female Wistar rats (n=10 per dose). Crinipan was found to be moderately toxic, with a LD₅₀ of 400 mg/kg.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

400 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute toxicity studies with crinipan were performed in rats (study report: Bayer/Symrise 1975039), mice (study report: Bayer/Symrise 1975038), rabbits (study report: Bayer/Symrise 1975040), and dogs (study report: Bayer/Symrise 1975039). The calculated oral LD₅₀ are summarized in the following table.

Species	Oral LD50 (mg/kg bw)	Number of animals / dose level	Test guideline	Remarks
Wistar rats	400	10 males	Comparable to OECD 401 before GLP	OECD 401 has been deleted, however the results are reliable and indicate crinipan as moderately toxic in all species
CF1/W 86 mice	644	10 males
Giant Chinchilla rabbits	250	2 females
Beagle dogs	250-500	2 animals

 

The results mentioned above clearly classify crinipan as moderately toxic with oral LD₅₀of 400 mg/kg bw in rats.

Justification for selection of acute toxicity – oral endpoint
The study was a good and reliable study conducted according to a method that is largely comparable to the current OECD guideline 401.

Justification for classification or non-classification

Due to the findings described above (LD50 oral in rats 400 mg/kg bw) the substance has to be classified as Acute toxicity category 4, H302: Harmful if swallowed according to the criteria laid down in the EU Classification Labelling and Packaging Regulation (1272/2008/EC).

 

It can reasonably be deduced that the substance does not exert systemic toxic effects after dermal application and thus does not have to be classified, because

- the substance has an LD50 400 mg/kg after administration of a single oral dose,

- and the dermal bioavailability of the substance is very low and was determined with a maximum value of 3.5% during 24 hours. It can thus be concluded that not enough substance would be systemically available upon dermal exposure to reach levels that could exert lethal effects.

 

No conclusion on classification and labeling regarding acute inhalation exposure can be derived due to lack of data.

 

The substance does not have to be classified forspecific target organ toxicity– single exposure according to Regulation (EC) No 1272/2008, as no specific toxic effects were observed after acute exposure.