1-[[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2001

Report date:

2001

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

1981

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1-[[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole

EC Number:

262-104-4

EC Name:

1-[[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole

Cas Number:

60207-90-1

Molecular formula:

C15H17Cl2N3O2

IUPAC Name:

1-{[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]methyl}-1H-1,2,4-triazole

Test animals

Species:

rat

Strain:

other: Hanlbm:WIST (SPF)

Sex:

male/female

Administration / exposure

Type of coverage:

occlusive

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

1% carboxymethylcellulose and 0.1% aqueous Tween80

Duration of treatment / exposure:

6 hours

Frequency of treatment:

4 weeks on an at least a 5 day/week basis

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

10 mg/kg bw/day

Doses / concentrations 2

Dose / conc.:

100 mg/kg bw/day

Doses / concentrations 3

Dose / conc.:

1 000 mg/kg bw/day

Control animals:

yes, concurrent vehicle

Results and discussion

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

organ weights and organ / body weight ratios

2

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

clinical biochemistry

dermal irritation

organ weights and organ / body weight ratios

Target system / organ toxicity

Critical effects observed:

no

Any other information on results incl. tables

There were no mortalities and no clinical signs or signs of local irritation. There were no treatmentrelated effects on body weight development, food consumption, food utilisation, ophthalmoscopy or haematological parameters.
Slightly higher values for protein and globulin with an associated decrease in the albumin to globulin ratio were recorded for females at 1000 mg/kg bw/day. In addition, females at 1000 mg/kg bw/day had an increased cholesterol level and females at 100 and 1000 mg/kg bw/day had lower values for chloride.
In the absence of a dose-response relationship, significantly lower glucose value in females at 100 mg/kg bw/day and significantly higher globulin value in females at 10 mg/kg bw/day were considered not relevant.
The blood chemistry profile of treated males was not affected. In the absence of a dose-response relationship, significantly lower triglyceride concentration in males at 10 mg/kg bw/day were considered not relevant. Significantly higher mean values for sodium in males at 100 and 1000 mg/kg bw/day dose levels were not considered to be treatment-related as the magnitude of the difference from controls was too small to be toxicologically relevant.

Table 1. Differences in clinical chemistry parameters in treated females (mean values) compared to control animals

Parameter	Unit	Control	10 mg/kg bw/day	100 mg/kg bw/day	1000 mg/kg bw/day
Glucose	mmol/L	6.689 S.D. 1.543	5.890 S.D. 0.683	5.272** S.D. 0.413	5.779 S.D. 0.844
Protein	g/L	62.680 S.D. 2.186	64.969 S.D 2.603	64.869 S.D. 1.569	66.205** S.D. 2.184
Albumin (A)	g/L	33.502 S.D. 1.452	34.467 S.D. 1.369	34.770 S.D. 1.230	34.620 S.D. 1.276
Globulin (G)	g/L	29.179 S.D. 1.077	30.502* S.D. 1.877	30.099 S.D. 0.659	31.585** S.D. 1.506
A/G		1.151 S.D. 0.047	1.133 S.D. 0.072	1.156 S.D. 0.039	1.099 S.D. 0.058
Cholesterol	mmol/L	1.258 S:D. 0.219	1.300 S.D. 0.378	1.321 S.D. 0.220	1.618* S.D. 0.324
Cl-	mmol/L	100.98 S.D. 2.37	100.01 S.D. 1.18	98.97* S.D. 1.68	98.64* S.D. 1.76

* = p < 0.05
** = p < 0.01

Table 2. Differences in clinical chemistry parameters in treated males (mean values) compared to control animals

Parameter	Unit	Control	10 mg/kg bw/day	100 mg/kg bw/day	1000 mg/kg bw/day
Triglycerides	mmol/L	0.540 S.D. 0.162	0.351* S.D. 0.100	0.501 S.D 0.136	0.758 S.D. 0.257
Na+	mmol/L	144.01 S.D. 1.12	145.20 S.D. 0.75	145.69* S.D. 1.20	145.73* S.D. 1.81

* = p < 0.05
The mean absolute/relative liver weights were increased in 1000 mg/kg bw/day males (+19%/+15%)
and females (+14%/+10%).

Table 3. Mean liver weights in males and females

Sex	Weight	Control	10 mg/kg bw/day	100 mg/kg bw/day	1000 mg/kg bw/day
Male	Liver g (absolute)	12.60 S.D. 1.6712	12.83 S.D. 1.4249	13.24 S.D. 0.9890	14.98** S.D. 1.3136
	Liver (relative)	43.8 S.D. 3.4	45.1 S.D. 3.7	46.6 S.D. 1.8	50.4** S.D. 3.0
Female	Liver g (absolute)	9.2178 S.D.1.2173	9.3556 S.D. 0.9558	9.4583 S.D. 1.3640	10.51 S.D. 1.0024
	Liver (relative)	45.5 S.D. 3.5	44.3 S.D. 3.7	45.2 S.D. 3.4	49.8* S.D. 3.8

 

There were no treatment-related macroscopic changes. There was an increased incidence of minimal acanthosis at the application site of skin of females at 1000 mg/kg bw/day. Minimal hyperkeratosis was increased in treated males but without a clear dose relationship.

Table 4. Findings at application site

Finding/Sex	Grade	Control	10 mg/kg bw/day	100 mg/kg bw/day	1000 mg/kg bw/day
Acanthosis/Male	1	8	7	9	8
	2	1	0	0	2
	Total	9	7	9	10
Acanthosis/Female	1	1	3	0	8
	2	0	0	0	0
	Total	1	3	0	8
Hyperkeratosis/Male	1	1	4	8	6
	Total	1	7	8	6
Hyperkeratosis/Female	1	2	0	1	1
	Total	2	0	1	1

 

Applicant's summary and conclusion

Conclusions:

Based on the increased liver weights in males and females and concomitant differences in clinical chemistry parameters at 1000 mg/kg bw/day in females and acanthosis at the application site of skin of females at 1000 mg/kg bw/day, the NOAEL in this 28-day dermal rat study was 100 mg/kg bw/day.

Executive summary:

This study in rats was conducted to determine the dermal toxicity of the test item when applied under occlusive dressing to the clipped area of skin on the back of rats for a period of 4 weeks on an at least 5 day/week basis. No application was performed on weekend days during treatment weeks 1, 2, and 3, but was done on the weekend days of treatment week 4. The exposure period was 6 hours per day. The test item, suspended in vehicle, was administered at the selected dose levels to a total of 80 rats, 10 males and 10 females per dose group. The applied quantities of test item were adjusted daily to individual animal body weights. Control animals (group 1) were treated with the vehicle only. Clinical signs, body weight, food consumption, and mortality were monitored throughout the study for all animals. In addition, detailed clinical observations were performed weekly. Hematological and blood chemistry analyses were performed at treatment end. At sacrifice, animals were examined macroscopically, and organ weights were recorded. Organs and tissues were collected and prepared for histopathological evaluation. Organs and tissues were examined microscopically. The test item was distributed homogeneously in the vehicle and was proven to be stable at the targeted concentrations.

There were no mortalities and no clinical signs or signs of local irritation. There were no treatmentrelated effects on body weight development, food consumption, food utilisation, ophthalmoscopy or haematological parameters. Slightly higher values for protein and globulin with an associated decrease in the albumin to globulin ratio were recorded for females at 1000 mg/kg bw/day. In addition, females at 1000 mg/kg bw/day had an increased cholesterol level and females at 100 and 1000 mg/kg bw/day had lower values for chloride. In the absence of a dose-response relationship, significantly lower glucose value in females at 100 mg/kg bw/day and significantly higher globulin value in females at 10 mg/kg bw/day were considered not relevant. The blood chemistry profile of treated males was not affected. In the absence of a dose-response relationship, significantly lower triglyceride concentration in males at 10 mg/kg bw/day were considered not relevant. Significantly higher mean values for sodium in males at 100 and 1000 mg/kg bw/day dose levels were not considered to be treatment-related as the magnitude of the difference from controls was too small to be toxicologically relevant. The mean absolute/relative liver weights were increased in 1000 mg/kg bw/day males (+19%/+15%) and females (+14%/+10%). There were no treatment-related macroscopic changes. There was an increased incidence of minimal acanthosis at the application site of skin of females at 1000 mg/kg bw/day. Minimal hyperkeratosis was increased in treated males but without a clear dose relationship.

Based on the increased liver weights in males and females and concomitant differences in clinical chemistry parameters at 1000 mg/kg bw/day in females and acanthosis at the application site of skin of females at 1000 mg/kg bw/day, the NOAEL in this 28-day dermal rat study was 100 mg/kg bw/day.