Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
calculation (if not (Q)SAR)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
accepted calculation method
Justification for type of information:
The calculation of acute toxicity values for 1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE is based on the current understanding and knowledge of the test substance. Toxicity data were obtained from publically available publications such as the opinion document from the Scientific Committee on Consumer Safety of the European Commission on 1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE, and study reports provided by Service Germany GmbH. If more (detailed) information becomes available or if updated guidance becomes available, the statement might be subject to review

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2017
Report Date:
2017

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The calculation of acute toxicity values for 1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE is based on the current understanding and knowledge of the test substance. Toxicity data were obtained from publically available publications such as the opinion document from the Scientific Committee on Consumer Safety of the European Commission on 1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE, and study reports provided by Service Germany GmbH. If more (detailed) information becomes available or if updated guidance becomes available, the statement might be subject to review

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Test material form:
solid: crystalline
Details on test material:
- Name of test material: C6-Pyrazole hemisulfate; 4,5-Diamino-1-hexyl-1H-pyrazole, hemisulfate- TSIN: WR804146- Substance type: Pure active substance- Physical state: White crystalline solid- Storage conditions: At room temperature (20°C to 24°C), protected from light, and purged with nitrogen

Results and discussion

Effect levels
Key result
Sex:
not specified
Dose descriptor:
LD50
Effect level:
ca. 1 050 mg/kg bw
Remarks on result:
other:
Remarks:
extrapolated and calculated

Any other information on results incl. tables

Data from anin vivoADME studies

 

The oral bioavailability of1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATEbased on the blood AUC was high (93%) compared to the AUC after i.v. administration. When calculated from the urine data from the mass balance groups, the oral bioavailability was also determined to be high and was 84% at 12 mg/kg bw (Table 2).

 

The average dermal absorption of1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE,when calculated from the urine data from the mass balance groups, was low, and was 9% at 11 mg/kg bw (0.5 hours exposure) and 17% at 11.5 mg/kg bw (24 hours exposure).

 

After i.v. and oral administration, elimination, mainly via the urine, was fast, with 85% of the total amount being excreted within in the first 48 h. The elimination after dermal doses was relatively slow, with 62% and 50% of the absorbed radioactive dose recovered by 48 h after a 0.5 h and 24 h exposure, respectively.

 

 

 

Table 2:   Overview of the mass balance data from the ADME study with1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATEin rats

Group No.

1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATEDose Level / Concentration

Dosing route

Absorption (%)

Excretion via urine/feces (%)

(relative to administered dose)

1

11.9 mg/kg bw

i.v.

100

69 / 12

2

12 mg/kg bw

oral

82

69 / 15

3

11 mg/kg bw; 0.186 mg/cm² (0.5 hours exposure)

dermal

9*

3 / 4

4

11.5 mg/kg bw; 0.208 mg/cm² (24 hours exposure)

dermal

17*

8 / 6

*: Percentage of the dose recovered from: excretion + exhaled air + cage-wash + carcass.

 

For appropriate comparability between the different application routes, the mass balance data were used in the calculations of inhalation and dermal acute toxicity according to the applicability to the endpoint to derive the most conservative extrapolation

Extrapolation from oral to dermal acute toxicity of1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE:

Values and assumptions used in the calculations:

 

  • 1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATELD50oral= 218 mg/kg bw in the rat

 

  • Oral Bioavailability = 82% (at 12 mg/kg bw, using the data from the toxicokinetics study in Wistar rats).

 

  • Dermal bioavailability = 17% (24 h exposure). This value was selected (assuming higher toxicity resulting from a higher bioavailability) because incorporation of this value into Equation 6 results in a lowerLD50 calcdermalvalue (with an assumed higher toxicity). In addition, dermal absorption is dose-dependent, such that higher does leads to lower absorption; therefore, the high LD50dose would be expected to have lower absorption than assumed for this calculation.

 

 

Calculation:

 

Determination of the correction factor oral vs. dermal route:

 

82% oral vs. 17% dermal = 9.11 (82 / 17 = 4.82)                                                         Equation 6

 

 

Determination of the LD50 calcdermal:

 

218 mg/kg bw x 4.82 = 1050 mg/kg bw                                                                       Equation 7

 

 

Result: LD50 calcdermal1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE = 1050 mg/L


Comparative data of similar functional and structural hair dye molecules

 

The calculated oral LD50and inhalation LC50values for1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATEwere compared to those with a structurally similar molecule (Table 3). Four other structurally similar chemicals to1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATEwere identified (CAS numbers 173994-77-9, 163183-00-4, 889657-07-2 and 173994-78-0); however, corresponding measured oral, inhalation and dermal acute toxicity data were unavailable.

 

 

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
As demonstrated by the toxicokinetics data, the bioavailability after application to the skin is lower than the oral bioavailability. The calculated acute dermal toxicity (LD50, dermal) of 1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE is 1050 mg/kg bw. Therefore, it should be classified as Acute Tox Cat.4; H312: “may be harmful in contact with skin”, according to the Globally Harmonized System of Classification and Labeling (GHS).

Executive summary:

The acute oral toxicity of 1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE was not investigated.

However, no deaths were observed at doses up to 240 mg/kg bw /day in a 28-day repeated dose range finding study in rats using the dihydrochloride salt. This value was adjusted using the conversion factor of 0.91 to result in an oral LD50 value of 218 mg/kg for the hemisulfate salt. Since no additional in vivo studies are available, a conservative value for the oral acute toxicity (LD50, oral) of 1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE was set at 218 mg/kg bw. This derived LD50 value is within the required test concentrations and possible LD50 estimations for the OECD. The LD50, calc, oral of 218 mg/kg bw was therefore used for the route extrapolation calculations.

For the dermal end point, the data derived from the ADME study (with respect to the duration of test item and animal number was in line with the OECD guideline 402 for acute dermal toxicity. The approach to determine dermal toxicity by using oral data is accepted by the German and EU regulatory bodies and is based on the current state-of-the-art science. For the determination of the acute dermal toxicity, the bioavailability after topical application was used, which is lower than the oral bioavailability. The calculated LD50 for dermal toxicity (LD50 calc dermal) was 1050 mg/kg bw.