Registration Dossier

Administrative data

Endpoint:
acute toxicity: inhalation
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:
UNLABELLED TEST SUBSTANCE- Name of test material: 4,5-diamino-1-hexyl-1H-pyrazole hemisulfate (Code: A0021277)- TSIN: WR804146 - Substance type: Pure active substance- Physical state: White feathery crystals- Storage condition of test material: Ambient temperature (in dark)LABELLED TEST SUBSTANCE- Name of test material: [14C] n-Hexylpyrazole Hemisulfate ([14C]-C6P)- Substance type: Pure active substance- Specific activity: 59 mCi/mmol (2.18 GBq/mmol) (measured by mass spectroscopy)- Locations of the label: Ring-14C- Storage condition of test material: At - 20°C.

Results and discussion

Effect levels
Key result
Sex:
not specified
Dose descriptor:
LC50
Effect level:
ca. 2.51 mg/L air
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 inhalation 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 (Ref 7).   Required max. exposure conc. to test material (OECD 403,(Ref 8)):                             5 mg/L  

  • Assumed body weight of the rat:                                                                                 250 g

 

  • Respiratory volume of the rat(Ref 9):                                                                           0.074 L/min

 

  • Required duration (OECD 403,(Ref 8))                                                                       4 h

 

  • Inhalation Bioavailability (assumed, worst case assumption):                                       100%

 

 

Calculations:

 

Maximum volume of exposure in 4 hours:

 

0.074 L/min x 60 min x 4 hours = 17.76 L                                                                   Equation 1

 

 

Determination of the correction factor oral vs. inhalation route:

 

Ratio of 82% oral : 100% inhalation = 0.82                                                                  Equation 2

 

 

 

Determination of the LC50 calcinhal.:     

 
[(218 mg/kg bw x 0.250 kg bw )/ 17.76L]x 0.82 = 2.51 mg/L Equation 3

 

 

Result: LC50 calcinhal.1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE   = 2.51 mg/L


Assessment of possible local effects of1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE in the lung

 

Local irritation of the lung mucosal membranes can lead to death; therefore, the potential for1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATEto cause local lung mucous membrane irritation was evaluated by comparing theLC50 calcinhal. for1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATEwith thelocal irritating effect measured in thein vitroIsolated Chicken Eye (ICE) Test and the conditions of the acute inhalation toxicity maximal tested dose .

 

 

Calculations:

 

Comparison with eye irritation effects:

 

1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATEas neat substance and at 1.5% (w/w) in aqueous solution is not irritating to eyes.1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATEtested at 5% (w/w) was identified as mildly irritating to eyes. The SCCS concluded that1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATEas neat substance and at 1.5% (w/w) in aqueous solution is not a strong eye irritant .

 

 

Conversion of LC50 calcinhal. to % (w/w):

 

1 L air: 1.2041 kg/m³ = 1204.1 g/m³ = 1204100 mg/m³ = 1204100/1000 L = 1201 mg/L           Equation 4

1201 mg/L = 100 %

2.51 mg/L air = 0.21 % (w/w)                                                                                                 Equation 5

 

The concentration of 0.21% (w/w)1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATEis 6.5-fold lower than the lowest concentration tested in the ICE test (1.5%) at which concentration no irritation was observed.

 

 

Result: The concentration of1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATErepresents 0.21% in an aerosol. By comparing the LC50 calcinhal. with the results of thein vitroICE test , it can be concluded that1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATEwould not havea local effect in thelungs.


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.

 

 

 

Table 3:   Overview of chemical structures as well as oral and acute inhalational toxicity data for a structurally-related molecule to1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE. For this chemical, the SCCS issued scientific opinion, which is included in regulatory requirements.

COLIPA Number

Chemical Structure

Chemical Name

CAS Number

Acute Toxicity

Oral

LD50

Dermal

LD50

Inhalation LC50

Colipa No. A163

1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE

1361000-03-4

218 mg/kg bw

1050 mg/kg bw

2.51 mg/L,

Colipa No. A154

1-Hydroxyethyl-4,5-diamino pyrazole sulphate

155601-30-2

>2000 mg/kg bw

(rat)

(Ref 12)

Not available

> 5.24 mg/L,

 (4 h, rat)

(Ref 12)

 

Conclusion: The calculated oral LD50for1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE was 10-fold lower than that of a structurally related chemical, indicating the conservative estimate of this value. Acute dermal toxicity data were not available for the analogue. The inhalation LC50derived in this document for1‑HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATEwas in line with that measured for the structurally similar molecule, hence further reassuring the validity of the scientific information.


Summary:

The acute oral toxicity of1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATEwas determined from a 28-day repeated dose finding study conducted using the dihydrochloride salt. The determined LD50, oralvalue of 218 mg/kg bw is considered conservative since none of the animals died at this dose and it was 10-fold lower than that of a structurally related chemical. It was also in accordance with the required test concentrations and possible LD50estimations (between 50 and 300 mg/kg bw) for the OECD. Based on the calculated L50oral. value,1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATEshould be classified as Acute Tox Cat.3; H301: “toxic if swallowed”, according to the Globally Harmonized System of Classification and Labeling (GHS).

 

Based on the available acute oral toxicity and toxicokinetics data for1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE, the acute dermal, as well as acute inhalation, toxic potential for1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATEcould be calculated.

 

The calculated inhalation toxicity value (LC50,inhal.) for1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATEis 2.51 mg/L. When this concentration is combined with the results ofin vitroeye irritation studies, it can be concluded that the substance would not havea local effect in the lungs. The calculated LC50,inhal. is consistent with the measured value (inin vivostudies) for an analogue of1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE, namely 1-hydroxyethyl-4,5-diamino pyrazole sulphate. Based on the calculated LC50inhal. value,1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATEshould be classified as Acute Tox Cat.3; H331: “toxic if inhaled”, according to the Globally Harmonized System of Classification and Labeling (GHS).

 

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) of1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATEis 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).

 

 

Applicant's summary and conclusion

Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
Based on the available acute oral toxicity and toxicokinetics data for 1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE, the acute dermal, as well as acute inhalation, toxic potential for 1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE could be calculated.

The calculated inhalation toxicity value (LC50, inhal.) for 1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE is 2.51 mg/L. When this concentration is combined with the results of in vitro eye irritation studies, it can be concluded that 2-METHOXY-METHYL-P-PHENYLENEDIAMINE would not have a local effect in the lungs. The calculated LC50, inhal. is consistent with the measured value (in in vivo studies) for an analogue of 1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE, namely 1-hydroxyethyl-4,5-diamino pyrazole sulphate. Based on the calculated LC50 inhal. value, 1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE should be classified as Acute Tox Cat.3; H331: “toxic if inhaled”, according to the Globally Harmonized System of Classification and Labeling (GHS).

Executive summary:

The acute dermal and inhalational toxicity of 1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE was determined using kinetics-based data derived from an ADME study in rats . The calculated LC50 for inhalation (LC50 calc inhal.) was 2.51 mg/L. When this concentration is combined with the results of in vitro eye irritation studies (ICE) it can be concluded that 1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE would not have a local effect in the lungs.