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Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Carbon disulphide is both a reagent in the manufacture, as well as a decomposition product of xanthates. Sodium isobutyl xanthate readily decomposes to carbon disulphide, especially in the presence of moisture/water. Therefore, the health effects of carbon disulphide (CS2) need to be considered in the assessment of sodium isobutyl xanthate. In addition, xanthates decompose on aging to form a number of byproducts, depending on the pH, temperature, etc. Risks associated with xanthate are, therefore, a function of the breakdown of the product or un-reacted raw materials remaining in the product.
Qualifier:
according to
Guideline:
OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.42 (Skin Sensitisation: Local Lymph Node Assay)
Deviations:
no
GLP compliance:
not specified
Type of study:
mouse local lymph node assay (LLNA)
Species:
mouse
Strain:
CBA
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS: Mice, CBA/CaOlaHsd
- Source: Harlan Laboratories B.V., Postbus 6174, 5960 AD Horst / The Netherlands
- Age at study initiation: 8 - 12 weeks (beginning of treatment)
- Weight at study initiation: 18.3 - 23.3 g
- Housing:single caging
- Diet: pelleted standard diet (Harlan Laboratories B.V., 5960 AD Horst / Netherlands), ad libidum
- Water: tap water, (Gemeindewerke, 64380 Rossdorf), ad libitum
- Bedding: granulated soft wood bedding (Rettenmaier & Söhne GmbH + Co. KG, 73494 Rosenberg)
- Acclimation period: At least 5 days prior to the start of dosing under test conditions after health examination. Only animals without any visible signs of illness were used for the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2°C
- Humidity (%): relative humidity 45-65%
- Photoperiod (hrs dark / hrs light): artificial light 6:00 a.m. - 6:00 p.m.
Vehicle:
acetone/olive oil (4:1 v/v)
Concentration:
The highest test item concentration which can be technically used was 100% of the undiluted test item. The dilutions were formulated in acetone/olive oil (4:1 v/v).
In the pre-test, two mice were treated with test item concentrations of 50 or 100%.
The test item in the main study was assayed at 25, 50, and 100%.
No. of animals per dose:
4
Details on study design:
RANGE FINDING TESTS:
- Compound solubility: The highest test item concentration which can be technically used was 100% of the undiluted test item. The dilutions were formulated in acetone/olive oil (4:1 v/v).
In the pre-test, two mice were treated by topical application to the dorsal surface of each ear with test item concentrations of 50 or 100% once daily each on three consecutive days. At those concentrations the animals did not show signs of systemic toxicity or local irritation.

MAIN STUDY:

TOPICAL APPLICATION:
Each test group of mice was treated by topical (epidermal) application to the dorsal surface of each ear (left and right) with different test item concentrations of 25, 50, and 100% (w/v) in acetone:olive oil (4:1). The application volume, 25 µl, was spread over the entire dorsal surface (~ 8 mm) of each ear once daily for three consecutive days. A further group of mice was treated with an equivalent volume of the relevant vehicle alone (control animals).
ADMINISTRATION OF ³H-METHYL THYMIDINE AND DETERMINATION OF INCORPORATED ³H-METHYL THYMIDINE

Five days after the first topical application, all mice were intraveneously injected into a tail vein with radio-labelled thymidine (³H-methyl thymidine). Approximately five hours after treatment with ³HTdR all mice were sacrificed and the draining lymph nodes were excised and pooled per group. Single cell suspensions lymph node cells were prepared from pooled lymph nodes, which were subsequently washed with phosphate buffered saline and incubated with trichloroacetic acid overnight. The proliferative capacity of pooled lymph node cells was determined by the incorporation of ³H-methyl thymidine measured in a ß-scintillation counter.

INTERPRETATION OF RAW DATA

The proliferative response of lymph node cells is expressed as the number of radioactive disintegrations per minute per lymph node (DPM/node) and as the ratio of ³HTdR incorporated into lymph node cells of test lymph nodes relative to that recorded for control lymph nodes (stimulation index). Before DPM/node values were determined, mean scintillation-background DPM was subtracted from test and control raw data. A test item is regarded as a sensitiser in the LLNA if the following criteria are fulfilled:
- First, that exposure to at least one concentration of the test item resulted in an incorporation of ³HTdR at least 3-fold or greater than that recorded in control mice, as indicated by the stimulation index.
- Second, that the data are compatible with a conventional dose response, although allowance must be made (especially at high topical concentrations) for either local toxicity or immunological suppression.
OBSERVATIONS

In addition to the sensitising reactions the following observations and data were recorded during the test and observation period:
- Mortality / Viability: Once daily (week day) from experimental start to necropsy.
- Body weights: In the pre-test prior to the first application and prior to sacrifice; in the main experiment prior to the first application and prior to treatment with 3HTdR.
- Clinical signs (local / systemic): In the pre-test clinical signs were recorded within 1 hour and 24 ± 4 hours after each application as well as on day 7. In the main experiment clinical signs were recorded within 1 hour each application, and 24 ± 4 hours after the first and second application as well as on the day of preparation. Especially the treatment sites were observed carefully.
Positive control substance(s):
hexyl cinnamic aldehyde (CAS No 101-86-0)
Statistics:
The mean values and standard deviations were calculated in the body weight tables.
Positive control results:
Experiment performend in November 2009:
5, 10, and 25% alpha-hexyl cinnamic aldehyde in acetone:olibe oil (4:1) yielded a S.I. of 1.78, 2.54, and 4.88, respectively. The EC3 value calculated was 12.9%.
The positive control substance alpha-hexyl cinnamic aldehyde was found to be a skin sensitizer under the described conditions, demonstrating the validity of the study.
Parameter:
SI
Remarks on result:
other: see Remark
Remarks:
In this study Stimulation Indices of 1.22, 0.99, and 3.46 were determined with the test item at concentrations of 25, 50, and 100% in acetone/olive oil (4:1 v/v), respectively. A conventional dose response curve could not be established and an EC3 value was not calculated because of the odd dose response.
Parameter:
other: disintegrations per minute (DPM)
Remarks on result:
other: As depicted in the table below.

Calculation and results of individual data; Vehicle: acetone/olive oil (4:1 v/v)

Test item concentration % (w/v)

Group

Measurement DPM

Calculation

Result

DPM-BGa)

number of lymph nodes

DPM per lymph nodeb )

S.I.

---

BG I

17

---

---

---

---

---

BG II

17

---

---

---

---

---

1

3517

3500

8

437.5

---

25

2

4282

4265

8

533.1

1.22

50

3

3479

3462

8

432.8

0.99

100

4

12129

12112

8

1514.0

3.46

VIABILITY / MORTALITY

No deaths occurred during the study period.

CLINICAL SIGNS

No symptoms of local toxicity at the ears of the animals and no systemic findings were observed during the study period.

BODY WEIGHTS

The body weight of the animals, recorded prior to the first application and prior to treatment with 3HTdR, was within the range commonly recorded for animals of this strain and age.

 

Interpretation of results:
not sensitising
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the numerical values of the stimulation indices one of which is slightly above 3, the test item Carbon disulfide has to be considered a skin sensitizer under the test condidions of this study. However, a conventional dose-response curve could not be established. An EC3 value was not calculated because of the odd dose-response.These factors contribute also in determining whether a borderline result shall be deemed as positive. In the opinion of the applicant this is a false positive and CS2 cannot be considered as a skin sensitizer base don this study.
Executive summary:

In this study carbon disulfide dissolved in acetone/olive oil (4:1 v/v) was assessed for its possible contact allergenic potential. For this purpose a local lymph node assay according to OECD guideline 429 was performed using test item concentrations of 25, 50, and 100%. All treated animals survived the scheduled study period and no signs of systemic toxicity or local irritation were observed. A test item is regarded as a sensitiser in the LLNA if the exposure to one or more test concentration results in a 3-fold or greater increase in incorporation of ³HTdR compared with concurrent controls, as indicated by the Stimulation Index (S.I.). The estimated concentration of test item required to produce a S.I. of 3 is referred to as the EC3 value. In this study Stimulation Indices of 1.22, 0.99, and 3.46 were determined with the test item at concentrations of 25, 50, and 100% in acetone/olive oil (4:1). Based on the numerical values of these stimulation indices, the test item carbon disulfide has to be considered a skin sensitizer under the test conditions of this study. However, a conventional dose-response curve could not be established. An EC3 value was not calculated because of the odd dose-response. These factors contribute also in determining whether a borderline result shall be deemed as positive. In the opinion of the applicant this is a false positive and CS2 cannot be considered as a skin sensitizer base don this study.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Skin sensitisation

No evidence of sensitisation in the study of of Vogel 2010.Based on the numerical values of the stimulation indices one of which is slightly above 3, the test item Carbon disulfide has to be considered a skin sensitizer under the test condidions of this study.

 However, a conventional dose-response curve could not be established. An EC3 value was not calculated because of the odd dose-response.These factors contribute also in determining whether a borderline result shall be deemed as positive. In the opinion of the applicant this is a false positive and CS2 cannot be considered as a skin sensitizer base don this study.

 

Because carbon disulphide is both a reagent in the manufacture, as well as a decomposition product of xanthates. Sodium isobutyl xanthate readily decomposes to carbon disulphide, especially in the presence of moisture/water.Therefore, the health effects of carbon disulphide (CS2) need to be considered in the assessment of sodium isobutyl xanthate.

This result can be reliably be read across to the substance Sodium isobutyl xanthate

 

Synopsis

Not sensitising

 

In other study SodiumHydroxide was tested for skin sensitisation using 15 volunteers.

Patch testing for 24 hours with visual scoring being recorded by the subjective evaluation method and by the transepidermal water loss method. After the seventh day reading sodium hydroxide (0.125%) was re-applied to all pretested sites and reading was performed on the next day.

The irritant response was well correlated to the concentration of the irritant. However, increased response was not observed when subclinical doses were rechallenged on the previously patch tested sites.

No evidence of skin sensitisation was seen in the study. Because SodiumHydroxide is used in the manufacturing processforSodium isobutyl xanthateand ispresent in the final productthe health effects of SodiumHydroxide need to be considered in the assessment of sodium isobutyl xanthate.

 

This result can be reliably be read across to the substanceSodium isobutyl xanthate

 Synopsis

Not sensitising


Migrated from Short description of key information:
No evidence of skin sensitisation. It is concluded that the substance Sodium isobutyl xanthate does notmeet the criteria to be classified for human health hazards for Inhalation - local effect: respiratory irritation/corrosion and/or respiratory sensitisation.

Respiratory sensitisation

Link to relevant study records
Reference
Endpoint:
respiratory sensitisation: in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted in accordance with generally accepted scientific principles, possibly with incomplete reporting or methodological deficiencies, which do not affect the quality of the relevant results.
Qualifier:
no guideline followed
Principles of method if other than guideline:
A 30-day repeated inhalation study for potassium amyl xanthate was conducted in 1976. Animals were exposed to potassium amyl xanthate as an aqueous aerosol. Attempts at dust exposure were unsuccessful as potassium amyl xanthate is hygroscopic.
Animals were exposed to concentrations of 0, 100 and 800 mg/m3 of potassium amyl xanthate. These concentrations were equivalent to actual doses of 0, 23 and 252 mg/m3. Analysis of the particle size indicated that all the particles at the lower dose of 100 mg/m3 were less than 10μm in diameter while approximately 80% of the particles had a diameter of 10μm or less at a dose of 800 mg/m3. It is not possible to state from the description of the exposure method whether air flow was dynamic or static.
GLP compliance:
not specified
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Route of induction exposure:
inhalation
Route of challenge exposure:
inhalation
Vehicle:
other: aqueous aerosol
Concentration:
10 male Sprague-Dawley rats were exposed to concentrations of 0, 200 or 800 mg/m3 of potassium amyl xanthate, 6 hrs daily for 10 exposures in 2 weeks.
No. of animals per dose:
10
Details on study design:
Animals were exposed to concentrations of 0, 100 and 800 mg/m3 of potassium amyl xanthate. These concentrations were equivalent to actual doses of 0, 23 and 252 mg/m3. Analysis of the particle size indicated that all the particles at the lower dose of 100 mg/m3 were less than 10μm in diameter while approximately 80% of the particles had a diameter of 10μm or less at a dose of 800 mg/m3. It is not possible to state from the description of the exposure method whether air flow was dynamic or static.
Exposure levels for the study were established by a preliminary experiment. In the preliminary experiment, three groups of 10 male Sprague-Dawley rats were exposed to concentrations of 0, 200 or 800 mg/m3 of potassium amyl xanthate, 6 hrs daily for 10 exposures in 2 weeks.
Positive control substance(s):
not specified
Negative control substance(s):
not specified
Results:
The results of this study indicate that potassium amyl xanthate has an adverse effect at concentration of 252mg/m3 on the central nervous system and liver in mice, the liver and kidneys in rats and the liver in dogs. There were no treatment-related changes in the haematological or urinalysis values in any of the animals. No signs of irritation of respiratory tract and Nasal effects were observed.

Table 5 Results of repeated inhalation study with potassium amyl xanthate in laboratory animals

 

 

 

Dogs

(2 animals)

 

Rabbits

(4 animals)

 

Rats

(10 animals)

 

Mice

(10,6 animals)

 

100 mg/m3

 

Eyes

 

No irritation

 

No irritation

 

No irritation

 

No irritation

 

 

Nasal effects and irritation of respiratory tract

 

No effects

 

No effects

 

No effects

 

No effects

 

 

Hair coat

 

Yellow brown staining.

 

Progressive yellow brown staining

 

Yellow brown stainingof

the hair coat of the rats.

 

No staining

 

 

Other effects

 

Staining of the appendages

and scrotum; ulceration of the

skin in the scrotal region.

 

None

 

None

 

None

 

 

Body weight

 

No change

 

No change

 

No change

 

No change

 

 

Organ weight

 

No change

 

No change

 

No change

 

Higher liver to body weight

ratio than controls

 

 

Liver enzyme changes

 

Marked elevation of serum

alanine aminotransferase and

alkaline phosphatase activities

 

No change

 

No change

 

No change

 

 

Histopathology

changes

 

Hepatocellular degeneration,

necrosis and inflammation

 

No treatment related change

 

No treatment related change

 

No treatment related change

 

 

Deaths

 

None

 

None

 

None

 

None

 

800 mg/m3

 

Eye changes

 

Excessive lacrimation

 

Conjunctival redness

 

No irritation

 

No changes

 

 

Nasal effects and irritation of respiratory tract

 

None

 

None

 

Reddish nasal discharge

 

None

 

 

Hair coat

 

Yellow brown staining

 

A more intense yellow brown

 

Yellow brown staining

 

No effects

 

 

Skin

 

Ulceration of the skin

 

No effect

 

No effect

 

No effect

 

 

Body weight

 

No effect

 

No effect

 

No effect

 

No effect

 

 

Organ weight

 

No change

 

No change

 

Higher liver to body weight

ratio than controls

 

Higher liver to body weight

ratio than controls

 

 

Liver enzyme changes

 

Marked elevations of serum

alanine aminotransferase and alkaline phosphatase activities.

 

 

No changes

 

High serum alanine

aminotransferase activity

 

No changes

 

 

Histopathology

changes

 

Hepatocellular degeneration,

necrosis and inflammation

 

No changes

 

Microscopically visible

granular degeneration

 

No changes

 

 

Deaths

 

None

 

None

 

One, but not related to

exposure

 

10 from the original group

and 5/6 replacement animals

died. Convulsions hyperactivity

in 5/16 prior to death.

 

 

Interpretation of results:
not sensitising
Conclusions:
The results of this study indicate that potassium amyl xanthate has an adverse effect at concentration of 252mg/m3 on the central nervous system and liver in mice, the liver and kidneys in rats and the liver in dogs. There were no treatment-related changes in the haematological or urinalysis values in any of the animals. No signs of irritation of respiratory tract and Nasal effects were observed.
Executive summary:

In the 30-day study, three groups of animals, each consisting of 10 male Swiss-Webster mice, 10 male Sprague-Dawley rats, 4 male New Zealand White rabbits and 2 male beagle dogs were exposed to either filtered room air or to concentrationsof 100 or 800 mg/m3 of potassium amyl xanthate. Whole body exposure was for 6 hrsdaily, 5 days a week for a total of 20 exposures in 1 month.

Ten mice of the 800 mg/m3group died along with 5/6 replacement mice.

The animals were observed during the exposures and body weights were recordedthree times a week throughout the experiment. Body weight data, organ to bodyweight ratios and clinical laboratory parameters were analysed statistically usinganalysis of variance and Dunnett’s test.

 

Most of the mice died when exposed to 800 mg/m3. Five of the 16 mice that diedshowed convulsions and hyperactivity prior to death. The adverse effects producedby the two doses of potassium amyl xanthate are shown in Table1.

 

The results of this study indicate that potassium amyl xanthate has an adverseeffect at concentration of 252mg/m3on the central nervous system and liver in mice, the liver and kidneys in ratsand the liver in dogs. There were no treatment-related changes in thehaematological or urinalysis values in any of the animals.No signs of irritation of respiratory tract and Nasal effectswere observed.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Respiratory sensitisation.

In the 30-day study, three groups of animals, each consisting of 10 male Swiss-Webster mice, 10 male Sprague-Dawley rats, 4 male New Zealand White rabbitsand 2 male beagle dogs were exposed to either filtered room air or to concentrationsof 100 or 800 mg/m3 of potassium amyl xanthate. Whole body exposure was for 6 hrsdaily, 5 days a week for a total of 20 exposures in 1 month.

Ten mice of the 800 mg/m3group died along with 5/6 replacement mice.

The animals were observed during the exposures and body weights were recordedthree times a week throughout the experiment. Body weight data, organ to bodyweight ratios and clinical laboratory parameters were analysed statistically usinganalysis of variance and Dunnett’s test.

Most of the mice died when exposed to 800 mg/m3. Five of the 16 mice that diedshowed convulsions and hyperactivity prior to death.

The results of this study indicate that potassium amyl xanthate has an adverseeffect at concentration of 252mg/m3on the central nervous system and liver in mice, the liver and kidneys in ratsand the liver in dogs. There were no treatment-related changes in thehaematological or urinalysis values in any of the animals.No signs of irritation of respiratory tract and Nasal effects were observed.

Synopsis

Not sensitising


Migrated from Short description of key information:
No signs of respiraratory sensitisation of respiratory tract were observed and the substance would not be not sensitising for respiratory sensitisation by the inhalation route.

Justification for classification or non-classification

Based on the hazard assessment of Sodium isobutyl xanthate section 2.1 and 2.2. in IUCLID 5.4., available data for the substance and following the “Guidance on Information Requirement and Chemical Safety Assessment R.8. Characterisation of dose [concentration]- response for human health” andaccording to the criteria described in Directive 67/548 and in the CLP Regulation:

Directive 67/548

Respiratory Sensitisation Xn

R42 May cause sensitization by inhalation

Respiratory Irritation Xi

R37 irritating to respiratory system

CLP

Respiratory Sensitisation

H334 Resp. Sens. 1 May cause allergy or asthma symptoms or breath-ing difficulties if inhaled

Respiratory Irritation

H335 STOT SE 3 May cause respiratory irritation

It is concluded that the substance Sodium isobutyl xanthate does not meet the criteria to be classified for human health hazards for Inhalation - local effect: respiratory irritation/corrosion and/or respiratory sensitisation.