Sodium O-isobutyl dithiocarbonate

Endpoint summary

Description of key information

- Acute oral toxicity:.The LD50 value of 500 mg/kg was determined for Sodium Isobutyl Xanthate. This show that SIBX  is of a moderately order of acute oral toxicity .
-Acute Dermal Toxicity: The dermal LD50 in male and female rabbits is >2000 and 2460 mg/kg, respectively.. This show  that SIBX   is of a slightly order of acute Dermal toxicity .
- Acute  inhalation toxicity :Inhalation LC50 values for vapor exposures were >6,000 ppm (18,180 mg/m3) in male and female rats.Decreases in motor activity were noted post-exposure in the 6000 ppm (18,18 0 mg/m3 ) groups but not the 3000 or 1500 ppm (9,090 or 4,550 mg/m3 )groups. No effect on motor activity was detected at the 7 and 14-day time points. No exposure-related effects were noted in the FOB assessment.
2-methylpropan-1-ol /Isobutyl alcohol/ is both reagents used in the manufacture of sodium O-isobutyl dithiocarbonate. Therefore, 2-methylpropan-1-ol /Isobutyl alcohol/ need to be considered in the assessment of sodium O-isobutyl dithiocarbonate
It is concluded that the substance SIBX  meet the criteria to be classified for human health hazards for acute oral and dermal effects.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Principles of method if other than guideline:

Method: other

GLP compliance:

no

Test type:

other: LD50

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS

- Weight at study initiation: 200-265g

- Fasting period before study: Over night

- Housing: Group housing (5 of each sex per cage), in metal cages provided with white pine and cheddar shavings.

- Diet: Purina Laboratory Chow, ad libitum.

- Water: ad libitum

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Exploratory doses were administered to 8 rats to estimate the order of toxicity of the test compound. Based on the preliminary estimation, groups of 10 rats (5M, 5F) were administered the test compound at graded dosage levels designed to blanket the toxicity range.

Doses:

500,2000 mg

No. of animals per sex per dose:

5 female, 5 male

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: Regular intervals on the day of dosing and daily thereafter for 14 days.

- Necropsy of survivors performed: yes

- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: Gross necropsies were performed on all survivors and any animals which died during the observation period. Body weights of survivors were recorded prior to sacrifice.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

500 mg/kg bw

Based on:

test mat.

Remarks on result:

other: The findings of this study indicate that Sodium Isobutyl Xanthate produces adverse effects on the central nervous system, liver and kidneys.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: The findings of this study indicate that Sodium Isobutyl Xanthate produces adverse effects on the central nervous system, liver and kidneys.

Mortality:

All death occurring 1 to 2 hours after administration.

Clinical signs:

other: Oral administration of Sodium Isobutyl Xanthate to rats produced increased motor activity, cyanosis, irritability, increased respiration and convulsions with death occurring 1 to 2 hours after administration.

Gross pathology:

Autopsy showed perivascular and pericellular oedema, multiple haemorrhages in the lungs, perivascular subarachnoid haemorrhages and acute
swelling of the cells of the cortex, subcortical ganglia and the brain stem. Fatty dystrophy of the liver and protein dystrophy of the twisted canaliculi of the
kidneys were observed.

Other findings:

The findings of this study indicate that Sodium Isobutyl Xanthate produces adverse effects on the central nervous system, liver and kidneys.

Table 3:	Oral toxicity of xanthates (from: Kirk-Othmer, 1984)16
Xanthate	Species		LD0	(mg/kg)	LD50	(mg/kg)	References
Sodium ethyl		rat	500		—		17
Potassium ethyl		Rat  mouse	500		1700 583		17, 18
Sodium isopropyl		rat	250		—		17
Potassium isopropyl		rat mouse	— —		1700  583		18 —
Potassium n-butyl		mouse	—		411  465		19,20
Sodium isobutyl		rat			500		17
Potassium isobutyl		rat mouse	— —		1290  480		18 18
Sodium sec-butyl		rat	—		>2000		17
Potassium amyl (mixed)		rat	1000		1000–2000		17, 21
Potassium iso amyl		rat mouse	— —		765 470		18 18
C5-C6 mixture		rat	—		1500		22

 

 

The LD50 value of 500 mg/kg was determined for Sodium Isobutyl Xanthate. This show that Sodium Isobutyl Xanthate is of a moderately order of acute oral toxicity .

 

The LD50 of the various xanthates are similar, ranging from 411 to 583mg/kg in mice and from 1000 to >2000 mg/kg in rats.

The acute oral toxic effects of one xanthate, potassium butyl xanthate, are providedin two summaries in Chemical Abstracts.

 Similar symptoms and pathologyfindings were seen in these studies carried out by Babayan.

 

References :

16.Kirk-Othmer Encyclopaedia of Chemical Technology,Vol 24, 2nd ed, pp 645-661,John Wiley & Sons, 1984.

17.Dow Chemical Company, 1964, unpublished toxicological data to C.B. Shaffer,American Cyanamid; data from P. Avotin, American Cyanamid, privatecommunication, 1982 as cited in Kirk-Othmer Encyclopaedia of Chemical

18.Babayan, E.A., 1963, “Toxicology of Potassium Butyl Xanthate” Material 2-oi[Vtoroi] Itog. Nauchn. Konf. Inst. Gigieny Truda I Prof. Zabolevan Posvyashch.Vopr. Gigieny Truda I Prof. Patol. Erevan, pp 75-77 (Pub 1964)(Russ)Chem Abstract,64, 8836e (1966).

19.Babayan, E.A., “Toxicological Characteristics of the Flotation Agent PotassiumButyl Xanthate”, Mater. Itogovoi Nauch. Konf. Vop. Gig Tr Profpatol. Khim.Gornorud. Prom., 3rd 1966 (Pub 1968) 97-102 (Russ) inChemical Abstracts,Vol 73,1970.

20.Fronk, N.G., The Dow Chemical Company, private communication, 1982, as cited inKirk-Othmer Encyclopaedia of Chemical Technology,Vol 24, 2nd Ed, pp 645-661,John Wiley & Sons, 1984.

21.Buzina, A.Z., Burkhanov, A.I. and Abeuev, Kh.B., 1977 Zdravookhr. Kaz., 88 ascited inKirk-Othmer Encyclopaedia of Chemical Technology,Vol 24, 2nd Ed, pp645-661, John Wiley & Sons, 1984.

22.Chemical Abstracts,Vol 64, 1966.

 

Interpretation of results:

other: moderately toxic

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The LD50 value of 500 mg/kg was determined in a reliable study. This show that SIBX is of a moderately order of acute oral toxicity .
Based on the data provided in this review, SReaction mass of SIBX e shall be classified for acute oral toxicity.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

other: published data

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Justification for type of information:

SIBX are related compound to PIBX

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

no

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS

- Weight at study initiation: 200-265g

- Fasting period before study: Over night

- Water: ad libitum

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

500,1000, 1290, 2000 mg

No. of animals per sex per dose:

10male

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days

Sex:

male

Dose descriptor:

LD50

Effect level:

1 290 mg/kg bw

Based on:

test mat.

Remarks on result:

other: oral administration of potassium butyl xanthate to rats produced increased motor activity, cyanosis, irritability, increased respiration and convulsions with death occurring 1 to 2 hours after administration.

Mortality:

All death occurring 1 to 2 hours after administration.

Clinical signs:

other: Oral administration of potassium butyl xanthate to rats produced increased motor activity, cyanosis, irritability, increased respiration and convulsions with death occurring 1 to 2 hours after administration.

Gross pathology:

Autopsy showed perivascular and pericellular oedema, multiple haemorrhages in the lungs, perivascular subarachnoid haemorrhages and acute
swelling of the cells of the cortex, subcortical ganglia and the brain stem. Fatty dystrophy of the liver and protein dystrophy of the twisted canaliculi of the
kidneys were observed.

Other findings:

The findings of these studies indicate that potassium isobutyl xanthate produces adverse effects on the central nervous system, liver and kidneys.

Interpretation of results:

other: sligthly toxic

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The LD50 value of1290 mg/kg was determined in a reliable study. This show that Potassium Isobutyl Xanthate is of a Slightly order of acute oral toxicity .
Based on the data provided in this review, Potassium Isobutyl Xanthate shall be classified for acute oral toxicity.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

other: published data

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Justification for type of information:

SIBX are related compound to PIBX

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

no

Test type:

acute toxic class method

Limit test:

no

Species:

mouse

Strain:

other: albino mice

Sex:

male

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

200, 480, ,1000, 2000 mg

No. of animals per sex per dose:

10male

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days

Sex:

male

Dose descriptor:

LD50

Effect level:

480 mg/kg bw

Based on:

test mat.

Remarks on result:

other: oral administration of potassium butyl xanthate to mice produced increased motor activity, cyanosis, irritability, increased respiration and convulsions with death occurring 1 to 2 hours after administration.

Mortality:

All death occurring 1 to 2 hours after administration.

Clinical signs:

other: Oral administration of potassium isobutyl xanthate to mice produced increased motor activity, cyanosis, irritability, increased respiration and convulsions with death occurring 1 to 2 hours after administration.

Gross pathology:

Autopsy showed perivascular and pericellular oedema, multiple haemorrhages in the lungs, perivascular subarachnoid haemorrhages and acute
swelling of the cells of the cortex, subcortical ganglia and the brain stem. Fatty dystrophy of the liver and protein dystrophy of the twisted canaliculi of the
kidneys were observed.

Other findings:

The findings of these studies indicate that potassium isobutyl xanthate produces adverse effects on the central nervous system, liver and kidneys.

Interpretation of results:

other: moderately toxic

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The LD50 value of480 mg/kg was determined in a reliable study. This show that Potassium Isobutyl Xanthate is of a moderately order of acute oral toxicity .
Based on the data provided in this review, Potassium Isobutyl Xanthate shal be classified for acute oral toxicity.

Reference 4

Endpoint:

acute toxicity: oral

Type of information:

other: published data

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Justification for type of information:

SIBX are related compound potassium O-butyl dithiocarbonate

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

no

Test type:

acute toxic class method

Limit test:

no

Species:

mouse

Strain:

other: albino mice

Sex:

male

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

200, 411, 465 ,1000, 2000 mg

No. of animals per sex per dose:

10male

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days

Sex:

male

Dose descriptor:

LD50

Effect level:

411 mg/kg bw

Based on:

test mat.

Remarks on result:

other: oral administration of Potassium n-butyl xanthate to mice produced increased motor activity, cyanosis, irritability, increased respiration and convulsions with death occurring 1 to 2 hours after administration.

Sex:

male

Dose descriptor:

LD50

Effect level:

465 mg/kg bw

Based on:

test mat.

Remarks on result:

other: oral administration of Potassium n-butyl xanthate to mice produced increased motor activity, cyanosis, irritability, increased respiration and convulsions with death occurring 1 to 2 hours after administration.

Mortality:

All death occurring 1 to 2 hours after administration.

Clinical signs:

other: Oral administration of potassium n-butyl xanthate to mice produced increased motor activity, cyanosis, irritability, increased respiration and convulsions with death occurring 1 to 2 hours after administration.

Gross pathology:

Autopsy showed perivascular and pericellular oedema, multiple haemorrhages in the lungs, perivascular subarachnoid haemorrhages and acute
swelling of the cells of the cortex, subcortical ganglia and the brain stem. Fatty dystrophy of the liver and protein dystrophy of the twisted canaliculi of the
kidneys were observed.

Other findings:

The findings of these studies indicate that potassium n-butyl xanthate produces adverse effects on the central nervous system, liver and kidneys.

Interpretation of results:

other: moderately toxic

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The LD50 value of411 mg/kg was determined in a reliable study. This show that Potassium n-butyl Xanthate is of a moderately order of acute oral toxicity .
Based on the data provided in this review, Potassium n-butyl Xanthate shall be classified for acute oral toxicity.

Reference 5

Endpoint:

acute toxicity: oral

Type of information:

other: published data

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Justification for type of information:

SIBX are related compound to SEX

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Principles of method if other than guideline:

The study was carried out in 1951 and complies generally with current test protocols such as the Organisation for Economic Cooperation and Development (OECD) guidelines for testing of chemicals No. 401. This study predates the requirements for good laboratory practice, however the study was considered adequate for this assessment. A 10% aqueous solution of sodium ethyl xanthate was administered orally by gavage. The pH of the solution was approximately 10.5 to 11. The animals were observed for signs of gross toxicological effects for seven days.

GLP compliance:

no

Test type:

other: LD50

Limit test:

no

Species:

mouse

Strain:

other: albino mice

Sex:

male

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

500,600,750,900,1000,1500,2000,5000 mg

No. of animals per sex per dose:

93 male

Control animals:

no

Details on study design:

- Duration of observation period following administration: 7 days

Sex:

male

Dose descriptor:

LD50

Effect level:

730 mg/kg bw

Based on:

test mat.

Mortality:

The majority of deaths occurred on the first day and the animals that survived appeared normal within two days. The study does not indicate how many animals
developed the symptoms, at what doses and the day of development of the symptoms.

Clinical signs:

other: Depression followed by hyperexcitability, tremors, paralysis, exophthalmia and clonic followed by tonic convulsions. Pinkness of feet and nose, preening and salivation.

Gross pathology:

Consolidated lungs, pale granular livers, unusually small spleens and atonic
intestines. Surviving animals showed no abnormalities.

Interpretation of results:

other: sligthly toxic

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The LD50 value of730 mg/kg was determined in a reliable study. This show that 10% aqueous solution of sodium ethyl xanthate is of a Slightly order of acute oral toxicity .
Based on the data provided in this review, sodium ethyl xanthate shall be classified for acute oral toxicity.

Executive summary:

The results of this study indicate that a 10% aqueous solution of sodium ethyl xanthate has an oral LD50 of 730 mg/kg in male mice. The target organs for oral toxicity of sodium ethyl xanthate were the central nervous system, liver and spleen.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

500 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

2-methylpropan-1-ol /Isobutyl alcohol/ is both reagents used in the manufacture of sodium O-isobutyl dithiocarbonate . Therefore, 2-methylpropan-1-ol /Isobutyl alcohol/ need to be considered in the assessment of sodium O-isobutyl dithiocarbonate

Qualifier:

according to guideline

Guideline:

other: 40 CFR 799 Multi-Substance Rule for the Testing of Neurotoxicity; 40 CFR Part 798.1150 Inhalation Test Guidelines; Test Guidelines 798.6050 & 798.6200 updated by Neurotoxicity Guideline 81-8, Subdivision F

Principles of method if other than guideline:

Male and female rats (10/sex) were exposed by inhalation for 6 hours to a vapor of isobutanol at 0, 1500, 3000 and 6000 ppm. The animals were observed for 14 days.

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Raleigh, NC, USA
- Age at study initiation: 8 weeks
- Weight at study initiation: males: 288-388 g; females: 187-290 g
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-24 °C
- Humidity (%): 40-60 %
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

- Exposure Chambers: Four 2000-liter stainless steel and glass Hazelton H-2000 chambers
- Animal Housing during Exposure: Individual stainless steel wire mesh cages, positioned in one tier in the chamber
Exposure Duration: 6 hours
- Test Atmosphere Generation System: Test material was fed into a Laskin-type nebulizer mounted in a filtered supply air inlet at top of the inhalation chamber. Exposure concentrations were controlled by using an adjustable-flow valveless pump to regulate the
rate at which isobutanol was delivered to the nebulizer.
- Test Atmosphere Sampling Method: Six test atmosphere samples were drawn through a Miran 1A infrared detector calibrated for isobutanol.
Sampling Location: In the animal breathing area from a port halfway down on the chamber door
- Chamber Atmosphere Distributions: Chamber atmospheres were sampled in 2 different locations for all 3 exposure concentrations.
- Gas Chromatography Analysis: Samples of the chamber atmospheres were collected in two impingers, in series, containing methanol. The solutions were analyzed for isobutanol content using gas chromatography with a flame ionization detector.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

6 h

Concentrations:

0, 1500, 3000, 6000 ppm (0, 4.54, 9.09, 18.18 mg/m3)

No. of animals per sex per dose:

10

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Checks for mortality and moribundity and noteworthy signs of toxicity were made daily from the day of
randomization until the day of sacrifice; weighing: day 0, day 7 and day 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

A two-way ANCOVA and Duncan’s multiple comparison test was used to determine statistical significance. The FOB evaluation was similar to methods published by Mosher (1991).

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 18.18 mg/m³ air

Based on:

test mat.

Exp. duration:

6 h

Remarks on result:

other: Decreases in motor activity were noted post-exposure in the 6000 ppm (18,18 0 mg/m3 )

Mortality:

1/10 male animals died at 6000 ppm. This death was attributed to an ophthalmic examination where atropine drops were applied to its eyes.
All other animals survived.

Clinical signs:

other: during exposure: There was clear evidence of generalized depression of the central nervous system (animals were non-responsive to tapping on side of inhalation chambers) and labored respiration in rats during the 6 hours of exposure to 6000 and 3000 ppm

Body weight:

Body weights of male rats in the 3000 and 6000 ppm groups were significantly lower than the male controls throughout the study. These statistically
significant results are due to pretest differences and not because of exposure to the chemical.

Gross pathology:

There were no treatment-related lesions or other gross changes in the tissues and organs examined during necropsy. Enlarged, dilated, distended
uteri were observed at necropsy in the low, mid, and high groups at incidences of 3/10, 1/10, and 1/10, respectively. This finding was not observed in the control group. The severity was minimal in all instances. This is a common observation and usually reflects physiologic changes related to the
estrus cycle. This is further substantiated by the inverse dose response. Therefore, although histologic examination was not conducted, it appears that these observations are unassociated with treatment and reflect the normal variation expected with different stages of the estrus cycle.

Interpretation of results:

sligthly toxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Inhalation LC50 values for vapor exposures were >6,000 ppm (18,180 mg/m3) in male and female rats.Decreases in motor activity were noted post-exposure in the 6000 ppm (18,18 0 mg/m3 ) groups but not the 3000 or 1500 ppm (9,090 or 4,550 mg/m3 )groups. No effect on motor activity was detected at the 7 and 14-day time points. No exposure-related effects were noted in the FOB assessment.

Executive summary:

Male and female rats exposed to atmospheric vapor levels of 0, 1500, 3000, or 6000 ppm (0, 4,550, 9,090, 18,180 mg/m3) for six hours were evaluated in a neurobehavioral battery (motor activity determination and a functional observational battery) within two hours post-exposure. Hypoactivity and diminished response to a startle reflex (during the inhalation exposure) was observed during exposure for the 3000 and 6000 ppm (9,090 and 18,180 mg/m3) exposures. Decreases in motor activity were noted post-exposure in the 6000 ppm (18,18 0 mg/m3 ) groups but not the 3000 or 1500 ppm (9,090 or 4,550 mg/m3 )groups. No effect on motor activity was detected at the 7 and 14-day time points. No exposure-related effects were noted in the FOB assessment. Inhalation LC50 values for vapor exposures were >6,000 ppm (18,180 mg/m3) in male and female rats.

Reference 2

Endpoint:

acute toxicity: inhalation

Type of information:

other: published data

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Carbon disulphide is both a reagent in the manufacture, as well as a decomposition product of xanthates. SIBX 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 SIBX. 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

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Deviations:

no

GLP compliance:

not specified

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: Harlan Laboratories B.V., Kreuzelweg 53, 5961 NM Horst, Netherlands
- Age at study initiation: 9 weeks
- Weight at study initiation: males: 254.6 to 274.2 g, females: 169.9 to 183.7 g
- Fasting period before study: none
- Housing: Animals were housed in groups of 5 of the same sex in Makrolon® type-IV cages with wire mesh tops and standard softwood bedding ("Lignocel" J. Rettenmaier & Söhne GmbH & Co KG, 73494 Rosenberg / Germany, imported by Provimi Kliba AG, 4303 Kaiseraugst / Switzerland) including paper enrichment (Enviro-dri from Lillico, Biotechnology, Surrey, UK)
- Diet (e.g. ad libitum): Animals were housed in groups of 5 of the same sex in Makrolon® type-IV cages with wire mesh tops and standard softwood bedding ("Lignocel" J. Rettenmaier & Söhne GmbH & Co KG, 73494 Rosenberg / Germany, imported by Provimi Kliba AG, 4303 Kaiseraugst / Switzerland) including paper enrichment (Enviro-dri from Lillico, Biotechnology, Surrey, UK)
- Water (e.g. ad libitum): Community tap water from Füllinsdorf ad libitum in water bottles, except during the period when they were restrained in exposure tubes
ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%): 30-70 %
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

This study was performed in an AAALAC-accredited laboratory in accordance with the Swiss Animal Protection Law under license no. 49.

Route of administration:

inhalation: gas

Type of inhalation exposure:

nose only

Vehicle:

clean air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The test atmosphere was generated using a Hudson nebulizer connected to a step dose pump. The entire polyethylene injector inside the nebulizer was replaced by a stainless steel injector. The concentration of the test item in the inhalation chamber was controlled by regulating the flow of the test item to the inhalation tower and by the addition of dilution air
- Exposure chamber volume: not applicable
- Method of holding animals in test chamber: The animals were confined separately in restraint tubes which were positioned radially around the exposure chamber
- Source and rate of air: compressed air was supplied by means of an oil free compressor and passed respiratory quality filters before it was introduced to the exposure system
- Method of conditioning air: respiratory quality filters
- System of generating particulates/aerosols: The test atmosphere was generated using a Hudson nebulizer connected to a step dose pump. The entire polyethylene injector inside the nebulizer was replaced by a stainless steel injector. The concentration of the test item in the inhalation chamber was controlled by regulating the flow of the test item to the inhalation tower and by the addition of dilution air
- Method of particle size determination: not applicable as test item was generated as gas
- Treatment of exhaust air: filtered
- Temperature, humidity, pressure in air chamber: 23.5 °C, 2.4 % relative humididty, 20.0 % oxygen
TEST ATMOSPHERE
- Brief description of analytical method used: The concentration was measured at least 4 times per hour of exposure per on-line gas chromatography. The analyses were performed according to the conditions listed below.

Column: DB-624 (30m x 0.320mm x 1.80µm)
Injector: 225°C
Oven: 100 °C for 0.1min; then 50°C/min to 250°C for 0 min.
Detector: µECD, 260°C

Calibration:
A calibration curve ranging between concentrations of approximately 2.5 mg/L to approximately 14 mg/L was constructed from the test item in gas bags as part of the technical trials. The calibration gas bags were prepared at each concentration.

Acceptance Criteria:
The coefficient of variation was < 10% for all calibration gas bag samples at each concentration. The correlation coefficient of the used regression was 0.995 and therefore within the acceptance criteria.

Standards constructed from the test item in gas bags were sampled prior to initiation of each exposure at the chamber-line and used to check the integrity of the sampling line and check the GC calibration. Plots of the peak area used for the calibration were used to assess trends regarding system stability. The acceptance criterion for standard samples was an accuracy of 90 - 110% of the theoretical value.
- Samples taken from breathing zone: yes

VEHICLE
- Composition of vehicle (if applicable): none
- Concentration of test material in vehicle (if applicable):
- Justification of choice of vehicle:
- Lot/batch no. (if required):
- Purity:

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: none
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.):

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration:

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

Nominal: 2.23 mg/L air
chemical: 10.35 mg/L air

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations for viability were recorded once before exposure on the day of exposure (test day 1), three times during exposure, immediately and 1 h after exposure on test day 1 and twice daily during the observation period. Each animal was examined three times during exposure, immediately and 1 h after exposure on test day 1 and once daily during the observation period. Observations were detailed and carefully recorded using explicitly defined scales as appropriate. Only grossly abnormal signs were detectable during exposure as the animals were restrained in the exposure tubes. The body weight of each animal was recorded on test days 1 (before exposure), 2, 4, 8 and 15 (before necropsy).

- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,

Statistics:

no

Sex:

male/female

Dose descriptor:

LC50

Effect level:

10.35 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Sex:

male/female

Dose descriptor:

LC50

Effect level:

32.19 mg/m³ air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: Conversion factors :1 mg/l(ppm)=3.11 mg/m3

Mortality:

three males and two females

Clinical signs:

other: Tachypnea was recorded in all animals during and immediately after exposure. Tachypnea persisted in all surviving animals until test day 2. Hunched or prostrate posture and/or decreased activity were observed in most of the animals one hour after end of e

Body weight:

From test day 1 to test day 2, slight to moderate body weight loss was noted in all surviving animals. Thereafter normal body weight development was recorded in these animals.

Gross pathology:

There were no macroscopic findings that were considered to be related to treatment with the test item. Red discoloration of the lung was recorded in animals that died spontaneously. This finding was considered to be due to delayed necropsy.

Other findings:

none

Test Atmosphere Conditions

Temperature, relative humidity and oxygen concentration during exposure were considered to be satisfactory for this type of study. Relative humidity values were quite low as dry air was used for atmosphere generation.

 

Data on temperature, relative humidity and oxygen concentration are presented in the following table.

 

Recording Time [hours:min]	O2Concentration [Vol %]	Temperature [°C]	Relative Humidity [% RH]
08:00	20.2	23.9	3.6
08:30	20.1	23.4	2.5
09:00	20.1	23.6	2.4
09:30	20.0	23.9	2.3
10:00	19.9	23.4	2.3
10:30	19.9	23.4	2.3
11:00	19.8	23.3	2.2
11:30	19.8	23.3	2.2
12:00	19.8	23.4	2.2
Mean	20.0	23.5	2.4
St. Dev.	0.2	0.2	0.5
N	9	9	9

 

  Determination of Nominal Atmosphere Concentration

The nominal atmosphere concentration was 12.23 mg/L air.

 

  Chemical Determination of Atmosphere Concentrations

The mean chemical atmosphere concentration determined was 10.35 mg/L air as targeted. Details on chemically determined atmosphere concentrations are presented in the following tables:

 

Measurement	Chemical Atmosphere Concentration mg/L air
1	14.01
2	12.03
3	14.13
4	13.88
5	11.52
6	12.42
7	11.54
8	6.36
9	10.51
10	9.65
11	10.67
12	10.57
13	9.39
14	12.08
15	11.41
16	12.30
17	6.86
18	11.24
19	9.98
20	10.74
21	11.16
22	9.17
23	10.26
24	12.22
25	6.98
26	11.22
27	6.10
28	12.67
29	11.22
30	5.34
31	11.29
32	10.97
33	6.62
34	10.47
35	5.13
36	10.96
37	8.40
38	8.50
39	12.75
40	13.41
41	8.79
42	9.42
43	12.02
44	11.14
45	8.10
46	9.38
47	13.00
48	7.92
Mean	10.35
SD	2.3
n	48

 

Interpretation of results:

moderately toxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Based on the results of this study, the LC50 of carbon disulfide obtained in this study was 32.19 mg/m³ air or 10.35 mg/L air (chemically determined mean atmosphere concentration). There was no indication of relevant sex-related differences in toxicity of the test item.

Executive summary:

Carbon disulphide is both a reagent in the manufacture, as well as a decomposition product of xanthates. SIBX 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 SIBX.

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.

A group of five male and five female albino rats was exposed by nose-only, flow-past inhalation for four hours to the test item at a chemically determined mean concentration of 10.35 mg/L air. All animals were observed for clinical signs and mortality during the inhalation exposure and the subsequent 14-day observation period. Body weights were recorded prior to exposure on test day 1, and during the observation period on test days 2, 4, 8 and 15 before necropsy. On test day 15 all animals were sacrificed and necropsied. The ranges of aerosol concentration, temperature, relative humidity, oxygen content and airflow rate measured during the exposure were considered to be satisfactory for a study of this type. In addition, the test item was considered to be respirable to rats. Five animals died during the first 24 hours after exposure. All other animals survived the scheduled observation period. Tachypnea was recorded in all animals during exposure and persisted until test day 2 in the surviving ones. Hunched or prostrate posture and / or decreased activity were recorded in most of the animals after exposure up to day 2. A transient effect on body weight was observed. There were no macroscopic findings that were considered to be related to treatment with the test item.

 

Based on the results of this study, the LC50 of Carbon Disulfide obtained in this study was 32.19 mg/m³ air or10.35 mg/L air (chemically determined mean atmosphere concentration).There was no indication of relevant sex-related differences in toxicity of the test item.

 

Reference 3

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

2-methylpropan-1-ol /Isobutyl alcohol/ is both reagents used in the manufacture of sodium O-isobutyl dithiocarbonate . Therefore, 2-methylpropan-1-ol /Isobutyl alcohol/ need to be considered in the assessment of sodium O-isobutyl dithiocarbonate

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Principles of method if other than guideline:

A group of 5 male and 5 female rats was exposed to a saturated vapor of isobutanol in air for 6 hours under static conditions. Survivors were observed for 14 days and weighed on days 7 and 14 post-exposure. All rats were subjected to a gross necropsy examination.

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Male and female Sprague Dawley* albino rats were received from Harlan Sprague Dawley, Inc. (Indianapolis, IN). The strain and species were selected because of their availability and existing historical data. Male rats were ordered to be approximately 195 to 215 g (designated by the supplier to be approximately 7 to 8 weeks of age). Female rats were ordered to be approximately 220 to 240 g (approximately 11 to 12 weeks of age). The females were ordered to be nulliparous and nonpregnant. Occasionally, male and female rats that were ordered in at 6 weeks of age (initially received for other acute testing) were used as long as weight requirements were met on the day of dosing.

Once a month, 5 rats/sex received for acute testing and housed in Room 109 were subjected to a quality control evaluation, including gross pathology, parasitology and viral serology testing. Periodically, a Clinical Veterinarian examined the rats for any signs of health deficiencies. All animals were assigned a unique number and identified by cage cards. Animals were also identified by an ear tagging procedure during the week of receipt.

The animals were separated by sex and group housed (up to 5/cage) in stainless steel, wire mesh cages (approximately 23.5 x 40.0 x 18.0 cm.). DACBQ (Deotized Animal Cage Board; Shepherd Specialty Papers, Inc.) was placed under each cage and changed regularly. An automatic timer was set to provide fluorescent lighting for a 12-hour photoperiod (approximately 0500 to 1700 hours for the light phase). Temperature and relative humidity were recorded (Cole-Parmer HygrothermographQ Seven-Day Continuous Recorder, Model No. 8368-00, Cole-Parmer Instrument Co., Chicago, IL). Temperature was routinely maintained at 66-77°F during the test period; relative humidity was routinely maintained at 40-70%. Any minor exceptions to these specified ranges can be found in the raw data.
Tap water (Municipal Authority of Westmoreland County, Greensburg, PA) was available ad libitum except during dosing and was delivered by an automatic watering system with demand control valves mounted on each rack. Water analyses were provided by the supplier, Halliburton NUS Environmental Laboratories, Materials Engineering & Testing Company, and Lancaster Laboratories, Inc. at regular intervals. EPA standards for maximum levels of contaminants were not exceeded. Pelleted, certified AGWAY@ PROLAB@ Animal Diet Rat, Mouse, Hamster 3000 (Agway Inc,) was available ad libitum. For the peroral test, the feed was removed the day before dose administration. After dosing, feed was again made available ad libitum. For the inhalation test, the feed was available ad libitum except during the 6-hour exposure period. Analyses for chemical composition and possible contaminants of each feed lot were performed by Agway Inc. and the results are included in BRRC files. Feed and water analysis reports were reviewed by the Study Director as they were available.

Animal Acclimation
The animals were acclimated for at least 5 days before dosing. Detailed clinical observations were conducted twice, at the time of receipt and during animal identification and/or dosing.

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

A substantially saturated vapor was produced by enclosing 110 g of isobutanol in a sealed 120 liter animal chamber for approximately 15 hours under static conditions. In order to aid in the distribution of the vapor, a mixing fan periodically agitated the chamber atmosphere. Oxygen was added as needed to the chamber in order to maintain a chamber oxygen content of approximately 20%. The average temperature and humidity in the chamber during the exposure period were approximately 22°C and 92%, respectively. No analysis was made of the chamber atmosphere for the concentration of the test substance.

Five male and 5 female rats were placed into the chamber and sealed inside for the 6-hour exposure period.

Analytical verification of test atmosphere concentrations:

no

Duration of exposure:

6 h

Concentrations:

Described as a near saturated atmosphere (test material was placed in a chamber 15 hours prior to the start of the animal exposure to the test material to allow time for air equilibrium to occur.

No. of animals per sex per dose:

5 males and 5 females

Control animals:

not specified

Details on study design:

Dosed rats were observed frequently during the exposure for signs of toxicity and twice a day thereafter (except on weekends or holidays when they were examined for death alone). Weights were recorded on the day of dosing and at 7 and 14 days after dosing. At 14 days, all animals were sacrificed using methoxyflurane and necropsied.

Following a 6-hour inhalation exposure, pseudopregnancy was observed in 1 female rat and the uterus was saved. Histology was performed on the uterus to verify this finding and also to compare results with those from the 1 female rat in the peroral test that appeared to be pregnant.

Statistics:

Means and Standard Deviations were calculated for body weights on days 1, 7 and 14.

Sex:

male/female

Dose descriptor:

LC0

Effect level:

>= 18.2 mg/m³ air

Based on:

test mat.

Exp. duration:

6 h

Sex:

male/female

Dose descriptor:

LC0

Effect level:

>= 6 000 ppm

Based on:

test mat.

Exp. duration:

6 h

Remarks on result:

other: original value; although the report did not provide nominal or analytical concentration, based on the acute neurotox study concentrations of 6000 ppm (18 mg/m3) are attainable.

Mortality:

Exposure to a statically-generated, substantially saturated vapor did not produce deaths in any of 5 male or 5 female rats during or following the 6-hour test.

Clinical signs:

other: Signs of toxicity observed during exposure included hypoactivity, lacrimation, narcosis, prostration, abnormal breathing (short, shallow breaths) and wetness of the periocular fur. Prostration, narcosis and negative reflexes (surface righting and toe and

Body weight:

Most animals had a consistent weight gain. One female rat exhibited a slight weight loss by 7 days but partially recovered within 14 days.

Gross pathology:

Necropsy revealed red or brown foci on the lungs. One female rat had several focal implants in the left uterine horn (pseudopregnancy).

The uterus from the 1 female rat that exhibited pseudopregnancy was saved and examined microscopically. Deciduoma of pseudopregnancy were
also apparent in this animal as in the rat from the peroral test and may have been related to the exposure.

Other findings:

No additional information available

Interpretation of results:

Category 4 based on GHS criteria

Remarks:

Migrated information

Conclusions:

A single static inhalation exposure of saturated vapor to rats produced no deaths but signs of toxicity were noted. One female rat appeared to be pregnant or exhibit pseudopregnancy at necropsy. Microscopic evaluation of the uteri from this animal revealed the presence of deciduoma resulting from pseudopregnancy.

Executive summary:

The acute inhalation toxicity of isobutanol was investigated. A single 6 hour static inhalation exposure of saturated vapor to rats produced no deaths but signs of toxicity were noted. One female rat appeared to be pregnant or exhibit pseudopregnancy at necropsy. Microscopic evaluation of the uteri from this animal revealed the presence of deciduoma resulting from pseudopregnancy. A similar finding of pseudopregnancy was observed in one female rat in the acute oral study conducted at the same time. A follow up study was conducted and is included in the acute oral section.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

18.18 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

2-methylpropan-1-ol /Isobutyl alcohol/ is both reagents used in the manufacture of sodium O-isobutyl dithiocarbonate . Therefore, 2-methylpropan-1-ol /Isobutyl alcohol/ need to be considered in the assessment of sodium O-isobutyl dithiocarbonate

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OTS 798.1100 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

Male and female New Zealand White rabbits were received from Hazleton Research Products, Inc. (Denver, PA). The strain and species were selected because of their availability and existing historical data. Rabbits were ordered to be between 2.0 and 2.3 kg (designated by the supplier to be approximately 12 to 14 weeks of age). The females were nulliparous and nonpregnant.

Periodically, a Clinical Veterinarian examined rabbits for any signs of health deficiencies. Within 1 or 2 days of receipt, all animals were assigned a unique number which was marked on the animal cage card. The rabbit number was also marked in indelible ink on 1 ear at the time of dosing.

The rabbits were housed individually in cages with wire floors (approximately 61.0 x 46.0 x 36.0 cm.). DACBQ (Deotized Animal Cage Board; Shepherd Specialty Papers, Inc.) was placed under each cage and changed regularly. An automatic timer was set to provide fluorescent lighting for a 12-hour photoperiod (approximately 0500 to 1700 hours for the light phase). Temperature and relative humidity were recorded (Cole-Parmer Hygrothermograph Seven-Day Continuous Recorder, Model No. 8368-00, Cole-Parmer Instrument Co., Chicago, IL). Temperature was routinely maintained at 61-70°F during the test period; relative humidity was routinely maintained at 40-70%. Any minor exceptions to these specified ranges were noted in the raw data.

Tap water (Municipal Authority of Westmoreland County, Greensburg, PA) was available ad libitum (except during dosing) and was delivered by an automatic watering system with demand control valves mounted on each rack. Water analyses were provided by the supplier, Halliburton NUS Environmental Laboratories, Materials Engineering & Testing Company, and Lancaster Laboratories, Inc. at regular intervals. EPA standards for maximum levels of contaminants were not exceeded. As available, water analysis reports were reviewed by the Study Director. AGWAYe PROLABe Animal Diet High Fiber Rabbit (Agway Inc.) was available ad libitum except during the actual dosing period. No analyses of chemical composition and possible contaminants of the feed were conducted by the supplier.
Animal Acclimation
The animals were acclimated for at least 5 days before dosing. Detailed clinical observations were conducted twice, at the time of receipt and during animal identification and/or dosing. In addition, rabbits were examined and weighed twice prior to dosing. Cage-side observations and mortality checks were conducted at least once daily. Animals considered unacceptable for the study, based on the clinical signs or body weights (rabbits), were rejected for use on this study.

Study Organization
The animals were weighed and inspected for health on the day of the test. Only those exhibiting a healthy state were used. Healthy animals appeared alert, active and well groomed, with no evidence of discharge, diarrhea, breathing difficulties or locomotor abnormalities. A BRRC veterinarian was available for consultation regarding any animal health concerns. Animals were randomly assigned to cages and were designated for dosing according to need and availability.

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

The fur was removed from the entire trunk of each rabbit using veterinary clippers at least 1 day before application of the test substance. As necessary, the rabbit skin was carefully trimmed (to remove excess regrowth of fur) up to the day before dosing. Only animals with an intact and normal epidermis were used in the study. A double layer of gauze sheeting was wrapped around the trunk and secured with adhesive tape. Polyethylene sheeting was then wrapped around the trunk over the gauze. To secure the polyethylene, plastic ties or rubber bands were added (at the ends of the trunk). The test substance had a tendency to adhere to the inside of the syringe during dosing causing the plunger to stick. Therefore, in order to minimize the potential for exposure by spraying, the undiluted test substance was applied under the plastic wraps for most animals, covering as large a skin area as possible. The area of skin covered/dose level could not be measured except for 1 rabbit at 1.0 g/kg for which the dose was applied directly to the skin prior to wrapping. The amount of test substance applied was recorded for each animal. The sheeting was then protected from removal or tearing by wrapping the rabbit trunk with VETRAP" bandaging tape. The ends of the VETRAP" were secured. After the 24-hour contact period, all coverings were removed.

Duration of exposure:

24 hours

Doses:

Probe study
8000 mg/kg (female)

Definitive study
1000, 2000 and 4000 mg/kg (females)
2000 mg/kg (males)

No. of animals per sex per dose:

Probe study
1 female

Definitive study
5 females/dose
3 males/dose

Control animals:

no

Details on study design:

In the definitive percutaneous toxicity test, 5 female rabbits were included on each of several dose levels in order to determine an LD50. Three male rabbits were included on an intermediate dose level for comparison. One female rabbit was used for preliminary percutaneous toxicity testing. For individual animals, the dose volume was adjusted according to body weight. Treated rabbits wera observed frequently for signs of toxic effect on the first day of the test and twice a day thereafter (except on weekends or holidays when they were examined for death alone). Weights were recorded on the day of dosing and at 7 and 14 days after dosing or at death.

After 14 days, all survivors were sacrificed by ear vein injection using Euthanasia-6 Solution (Veterinarian Laboratories Inc., Lenexa, KS). Necropsies were performed on all animals that died or were sacrificed. The following tissues (unless excessively autolyzed) were collected and retained in 10% neutral buffered formalin: kidneys, urinary bladder, liver, sciatic nerve and spleen. Because of possible lung damage as based on clinical signs, these tissues were also saved from selected animals.

Statistics:

LD50 value, along with evaluations of 95% confidence limits, were calculated by the moving average method (Thompson, 1947). Estimates of the slope will use the method of Weil (1983).

References
Thompson, W. R. (1947). Use of moving averages and interpolation to estimate median effective dose. Bact. Rev. 2, 115-145.
Weil, C. (5. (1983). Economical LD50 and slope determination. Druq Chem. Toxicol 595-603.

Sex:

female

Dose descriptor:

LD50

Effect level:

2 460 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 1790 to 3390

Sex:

male

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 0 of 3 died at 2000 mg/kg

Mortality:

One rabbit was dosed with 8.0 g/kg of isobutanol in preliminary percutaneous toxicity testing (24-hour occluded contact) and died.
Of the 5 female rabbits/group dosed with 1000, 2000 or 5000 mg/kg, there were 0, 1 and 5 animals that died, respectively. One animal from the 2000 and the 4000 mg/kg groups died on the after exposure. All other deaths occurred on the day of exposure. The earliest death occurred 3 hours after test material was applied to the skin.

None of 3 male rabbits died following application of 2000 mg/kg.

Clinical signs:

other: Dermal reactions included erythema, edema, necrosis, ecchymoses (on 2), fissuring, ulceration (on l), desquamation, scabs and alopecia. Signs of toxicity observed included sluggishness, lacrimation (in l), transient tremors (in I), prostration, an unstead

Gross pathology:

Gross pathologic evaluation of animals that died revealed red patches or areas on the lungs, dark red lungs (in l), discolored and/or mottled livers (tan or darkened), gas-filled (characterized by bubbles) intestines (in 2), darkened spleens (in 2), dark red foci on 1 spleen, enlarged adrenals (in l), kidneys with a pitted surface (in 1) and a trace amount of blood in the urine of 1 (positive by HEMASTIX@ Reagent Strips). Necropsy of survivors revealed red to dark red patches or areas on the lungs (in 2 ) , gas-filled intestines (in l), 1 mottled dark maroon and light tan spleen, kidneys with a pitted surface (in 1) and tan kidneys (in 2).

Other findings:

No additional information available.

Interpretation of results:

Category 4 based on GHS criteria

Remarks:

Migrated information

Conclusions:

The dermal LD50 in male and female rabbits is >2000 and 2460 mg/kg, respectively.
2-methylpropan-1-ol /Isobutyl alcohol/ is both reagents used in the manufacture of sodium O-isobutyl dithiocarbonate . Therefore, 2-methylpropan-1-ol /Isobutyl alcohol/ need to be considered in the assessment of sodium O-isobutyl dithiocarbonate

Executive summary:

The acute dermal toxicity was examined. The dermal LD50 in male and female rabbits is >2000 and 2460 mg/kg, respectively.

2-methylpropan-1-ol/Isobutyl alcohol/is both reagents used in the manufactureof sodium O-isobutyl dithiocarbonate .Therefore,2-methylpropan-1-ol/Isobutyl alcohol/need to be considered in the assessment of sodium O-isobutyl dithiocarbonate

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

other: published data

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

SIBX are related compound to SEX

Qualifier:

no guideline followed

Principles of method if other than guideline:

This study was conducted in 1951 and was repeated later in the same year. Exposure in both studies was for 18 hrs and was not according to the OECD Guidelines for acute dermal irritation (4 hrs) or for dermal toxicity (24 hrs). The initial study was performed to assess dermal irritation but deaths during the study led to further studies. Sodium ethyl xanthate was administered by occlusive application to the shaved abdomen of the rabbits either as 1.0 ml/kg of a 10% aqueous solution or as 1 gm/kg of the 100% dry material in a paste formed with water. The animals were observed for 12 days.

GLP compliance:

no

Test type:

other: LD50

Limit test:

no

Species:

rabbit

Strain:

not specified

Sex:

male

Type of coverage:

occlusive

Vehicle:

water

Details on dermal exposure:

Sodium ethyl xanthate was administered by occlusive application to the shaved abdomen of the rabbits either as 1.0 ml/kg of a 10% aqueous solution or as 1 gm/kg of the 100% dry material in a paste formed with water. The animals were observed for 12 days.

Duration of exposure:

The animals were observed for 12 days.

Doses:

1.0 ml/kg of a 10% aqueous solution or as 1 gm/kg

No. of animals per sex per dose:

12

Control animals:

yes

Details on study design:

This study was conducted in 1951 and was repeated later in the same year. Exposure in both studies was for 18 hrs and was not according to the OECD Guidelines for acute dermal irritation (4 hrs)or for dermal toxicity (24 hrs).The initial study was performed to assess dermal irritation but deaths during the study led to further studies. Sodium ethyl xanthate was administered by occlusive application to the shaved abdomen of the rabbits either as 1.0 ml/kg of a 10% aqueous solution or as 1 gm/kg of the 100% dry material in a paste formed with water. The animals were observed for 12 days.

Sex:

male

Dose descriptor:

LD50

Effect level:

< 1 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: The dermal irritation/toxicity study in rabbits indicates that sodium ethyl xanthate powder has an LD50 of <1000 mg/kg and is a moderate irritant while the 10% solution is non irritating to the skin.

Mortality:

Application of 1 gm/kg of sodium ethyl xanthate in the form of a paste resulted in the death of ten out of twelve animals within 24 hrs. The surviving animals developed irritant effects including oedema and pigmentation of the skin.

Clinical signs:

other: Clinical Observations :surviving animal had moderate irritation with oedema and pigmentation of the skin.

Gross pathology:

Moderate amount of peritoneal fluid, visceral organs were normal.
Haemorrhagic lungs and peritoneal and pleural fluid. Other changes were markedly cyanotic ears (2/5), haemorrhagic conditions (2/5) and evidence of diarrhoea (3/5).
The liver appeared darkand mottled and the kidneys showed spotty haemorrhages

The dermal irritation/toxicity study in rabbits indicates that sodium ethyl xanthate powder has an LD50 of <1000 mg/kg and is a moderate irritant while the10% solution is non irritating to the skin.

Table 4:	Effects of sodium ethyl xanthate following dermal application
Animals	Dose	Clinical Observations	Gross pathology
3 rabbits	1 ml/kg, as 10% solution	No skin irritation.	No substance related changes.
3 rabbits	1 gm/kg, as a paste	2/3 died; surviving animalhad moderate irritationwith oedema andpigmentation of the skin.	Moderate amount of peritoneal fluid, visceral organs were normal.
5 male rabbits	1 gm/kg, as a paste	5/5 died following overnight exposure; oedemaof the skin with pigmentation.	Haemorrhagic lungs andperitoneal and pleural fluid. Other changes were markedly cyanotic ears (2/5), haemorrhagic conditions (2/5) and evidence of diarrhoea (3/5).
1 male rabbit	1 gm/kg, as a more liquid paste than above	Moderate oedema and pigmentation of the skin.	No substance related changes.
3 rabbits	1 gm/kg as a paste	All 3 animals died within24 hrs; retropulsion,salivation, loss of rightingreflex and haemorrhagicand oedematous areas of the skin were noted.	The liver appeared dark and mottled and the kidneysshowed spotty haemorrhages.

Interpretation of results:

moderately toxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of the study, application of 10% solution of sodium ethyl xanthate (pH 10.5 to 11) for 18 hrs did not cause skin irritation in rabbits. Similar application of 1 gm/kg of sodium ethyl xanthate in the form of a paste resulted in the death of ten out of twelve animals within 24 hrs. The surviving animals developed irritant effects including oedema and pigmentation of the skin. The sulphide odour noted during the study suggests that decomposition of sodium ethyl xanthate occurred. The dermal LD50 was < 1000 mg/kg.

Executive summary:

Under the conditions of the study of Hazleton Laboratories, application of 10% solution of sodium ethyl xanthate (pH 10.5 to 11) for 18 hrs did not cause skin irritation in rabbits.

Similar application of 1 gm/kg of sodium ethyl xanthate in the form of a paste resulted in the death of ten out of twelve animals within 24 hrs. The surviving animals developed irritant effects including oedema and pigmentation of the skin. The sulphide odour noted during the study suggests that decomposition of sodium ethyl xanthate occurred. The dermal LD50 was < 1000 mg/kg.

Reference 3

Endpoint:

acute toxicity: dermal

Type of information:

other: published data

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Dithiocarbamates are related compounds to xanthates. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium hydroxide: They arise from the reaction of the amine with CS2

Qualifier:

according to guideline

Guideline:

EPA OPP 81-2 (Acute Dermal Toxicity)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

24h exposure

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source: A. Smith, Warlingham, Surrey and Froxfield Rabbits, England
- Age at study initiation: 9-13 weeks
- Weight at study initiation: 2.2-2.9 kg

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Duration of exposure:

24h

Doses:

2 g/kg

No. of animals per sex per dose:

5

Control animals:

not required

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths occured.

Clinical signs:

other: There were no signs of toxicity.

Gross pathology:

Pale renal cortices were observed in the kidneys of one male at post-mortem. Terminal autopsy revealed no other macroscopic abnormalities.

Other findings:

Dermal responses:
Slight erythema only was observed in two males and two females. The reactions had resolved completely by Day 3 or 4 of the study. The remaining three males and three females showed no response to treatment.

Interpretation of results:

Category 4 based on GHS criteria

Remarks:

Migrated information

Conclusions:

The dermal LD50 in male and female rabbits is >2000 .
Dithiocarbamates are related compounds to xanthates. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium hydroxide: They arise from the reaction of the amine with CS2

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

    

Oral toxicity

Table 3:	Oral toxicity of xanthates (from: Kirk-Othmer, 1984)16
Xanthate	Species		LD0	(mg/kg)	LD50	(mg/kg)	References
Sodium ethyl		rat	500		—		17
Potassium ethyl		Rat  mouse	500		1700 583		17, 18
Sodium isopropyl		rat	250		—		17
Potassium isopropyl		rat mouse	— —		1700  583		18 —
Potassium n-butyl		mouse	—		411  465		19,20
Sodium isobutyl		rat			500		17
Potassium isobutyl		rat mouse	— —		1290  480		18 18
Sodium sec-butyl		rat	—		>2000		17
Potassium amyl (mixed)		rat	1000		1000–2000		17, 21
Potassium iso amyl		rat mouse	— —		765 470		18 18
C5-C6 mixture		rat	—		1500		22

 The LD50 of the various xanthates are similar, ranging from 411 to 583 mg/kg in mice and from 1000 to >2000 mg/kg in rats.

The acute oral toxic effects of one xanthate, potassium butyl xanthate, are provided in two summaries in Chemical Abstracts.

Similar symptoms and pathology findings were seen in these studies carried out by Babayan.

 

References :

16.Kirk-Othmer Encyclopaedia of Chemical Technology,Vol 24, 2nd ed, pp 645-661,John Wiley & Sons, 1984.

17.Dow Chemical Company, 1964, unpublished toxicological data to C.B. Shaffer,American Cyanamid; data from P. Avotin, American Cyanamid, privatecommunication, 1982 as cited in Kirk-Othmer Encyclopaedia of Chemical

18.Babayan, E.A., 1963, “Toxicology of Potassium Butyl Xanthate” Material 2-oi[Vtoroi] Itog. Nauchn. Konf. Inst. Gigieny Truda I Prof. Zabolevan Posvyashch.Vopr. Gigieny Truda I Prof. Patol. Erevan, pp 75-77 (Pub 1964)(Russ)Chem Abstract,64, 8836e (1966).

19.Babayan, E.A., “Toxicological Characteristics of the Flotation Agent PotassiumButyl Xanthate”, Mater. Itogovoi Nauch. Konf. Vop. Gig Tr Profpatol. Khim.Gornorud. Prom., 3rd 1966 (Pub 1968) 97-102 (Russ) inChemical Abstracts,Vol 73,1970.

20.Fronk, N.G., The Dow Chemical Company, private communication, 1982, as cited inKirk-Othmer Encyclopaedia of Chemical Technology,Vol 24, 2nd Ed, pp 645-661,John Wiley & Sons, 1984.

21.Buzina, A.Z., Burkhanov, A.I. and Abeuev, Kh.B., 1977 Zdravookhr. Kaz., 88 ascited inKirk-Othmer Encyclopaedia of Chemical Technology,Vol 24, 2nd Ed, pp645-661, John Wiley & Sons, 1984.

22.Chemical Abstracts,Vol 64, 1966.

 

 Dermal toxicity

Table 4:	Effects of sodium ethyl xanthate following dermal application
Animals	Dose	Clinical Observations	Gross pathology
3 rabbits	1 ml/kg, as 10% solution	No skin irritation.	No substance related changes.
3 rabbits	1 gm/kg, as a paste	2/3 died; surviving animalhad moderate irritationwith oedema andpigmentation of the skin.	Moderate amount of peritoneal fluid, visceral organs were normal.
5 male rabbits	1 gm/kg, as a paste	5/5 died following overnight exposure; oedemaof the skin with pigmentation.	Haemorrhagic lungs andperitoneal and pleural fluid. Other changes were markedly cyanotic ears (2/5), haemorrhagic conditions (2/5) and evidence of diarrhoea (3/5).
1 male rabbit	1 gm/kg, as a more liquid paste than above	Moderate oedema and pigmentation of the skin.	No substance related changes.
3 rabbits	1 gm/kg as a paste	All 3 animals died within24 hrs; retropulsion,salivation, loss of rightingreflex and haemorrhagicand oedematous areas of the skin were noted.	The liver appeared dark and mottled and the kidneysshowed spotty haemorrhages.

Based on the results of thе study (Arkema Inc. 2010), the LC50 for Acute inhalation toxicity of carbon disulfide obtained was 32.19 mg/m³ air or 10.35 mg/L air (chemically determined mean atmosphere concentration). There was no indication of relevant sex-related differences in toxicity of the test item.

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.

Justification for classification or non-classification

Based on the hazard assessment of  SIBX,in section 2.1 and 2.2. in IUCLID 6., 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”, according to the EU’s list of dangerous substances (OJEC No L200/130.7.99)and according to the criteria described in Directive 67/548 and in the CLP Regulation:

Directive 67/548

Very Toxic (T+) R28: Very toxic if swallowed R27: Very toxic in contact with skin R26: Very toxic by inhalation R39/26 R39/27 R39/28: Dangerous of very serious irreversible effects Toxic (T):  R25: Toxic if swallowed R24: Toxic in contact with skin R23: Toxic by inhalation R39/23 R39/24 R39/25: Danger of very serious irreversible effects Harmful (Xn): R22: Harmful if swallowed R21: Harmful in contact with skin R20: Harmful by inhalation R65: Harmful may cause lung damage if swallowed R21/22 Harmful; Harmful in contact with skin and if swallowed. R68/20 R68/21 R68/22: Possible risk of irreversible effects Other toxicological properties R67: Vapours may cause drowsiness and dizziness

CLP

H300 Acute Tox. 2 Fatal if swallowed H310 Acute Tox. 1 Fatal in contact with skin H330 Acute Tox. 2 Fatal if inhaled H370 STOT SE 1 H301 Acute Tox. 3 Toxic if swallowed H311 Acute Tox. 3 Toxic in contact with skin H331 Acute Tox. 3 Toxic if inhaled H370 STOT SE 1 H302 Acute Tox. 4 Harmful if swallowed H312 Acute Tox. 4 Harmful in contact with skin H332 Acute Tox. 4 Harmful if inhaled H304 Asp. Tox. 1 H371 STOT SE 2 (May cause damage to organs (or state all organsaffected if known) (state route of exposure if it is conclusively proventhat no other routes of exposure cause the hazard) Other toxicological properties H336 STOT SE 3 May cause drowsiness or dizziness

It is concluded that the substance SIBX, meet the criteria to be classified for human health hazards for acute oral and dermal effects:

R22: Harmful if swallowed

R21: Harmful in contact with skin

H302 Acute Tox. 4 Harmful if swallowed

H312 Acute Tox. 4 Harmful in contact with skin