Proxan-sodium

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

4 months

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Read-across from potassium salt
Some limitations in terms of details in the Australian Government review, but allows for classification
The potassium salty is considered suitable as a source of data for the corresponding sodium salt
Considered valid for read-across for purposes of classification.
No further vertebrate testing can be justified.

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Principles of method if other than guideline:

Extended to 4 months

GLP compliance:

not specified

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

ENVIRONMENTAL CONDITIONS
After an adequate acclimatisation period (at least five days), the animals were barrier maintained (full-barrier) in air conditioned rooms under the following conditions: temperature: 22 ± 3 °C, relative humidity: 55 ± 10%, artificial light, sequence being 12 hours light, 12 hours dark, air change: 10 x / hour, free access to Altromin 1324 maintenance diet, free access to tap water, sulphur acidified to a pH of approximately 2.8 (drinking water, municipal residue control, microbiol. controlled periodically), housed individually in IVC cages, type III H, polysulphone cages on Altromin saw fibre bedding

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

4 months

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

At least weekly checks to confirm stability and achieved concentrations

Duration of treatment / exposure:

4 months

Frequency of treatment:

Daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

Control

Dose / conc.:

5 mg/kg bw/day (nominal)

Dose / conc.:

10 mg/kg bw/day (nominal)

Dose / conc.:

15 mg/kg bw/day (nominal)

No. of animals per sex per dose:

20 animals per sex

Control animals:

yes, concurrent no treatment

Details on study design:

Potassium butyl xanthate was administered orally (0,5, 10 and 15 mg/kg) to rats, rabbits and dogs for 4 months. During administration effects observed from week 6 to week 7 of treatment were tachypnoea, cyanosis, loss of hair and dermatitis. Loss of weight and increase in blood sugar and cholesterol were observed later. Convulsions and paralysis of the extremities were observed in some animals from week 9 of administration. Some animals died during the administration.

Observations and examinations performed and frequency:

Daily clinical observations.
At least weekly body weights.
During administration effects observed from week 6 to week 7 of treatment were tachypnoea, cyanosis, loss of hair and dermatitis. Loss of weight and increase in blood sugar and cholesterol were observed later. Convulsions and paralysis of the extremities were observed in some animals from week 9 of administration. Some animals died during the administration.

Sacrifice and pathology:

Gross necropsy and pathology performed

Statistics:

Yes, as applicable

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

tachypnoea, cyanosis, loss of hair and dermatitis. Convulsions and paralysis of the extremities were observed in some animals from week 9 of administration.

Mortality:

mortality observed, treatment-related

Description (incidence):

Some animals died during the administration.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Loss of weight

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Endocrine findings:

not specified

Urinalysis findings:

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

A slight decrease in testes weight in highest group males was observed when compared to control animals, but not statistically significant.
Individual animals in different groups showed other adverse effects, but not considered treatment related and not considered significant.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Most changes minor and of limited significance.
tachypnoea, cyanosis, loss of hair and dermatitis

Neuropathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Individual animals in different groups showed some adverse effects, but not considered treatment related and not considered significant.

Histopathological findings: neoplastic:

no effects observed

Details on results:

During administration effects observed from week 6 to week 7 of treatment were tachypnoea, cyanosis, loss of hair and dermatitis. Loss of weight and increase in blood sugar and cholesterol were observed later. Convulsions and paralysis of the extremities were observed in some animals from week 9 of administration. Some animals died during the administration.

Dose descriptor:

LOAEL

Effect level:

10 mg/kg bw/day (actual dose received)

Basis for effect level:

other: see 'Remark'

Critical effects observed:

not specified

Organ:

liver

spleen

Conclusions:

Findings were included central nervous system, liver and spleen effects.

Executive summary:

During administration effects observed from week 6 to week 7 of treatment were tachypnoea, cyanosis, loss of hair and dermatitis. Loss of weight and increase in blood sugar and cholesterol were observed later. Convulsions and paralysis of the extremities were observed in some animals from week 9 of administration. Some animals died during the administration

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

10 mg/kg bw/day

Study duration:

chronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Type of 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:

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

Justification for type of information:

Read-across from potassium salt
The potassium salty xanthates is considered suitable as a source of data for the corresponding sodium salt xanthates
Considered valid for read-across for purposes of classification.
No further vertebrate testing can be justified.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

GLP compliance:

not specified

Species:

dog

Strain:

Beagle

Sex:

male

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

MMAD / GSD: 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.

Details on inhalation exposure:

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.
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. No signs of toxicity were observed in animals exposed to a concentration of 200 mg/m3. Rats exposed to a concentration of 800 mg/m3 showed a statistically significant decrease in body weight after the fifth exposure. Recovery of the body weight occurred within 4 days and may not have been exposure related.
The only substance related adverse effect observed was a yellow-brown staining of the hair coat of the rats.
Overexposure of the animals exposed to a concentration of 800 mg/m3 occurred because of a technical problem in the aerosol generating apparatus.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

30-day

Frequency of treatment:

6 hrs daily, 5 days a week for a total of 20 exposures in 1 month

Dose / conc.:

0 mg/m³ air (nominal)

Remarks:

Control

Dose / conc.:

100 mg/m³ air (nominal)

Remarks:

Doses / Concentrations:100 mg/m3Basis:nominal conc.

Dose / conc.:

800 mg/m³ air (nominal)

Remarks:

Doses / Concentrations:800 mg/m3Basis:nominal conc.

No. of animals per sex per dose:

2

Control animals:

yes

Details on study design:

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 concentrations of 100 or 800 mg/m3 of potassium amyl xanthate. Whole body exposure was for 6 hrs daily, 5 days a week for a total of 20 exposures in 1 month.
Ten mice of the 800 mg/m3 group died along with 5/6 replacement mice.
The animals were observed during the exposures and body weights were recorded three times a week throughout the experiment. Body weight data, organ to body weight ratios and clinical laboratory parameters were analysed statistically using analysis of variance and Dunnett’s test.

Most of the mice died when exposed to 800 mg/m3. Five of the 16 mice that died showed convulsions and hyperactivity prior to death. The adverse effects produced by the two doses of potassium amyl xanthate are shown in Table 1.

Positive control:

no data

Observations and examinations performed and frequency:

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. No signs of toxicity were observed in animals exposed to a concentration of 200 mg/m3. Rats exposed to a concentration of 800 mg/m3 showed a statistically significant decrease in body weight after the fifth exposure. Recovery of the body weight occurred within 4 days and may not have been exposure related.
The only substance related adverse effect observed was a yellow-brown staining of the hair coat of the rats.
Overexposure of the animals exposed to a concentration of 800 mg/m3 occurred because of a technical problem in the aerosol generating apparatus.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, the presence of tumours in the lungs, liver, kidneys, pancreas, spleen and any other organs were recorded.
HISTOPATHOLOGY: Yes, the lungs, liver, kidneys, pancreas, spleen and any other organs with tumours were sampled at necropsy.

Other examinations:

See table 1.

Clinical signs:

no effects observed

Description (incidence and severity):

See table 1.

Mortality:

no mortality observed

Description (incidence):

See table 1.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

See table 1.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

No statistically significant treatment related effects were observed.See table 1.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

No statistically significant treatment related effects were observed.See table 1.

Endocrine findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

No significant differences were observed between the test and control groups. See table 1.

Gross pathological findings:

no effects observed

Description (incidence and severity):

No significant differences were observed between the test and control groups. See table 1.

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No significant differences were observed between the test and control groups. See table 1.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

No significant differences were observed between the test and control groups. See table 1.

Dose descriptor:

LOEC

Effect level:

100 mg/m³ air (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Hepatotoxic effects

Critical effects observed:

not specified

Table 1 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	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	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.

 

 

Conclusions:

The results of this study indicate that potassium amyl xanthate has an adverse effect on the the liver in dogs. There were no treatment-related changes in the haematological or urinalysis values in any of the animals.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

100 mg/m³

Study duration:

subacute

Species:

dog

Quality of whole database:

Inhalation of potassium amyl xanthate produces adverse effects in the livers of dogs.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

 

In the absence of reliable information, the data for potassium amyl xanthate (CAS# 2720-73-2) may be used as a surrogate for sodium )-Isopropyl dithiocarbonate (CAS# 140-93-2).

The target sites for Sodium Isopropyl xanthate, and other xanthates are the central nervous system, liver and kidneys. The adverse effects seen in the toxicity studies could be due to the xanthates (such as Sodium Isopropyl xanthate), their decomposition products or a combination of both.

 

There is no human information available concerning reproductive toxicity for xanthates (CHEMINFO ,2004, Chemical Profiles Created by CCOHS , www.ccohs.ca).

Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: other; neurologic: central nervous system

Repeated dose toxicity: inhalation - systemic effects (target organ) digestive: liver