Registration Dossier

Administrative data

Description of key information

-NOAEL of 10 mg/kg bw/day was established based on the haemolytic effects, characterized by statistically significant reduction in erythrocyte count together with increases in mean corpuscular haemoglobin and mean corpuscular volume (both sexes), and lower severities of adipose iniltration indicative of marrow hyperplasia (in females), higher incidence and severity of haemosiderin accumulation in kidney (males), acanthosis and hyperkeratosis of the epithelium of the forestomach (males) and statistically significant increase in total activity (males).
-NOAEC of 23 mg/m3 was established based on no effects in rats.
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.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: 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:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Qualifier:
according to
Guideline:
EU Method B.26 (Sub-Chronic Oral Toxicity Test: Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Qualifier:
according to
Guideline:
EPA OPPTS 870.3100 (90-Day Oral Toxicity in Rodents)
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent, UK
- Age at study initiation: 5-8 weeks
- Weight at study initiation: males: 164-217 g, females: 143-193 g
- Housing: in groups of 5 by sex in polypropylene grid-floor cages suspended over trays lined with absorbent paper.
- Diet: a pelleted diet (Rat and Mouse SQC Diet No. 1, Special Diets Services Limited, Witham, Essex, UK), ad libitum
- Water: Mains drinking water from polycarbonate bottles attached to the cage, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2
- Humidity (%): 55 ± 15
- Air changes (per hr): at least 15 per hour
- Photoperiod (hrs dark / hrs light): 12/ 12
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: the test material was prepared at the appropriate concentrations as solution in distilled water. Formulations were stable for at least 3 days. Fresh formulations were therefore prepared daily and used wherever possible within 3 hours of preparation. Correction for 41% purity was taken into account.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were taken once weekly of each test material formulation and analysed for concentration of SDDC at Safepharm Analytical Laboratory by gas chromatography. The results indicate that the prepared formulations were on most occasions within ±10% of nominal.
Duration of treatment / exposure:
90 consecutive days
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
0. 10, 50 and 250 mg/kg bw/day
Basis:
nominal in water
No. of animals per sex per dose:
10/sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on the results of a range-finding study
- Rationale for animal assignment (if not random): the animals were randomly allocated to treatment grouops using random letter tables and the group mean bodyweights were then determined to ensure similarity between the treatment groups
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: all animals were examined for overt signs of toxicity, ill-health or behavioural change immediately before dosing and one and 5 hours after doing during the working week. Animals were observed immediately before dosing and one hour after dosing at weekends and public holidays.

DETAILED CLINICAL OBSERVATIONS: Yes
Detailed individual clinical observations were performed on each animal using a purpose built arena. The following parameters were observed: gait, tremors, twitches, convulsions, bizarre/abnormal/stereotypic behaviour, salivation, piloerection, exophthalmia, lachrymation, hyper/hypothermia, skin colour, respiration, palpebral closure, urination, defecation, trasfer arousal, tail elevation.

BODY WEIGHT: Yes
- Time schedule for examinations: at day 0 (the day before the start of treatment) and at weekly intervals thereafter. Bodyweights were also recorded at terminal kill.

FOOD CONSUMPTION: yes
Food consumption was recorded for each group at weekly intervals throughout the study.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: daily, by visual inspection of the water bottles for any overt change.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pre-treatment and before termination of treatment (during week 12)
- Dose groups that were examined: control and high-dose animalsHAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the study (day 90); where necessary, repeat were obtained on day 21.
- Anaesthetic used for blood collection: No data
- Animals fasted: No
- How many animals: all animals from each test and control groups
- Parameters examined: haemoglobin (Hb), erythrocyte count (RBC), haematocrit (Hct), erythrocyte indices (mean corpuscular haemoglobin, mean corpuscular volume, mean corpuscular haemoglobin concentration), total leucocyte count (WBC), differential leucocyte count (neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet count (PLT), reticulogyte count (Retic, prothrombin time and activated partial thromboplastin time.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the study (day 90); where necessary, repeat were obtained on day 21.
- Anaesthetic used for blood collection: No data
- Animals fasted: No
- How many animals: all animals from each test and control groups
- Parameters examined: urea, glucose, total protein, albumin, albumin/globulin ratio, sodium, potassium, chloride, calcium, inorganic phosphorus, aspartate aminotransferase, alanine aminotransferase, alkalline phosphatase, creatinine, total cholesterol, total bilirubin, cholinesteraseNEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: prior to the start of treatent and at weekly intervals thereafter, all animals were observed for signs of functional/behavioural toxicity. During Week 12 functional performance tests were also performed on all animals together with an assessment of sensory reactivity to different stimuli.
- Dose groups that were examined: all
- Battery of functions tested: sensory reactivity, forelimb/hindlimb grip strength, motor activity
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes. Samples of the following tissues were removed from all animals and preserved in buffered 10% formalin: adrenals, aorta (thoracic), bone & bone marrow (femur including stifle joint, sternum), brain (including cerebrum, cerebellum and pons), caecum, colon, duodenum, epididymides, eyes, gross lesions, heart, ileum (including Peyer's patches), jejunum, kidneys, liver, lungs (with bronchi), lymph nodes (cervical and mesenteric), mammary glands, muscle (skeletal), oesophagus, ovaries, pancreas, pituitary, prostate, rectum, salivary glands (submaxillary), sciatic nerve, seminal vesicles, skin (hind limb), spinal cord (cervical, mid-thoracic and lumbar), spleen, stomach, testes, thymus, thyroid/parathyroid, tongue, trachea, urinary bladder, uterus
Statistics:
Haematological, blood chemical, organ weight, weekly bodyweight gain and quantitative functional performance and sensory reactivity data were assessed for control and test material treatment groups for dose response relationships by linear regression analysuis followed by one way analysis of variance (ANOVA) incorporating Levene's test for homogeneity of variance. Wheere variances were shown to be homogenous pairwise comparisons were conducted using Dunnett's test. Where Levene's test showed unequal variances the data were analysed using non-parametric methods: Kruskal-Wallis ANOVA and Mann-Whitney "U" test.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
There were no deaths. Increased salivation around the time of dosing was detected for animals of either sex treated with 250 mg/kg bw/day from day 1 or day 2 onwards, accompanied in females with associated isolated findings of red/brown staining and/or wetness of the external body fur and generalised fur loss. Females treated with 250 mg/kg bw/day also showed hunched posture and isolated signs of tiptoe gait from day 28. Instances of transient increased salivation were also seen in either sex treated with 50 mg/kg bw/day. Excessive visible salivation and its associated findings are commonly reported following the oral administration of a test material, and are considered to be attributable to the repeated administration of a locally irritant test material formulation by gavage rather than an indication of systemic toxicity. No treatment-related clinical signs were observed at 10 mg/kg bw/day.

BODY WEIGHT AND WEIGHT GAIN
Animals of either sex treated with 250 mg/kg bw/day showed reductions in bodyweight gain throughout the study period compared with controls. No adverse bodyweight effect was noted at the other dose levels.

FOOD CONSUMPTION:
A reduction in dietary intake was detected for animals of either sex treated with 250 mg/kg bw/day throughout the study period compared with controls. No noteworthy differences in food consumption were observed at the other dose levels.
WATER CONSUMPTION:
Daily visual inspection of water bottles revealed no overt intergroup differences.

OPHTHALMOSCOPIC EXAMINATION
There were no treatment-related ocular effects.

HAEMATOLOGY
A clear haemolytic effect was identified for animals treated with 250 mg/kg bw/day and likely also in animals treated with 50 mg/kg bw/day, characterised by a statistically significant reduction in erythrocyte count in animals treated with 250 mg/kg bw/day together with increases in mean corpuscular haemoglobin (MCH) and mean corpuscular volume (MCV). Males treated with 250 mg/kg bw/day also shwoed an increase in mean corpuscular haemoglobin concentration. An increase in MCH and MCV was also apparent in either sex treated with 50 mg/kg bw/day.

CLINICAL CHEMISTRY
Findings were confined to increases in plasma levels of total protein, sodium and cholesterol in males treated with 250 mg/kg bw/day.
NEUROBEHAVIOUR
Males treated with 250 or 50 mg/kg bw/day showed a statistically significant increase in total activity compared with controls. No treatment-related changes were detected for females or for 10 mg/kg bw/day males.
Females treated with 250 mg/kg bw/day showed statisitically significant increases in startle reflex for percentile average response, root of the mean square and peak response, compared with controls. A slight but statistically significant increase in percentile average response was also noted in females treated with 50 or 10 mg/kg bw/day but this was considered not to be toxicologically significant.

ORGAN WEIGHTS
Increases in kidney, liver and spleen weight were evident in both sexes treated with 250 mg/kg bw/day compared with controls. The other organs were unaffected and there were no other changes in organ weight that could be considered toxicologically important.

GROSS PATHOLOGY
Treatment-related gastric changes were detected in the majority of male animals treated with 250 mg/kg bw/day together with enlarged and darkened spleens in two males treated with 250 mg/kg bw/day. No treatment-related macroscopic abnormalities were detected for animals treated with 50 or 10 mg/kg bw/day.
HISTOPATHOLOGY: NON-NEOPLASTIC
The following treatment-related changes were detected:
Spleen: higher severities of extramedullary haemopoiesis were observed in relation to treatment for rats of either sex dosed at 250 mg/kg bw/day. A similar effect was also seen for male rats dosed at 50 mg/kg bw/day and 10 mg/kg bw/day. In addition, higher severities of pigment accumulation were seen for rats of either sex dosed at 250 mg/kg bw/day or at 50 mg/kg bw/day. The pigment was determined to be haemosiderin by Perl's staining technique.
Kidneys: a higher incidence and greater severity of pigment accumulation was seen in the renal tubules of rats of either sex dosed at 250 mg/kg bw/day and for male rats dosed at 50 mg/kg bw/day. The pigment was determined to be haemosiderin by Perl's staining technique.
Urinary bladder: there were indications of an effect of treatment on the transitional epithelium of the bladder resulting in hyperplasia. This is reasonably convincing for male rats dosed at 250 mg/kg bw/day, but for females, this condition is also present among control animals.
Thyroids: higher severities of follicular cell hyperthrophy were observed for male rats dosed at 250 mg/kg bw/day. A higher incidence of associated colloird depletion was also seen.
Stomach: acanthosis and heperkeratosis of the epithelium of the forestomach was seen among rats of either sex dosed at 250 mg/kg bw/day. Similar effects were also seen for male rats receiving 50mg/kg bw/day of the test material.
Duodenum: mucosal hypertrophy was seen for four males and for 1 female rat dosed at 250 mg/kg bw/day. This condition was considered to be related to treatment for male rats, but probably not for females.
Salivary glands: treatment-related atrophy of the serous acini of the submaxillary salivary glands was seen for rats of either sex receiving 250 mg/kg bw/day of the test material.
Bone marrow: lower severities of adipose infiltration of the bone marrow indicative of marrow hyperplasia were seen in female rats dosed at 250 mg/kg bw/day and 50 mg/kg bw/day.
All remaining morphological changes were those commonly observed in laboratory maintained rats of the age and strain employed. Although group differences in the incidence or severity of lesions occasionally attained statistical significance, none was considered to be related to treatment.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)

HISTORICAL CONTROL DATA (if applicable)
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified

 

Table 7.5.1 -A1 Results of haematology and blood chemistry (after 90 days)

 

Parameter

Control

10 mg/kg

50 mg/kg

250 mg/kg

Dose-response

+/–

Number of animals examined

10

10

10

10

10

10

10

10

 

 

Haematology

 

 

 

 

 

 

 

 

 

 

RBC count

+

+

MHC

+

+

MCV

+

+

MCHC

+

Blood chemistry

 

 

 

 

 

 

 

 

 

 

Total protein

+

Na+

+

Cholesterol

+

↑, ↓: statistically significant increase and decrease, respectively
– : no significant difference from control values

 


Table 7.5.1 -A2 Results of repeated dose toxicity study (after 90 days)

 

Parameter

Control

10 mg/kg

50 mg/kg

250 mg/kg

Dose-response

+/–

Number of animals examined

10

10

10

10

10

10

10

10

 

 

Organ weights

 

 

 

 

 

 

 

 

 

 

Kidney, rel.

+

+

Liver, rel.

+

+

Spleen, rel.

+

+

Spleen, abs.

+

Gross necropsy

 

 

 

 

 

 

 

 

 

 

Stomach – non glandular region thickened

0

0

0

0

0

0

7

3

+

+

Stomach – non glandular region sloughing

0

0

0

0

0

0

6

2

+

+

Histopathology

 

 

 

 

 

 

 

 

 

 

Spleen,
extramedullary haemopoiesis, slight a

1

0

6

0

6

3

9

8

+

+

Spleen,
haemosiderin deposition

moderate

2

6

4

7

7

9

9

1

+

+

marked

0

0

0

0

0

1

1

8

Kidneys,
haemosiderin deposition

minimal

0

7

2

9

5

6

4

3

+

slight

0

0

0

0

0

3

0

5

Urinary Bladder,
hyperplasia, minimal ( ♂ )/ slight ( ♀ )

0

0

0

0

0

0

4

2

+

+

Thyroids,
follicular cell hypertrophy, moderate ( ♂ )/ slight ( ♀ )

1

1

0

0

1

1

4

2

+

Stomach,
Acanthosis, slight

0

0

0

0

0

0

7

7

+

+

Stomach,
Hyperkeratosis, slight

0

0

0

0

0

0

6

5

+

+

Duodenum,
mucosal hypertrophy, minimal

0

0

1

0

2

0

4

1

+

Salivary Glands,
atrophy serous acini, present

0

0

0

0

0

1

7

7

+

+

Bone marrow,
adipose infiltration, slight

1

7

0

4

0

2

1

1

+

 

 

 

 

 

 

 

 

 

 

 

 

 

  a   number of animals affected

Conclusions:
NOAEL of 10 mg/kg bw/day was established based on the haemolytic effects, characterized by statistically significant reduction in erythrocyte count together with increases in mean corpuscular haemoglobin and mean corpuscular volume (both sexes), and lower severities of adipose iniltration indicative of marrow hyperplasia (in females), higher incidence and severity of haemosiderin accumulation in kidney (males), acanthosis and hyperkeratosis of the epithelium of the forestomach (males) and statistically significant increase in total activity (males).
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
10 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
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:
no
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
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.
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:
no
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.
Remarks:
Doses / Concentrations:
0, 100 and 800 mg/m3
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0, 23 and 252 mg/m3.
Basis:
other: actual doses
No. of animals per sex per dose:
10 male Sprague-Dawley rats were exposed to 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.
Control animals:
yes
Details on study design:
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.
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.
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 statistically significant treatment related effects were observed.See table 1.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
o statistically significant treatment related effects were observed.See table 1.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No statistically significant treatment related effects were observed.See table 1.
Details on results:
NOAEC of 23 mg/m3 was established based on no effects in rats.
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.
Dose descriptor:
NOAEC
Effect level:
23 mg/m³ air
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No statistically significant effects were noted in the study at the concentration tested.
Dose descriptor:
dose level:
Effect level:
252 mg/m³ air
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Nephrotoxic effects.High serum alanine aminotransferase activity,Microscopically visible granular degeneration, One Death, but not related to exposure
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:
NOAEC of 23 mg/m3 was established based on no effects in rats.
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.
Executive summary:

NOAEC of 23 mg/m3 was established based on no effects in rats.

The results of this study indicate that potassium amyl xanthate has an adverse effect at concentration of 252 mg/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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
23 mg/m³
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
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:
no
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
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.
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:
no
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.
Remarks:
Doses / Concentrations:
0, 100 and 800 mg/m3
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0, 23 and 252 mg/m3.
Basis:
other: actual doses
No. of animals per sex per dose:
10 male Sprague-Dawley rats were exposed to 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.
Control animals:
yes
Details on study design:
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.
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.
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 statistically significant treatment related effects were observed.See table 1.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
o statistically significant treatment related effects were observed.See table 1.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No statistically significant treatment related effects were observed.See table 1.
Details on results:
NOAEC of 23 mg/m3 was established based on no effects in rats.
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.
Dose descriptor:
NOAEC
Effect level:
23 mg/m³ air
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No statistically significant effects were noted in the study at the concentration tested.
Dose descriptor:
dose level:
Effect level:
252 mg/m³ air
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Nephrotoxic effects.High serum alanine aminotransferase activity,Microscopically visible granular degeneration, One Death, but not related to exposure
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:
NOAEC of 23 mg/m3 was established based on no effects in rats.
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.
Executive summary:

NOAEC of 23 mg/m3 was established based on no effects in rats.

The results of this study indicate that potassium amyl xanthate has an adverse effect at concentration of 252 mg/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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
23 mg/m³

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
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: 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:
equivalent or similar to
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
yes
Remarks:
Data about the area covered by the test material and occlusion are not reported.
GLP compliance:
not specified
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Interfauna U.K. Ltd., Huntingdon, Cambridgeshire, England
- Age at study initiation: 10-12 weeks on arrival
- Weight at study initiation: fehlt noch
- five male and five female New Zealand white rabbits, weighing 2.2-2.6 kg
Type of coverage:
not specified
Vehicle:
water
Details on exposure:
TEST SITE
- Area of exposure: no data

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with water
- Time after start of exposure: 6 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100, 300, 1000 mg/kg bw/day
- For solids, paste formed: Yes. Powder was moistened with water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
purity of ziram was analysed
Duration of treatment / exposure:
21 days
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
100, 300, 1000 mg/kg bw/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
Ziram (purity 98.5%) was applied to the intact skin of groups of five male and five female New Zealand white rabbits, weighing 2.2-2.6 kg, daily for 21 consecutive days at doses of 0, 100, 300, or 1000 mg/kg bw per day. The test substance was moistened with distilled water and maintained on the backs of the rabbits for 6 h each day, after which the dressings were removed and the treated skin washed with tap-water at 30-40°C and gently blotted dry. No dermal reaction to the treatment was observed at any dose. Significant losses in body weight or low body-weight gain and reduced food consumption were recorded for female rabbits receiving 1000 mg/kg bw. The number of lymphocytes was reduced in both males and females at 1000 mg/kg bw, and alanine and aspartate transaminase activities were increased at 300 and 1000 mg/kg bw. At the highest dose, significantly increased levels of bilirubin were found in females and of cholesterol in animals of each sex. The NOAEL was 300 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin and cholesterol levels at 1000 mg/kg bw per day.
Positive control:
no
Observations and examinations performed and frequency:
CLINICAL SIGNS
- Time schedule: once daily

MORTALITY
- Time schedule: once daily

DERMAL IRRITATION
- Time schedule for examinations: Prior to the first application and subsequent daily (erythema and eschar / oedema formation) .

BODY WEIGHT
- Time schedule for examinations: Prior to dosing and then once weekly.

FOOD CONSUMPTION
- Time schedule for examinations: Once weekly.

HAEMATOLOGY
- Time schedule for collection of blood: For all animals at Day 20. For specified animals procedure was repeated on Day 22.
- Animals fasted: Yes
- Parameters: haematocrit, erythrocyte count, haemoglobin, mean corpuscular volume, mean corpuscular haemoglobin concentration, platelet count, total leukocyte count, differential leukocyte count, cell morphology, thrombotest
CLINICAL CHEMISTRY
- Time schedule for collection of blood: For all animals at Day 20. For specified animals procedure was repeated on Day 22.
- Animals fasted: Yes
- Parameters: glucose, blood urea nitrogen, creatinine, total bilirubin, total cholesterol, alanine aminotransferase (GPT), aspartate aminotransferase (GOT), alkaline phosphatase, calcium, phosphorus, sodium, potassium, chloride, albumin, total protein, albumin/globulin ratio
Sacrifice and pathology:
ORGAN WEIGHTS
From all animals sacrificed at termination.
- Organs: adrenals, liver, kidneys, testes with epididymides/ovaries

GROSS AND HISTOPATHOLOGY
All animals were sacrificed at study termination and a gross pathological examination was performed.
- Histopathology: from all animals of the control and highest dose group
- Organs: abnormal tissue, skin (treated and untreated), kidneys, liver
Statistics:
All analyses were carried out separately for male and female.
The following tests were used for food and water consumption, bodyweight, relative organ weight and clinical pathology data:
- If the data consisted predominantly of one particular value (relative frequency of the mode exceeds 75%), the proportion of animals with values different from the mode was analysed by appropriate methods. Otherwise:
- Bartlett’s test was applied to test for heterogeneity of variance between treatments. Where significant (at the 1% level) heterogeneity was found, a logarithmic transformation was tried to see if a more stable variance structure could be obtained.
- If no significant heterogeneity was detected (or if a satisfactory transformation was found), a one-way analysis of variance was carried out. If significant heterogeneity of variance was present, and could not be removed by a transformation, the Kruskal-Wallis analysis of ranks was used.
- Analyses of variance were followed by a Student’s ‘t’ test and Williams’ test for a dose-related response, although only the one thought most appropriate for the response pattern observed has been reported. The Kruskal-Wallis analyses were followed by the non-parametric equivalents of the ‘t’ test and Williams’ test (Shirleys’ test).
Where appropriate for organ weight data, analysis of covariance was used in place of analysis of variance.
Clinical signs:
no effects observed
Dermal irritation:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
BODY WEIGHT AND WEIGHT GAIN
Bodyweight losses or reduced bodyweight gain was observed in females dosed at 1000 mg/kg bw/day.

FOOD CONSUMPTION
Reduction was measured for females dosed at 1000 mg/kg bw/day in week 1. Food consumption was also reduced in the following weeks but did not achieve statistical significance.

HAEMATOLOGY
Significant lower lymphocyte counts for females dosed at 1000 mg/kg bw/day.

CLINICAL CHEMISTRY
Liver enzymes GOT and GPT were increased in females dosed at 1000 mg/kg bw/day and in case of GOT also at 300 mg/kg bw/day.
Increased levels of bilirubin amongst females and cholesterol amongst both sexes dosed at 1000 mg/kg bw/day were also observed.

GROSS PATHOLOGY
Increased incidence of irregular cortical scarring of the kidney in all groups was not considered to be treatment-related.
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: The NOAEL was 300 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin and cholesterol levels at 1000 mg/kg bw per day.
Dose descriptor:
NOAEL
Effect level:
169 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified

On a molecular weight scaled basis, the NOAELwould be 169 mg/kg bw

(300x 172.24) /305.84 = 169 mg/kg bw

Conclusions:
On a molecular weight scaled basis, the NOAELwould be 169 mg/kg bw(300x 172.24) /305.84 = 169 mg/kg bw
The NOAEL was 169 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin
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



Executive summary:

Ziram (purity 98.5%) was applied to the intact skin of groups of five male and five female New Zealand white rabbits, weighing 2.2-2.6 kg, daily for 21 consecutive days at doses of 0, 100, 300, or 1000 mg/kg bw per day. The test substance was moistened with distilled water and maintained on the backs of the rabbits for 6 h each day, after which the dressings were removed and the treated skin washed with tap-water at 30-40°C and gently blotted dry. No dermal reaction to the treatment was observed at any dose. Significant losses in body weight or low body-weight gain and reduced food consumption were recorded for female rabbits receiving 1000 mg/kg bw. The number of lymphocytes was reduced in both males and females at 1000 mg/kg bw, and alanine and aspartate transaminase activities were increased at 300 and 1000 mg/kg bw. At the highest dose, significantly increased levels of bilirubin were found in females and of cholesterol in animals of each sex. The NOAEL was 300 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin and cholesterol levels at 1000 mg/kg bw per day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
169 mg/kg bw/day
Study duration:
subacute
Species:
rabbit

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
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: 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:
equivalent or similar to
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
yes
Remarks:
Data about the area covered by the test material and occlusion are not reported.
GLP compliance:
not specified
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Interfauna U.K. Ltd., Huntingdon, Cambridgeshire, England
- Age at study initiation: 10-12 weeks on arrival
- Weight at study initiation: fehlt noch
- five male and five female New Zealand white rabbits, weighing 2.2-2.6 kg
Type of coverage:
not specified
Vehicle:
water
Details on exposure:
TEST SITE
- Area of exposure: no data

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with water
- Time after start of exposure: 6 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100, 300, 1000 mg/kg bw/day
- For solids, paste formed: Yes. Powder was moistened with water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
purity of ziram was analysed
Duration of treatment / exposure:
21 days
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
100, 300, 1000 mg/kg bw/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
Ziram (purity 98.5%) was applied to the intact skin of groups of five male and five female New Zealand white rabbits, weighing 2.2-2.6 kg, daily for 21 consecutive days at doses of 0, 100, 300, or 1000 mg/kg bw per day. The test substance was moistened with distilled water and maintained on the backs of the rabbits for 6 h each day, after which the dressings were removed and the treated skin washed with tap-water at 30-40°C and gently blotted dry. No dermal reaction to the treatment was observed at any dose. Significant losses in body weight or low body-weight gain and reduced food consumption were recorded for female rabbits receiving 1000 mg/kg bw. The number of lymphocytes was reduced in both males and females at 1000 mg/kg bw, and alanine and aspartate transaminase activities were increased at 300 and 1000 mg/kg bw. At the highest dose, significantly increased levels of bilirubin were found in females and of cholesterol in animals of each sex. The NOAEL was 300 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin and cholesterol levels at 1000 mg/kg bw per day.
Positive control:
no
Observations and examinations performed and frequency:
CLINICAL SIGNS
- Time schedule: once daily

MORTALITY
- Time schedule: once daily

DERMAL IRRITATION
- Time schedule for examinations: Prior to the first application and subsequent daily (erythema and eschar / oedema formation) .

BODY WEIGHT
- Time schedule for examinations: Prior to dosing and then once weekly.

FOOD CONSUMPTION
- Time schedule for examinations: Once weekly.

HAEMATOLOGY
- Time schedule for collection of blood: For all animals at Day 20. For specified animals procedure was repeated on Day 22.
- Animals fasted: Yes
- Parameters: haematocrit, erythrocyte count, haemoglobin, mean corpuscular volume, mean corpuscular haemoglobin concentration, platelet count, total leukocyte count, differential leukocyte count, cell morphology, thrombotest
CLINICAL CHEMISTRY
- Time schedule for collection of blood: For all animals at Day 20. For specified animals procedure was repeated on Day 22.
- Animals fasted: Yes
- Parameters: glucose, blood urea nitrogen, creatinine, total bilirubin, total cholesterol, alanine aminotransferase (GPT), aspartate aminotransferase (GOT), alkaline phosphatase, calcium, phosphorus, sodium, potassium, chloride, albumin, total protein, albumin/globulin ratio
Sacrifice and pathology:
ORGAN WEIGHTS
From all animals sacrificed at termination.
- Organs: adrenals, liver, kidneys, testes with epididymides/ovaries

GROSS AND HISTOPATHOLOGY
All animals were sacrificed at study termination and a gross pathological examination was performed.
- Histopathology: from all animals of the control and highest dose group
- Organs: abnormal tissue, skin (treated and untreated), kidneys, liver
Statistics:
All analyses were carried out separately for male and female.
The following tests were used for food and water consumption, bodyweight, relative organ weight and clinical pathology data:
- If the data consisted predominantly of one particular value (relative frequency of the mode exceeds 75%), the proportion of animals with values different from the mode was analysed by appropriate methods. Otherwise:
- Bartlett’s test was applied to test for heterogeneity of variance between treatments. Where significant (at the 1% level) heterogeneity was found, a logarithmic transformation was tried to see if a more stable variance structure could be obtained.
- If no significant heterogeneity was detected (or if a satisfactory transformation was found), a one-way analysis of variance was carried out. If significant heterogeneity of variance was present, and could not be removed by a transformation, the Kruskal-Wallis analysis of ranks was used.
- Analyses of variance were followed by a Student’s ‘t’ test and Williams’ test for a dose-related response, although only the one thought most appropriate for the response pattern observed has been reported. The Kruskal-Wallis analyses were followed by the non-parametric equivalents of the ‘t’ test and Williams’ test (Shirleys’ test).
Where appropriate for organ weight data, analysis of covariance was used in place of analysis of variance.
Clinical signs:
no effects observed
Dermal irritation:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
BODY WEIGHT AND WEIGHT GAIN
Bodyweight losses or reduced bodyweight gain was observed in females dosed at 1000 mg/kg bw/day.

FOOD CONSUMPTION
Reduction was measured for females dosed at 1000 mg/kg bw/day in week 1. Food consumption was also reduced in the following weeks but did not achieve statistical significance.

HAEMATOLOGY
Significant lower lymphocyte counts for females dosed at 1000 mg/kg bw/day.

CLINICAL CHEMISTRY
Liver enzymes GOT and GPT were increased in females dosed at 1000 mg/kg bw/day and in case of GOT also at 300 mg/kg bw/day.
Increased levels of bilirubin amongst females and cholesterol amongst both sexes dosed at 1000 mg/kg bw/day were also observed.

GROSS PATHOLOGY
Increased incidence of irregular cortical scarring of the kidney in all groups was not considered to be treatment-related.
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: The NOAEL was 300 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin and cholesterol levels at 1000 mg/kg bw per day.
Dose descriptor:
NOAEL
Effect level:
169 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified

On a molecular weight scaled basis, the NOAELwould be 169 mg/kg bw

(300x 172.24) /305.84 = 169 mg/kg bw

Conclusions:
On a molecular weight scaled basis, the NOAELwould be 169 mg/kg bw(300x 172.24) /305.84 = 169 mg/kg bw
The NOAEL was 169 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin
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



Executive summary:

Ziram (purity 98.5%) was applied to the intact skin of groups of five male and five female New Zealand white rabbits, weighing 2.2-2.6 kg, daily for 21 consecutive days at doses of 0, 100, 300, or 1000 mg/kg bw per day. The test substance was moistened with distilled water and maintained on the backs of the rabbits for 6 h each day, after which the dressings were removed and the treated skin washed with tap-water at 30-40°C and gently blotted dry. No dermal reaction to the treatment was observed at any dose. Significant losses in body weight or low body-weight gain and reduced food consumption were recorded for female rabbits receiving 1000 mg/kg bw. The number of lymphocytes was reduced in both males and females at 1000 mg/kg bw, and alanine and aspartate transaminase activities were increased at 300 and 1000 mg/kg bw. At the highest dose, significantly increased levels of bilirubin were found in females and of cholesterol in animals of each sex. The NOAEL was 300 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin and cholesterol levels at 1000 mg/kg bw per day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
3.33 mg/cm²
Study duration:
subacute
Species:
rabbit

Additional information

Oral repeated dose toxicity

 NOAEL of 10 mg/kg bw/day was established based on the haemolytic effects, characterized by statistically significant reduction in erythrocyte count together with increases in mean corpuscular haemoglobin and mean corpuscular volume (both sexes), and lower severities of adipose iniltration indicative of marrow hyperplasia (in females), higher incidence and severity of haemosiderin accumulation in kidney (males), acanthosis and hyperkeratosis of the epithelium of the forestomach (males) and statistically significant increase in total activity (males).

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

NOAEL= 10 mg/kg bw/day

Dermal repeated dose toxicity

 

The NOAEL was 169 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin.On a molecular weight scaled basis, the NOAEL for Sodium isobutyl xanthate would be 169 mg/kg bw(300x 172.24) /305.84 = 169 mg/kg bw

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

NOAEL = 169 mg/kg bw/day

 

Inhalation repeated dose toxicity

NOAEC of 23 mg/m3 was established based on no effects in rats.

NOAEC = 23 mg/m3


Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: other; other: all gross lesions and masses

Repeated dose toxicity: inhalation - systemic effects (target organ) digestive: liver; other: all gross lesions and masses

Repeated dose toxicity: dermal - systemic effects (target organ) other: skin

Justification for classification or non-classification

 

Based on the hazard assessment of Sodium isobutyl xanthate in section 2.1 and 2.2. in IUCLID 5.4., available data for the substance and following the “Guidance onInformation 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

Repeated dose toxicity

R33 Danger of cumulative effects.

T; R48/23 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation.

T; R48/23/24 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation and in contact with skin.

T; R48/23/24/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed.

T; R48/23/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed.

T; R48/24 Toxic; Toxic: danger of serious damage to health by prolonged exposure in contact with skin.

T; R48/24/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure in contact with skin and if swallowed.

T; R48/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure if swallowed.

Xn; R48/20 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation.

Xn; R48/20/21 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation and in contact with skin.

Xn; R48/20/21/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed.

Xn; R48/20/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation and if swallowed.

Xn; R48/21 Harmful; Harmful: danger of serious damage to health by prolonged exposure in contact with skin.

Xn; R48/21/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure in contact with skin and if swallowed.

Xn; R48/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure if swallowed.

 

CLP

Repeated dose toxicity

STOT Rep. Exp. 1

STOT Rep. Exp. 2

H372: Causes damage to organs <or state all organs affected, if known> through prolonged or repeated exposure <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>.

H373: May cause damage to organs <or state all organs affected, if known> through prolonged or repeated exposure <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>.

 

 

It is concluded that the substance Sodium isobutyl xanthate does not meet the criteria to be classified for human health hazards for Repeated dose toxicity