Registration Dossier

Administrative data

Description of key 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 and xanthate esters. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium or potassium hydroxide: They arise from the reaction of the amine with CS2

NOAEL= 10 mg/kg bw/day

 

In the (Q)SAR study, NOAEL for Repeated dose oral toxicity was 385 mg/kg bw/day (No adverse effects on the highest dose tested) for S-allyl O-pentyl dithiocarbonate. This HESS QSAR grouping method contains simple categories for Repeated dose oral toxicity.This method is relevant for Repeated dose oral toxicity endpoints in mammals. The database include a set of 75 chemicals that have been evaluated for their repeated dose oral toxicity potential.

NOAEL= 385 mg/kg bw/day

 

Dermal repeated dose toxicity

 

The NOAEL was 200.45 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 NOAELwould be 200.45 mg/kg bw(300x 204.35) /305.84 = 200.45mg/kg bw .

 

The NOAEL was200.45mg/kg bw per day.

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

 

NOAEL =200.45 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

 Justification for selection of repeated dose toxicity dermal - local effects endpoint:

 The generic modification from the NOAELtest (in mg/kg of body weight) to NOAELmodified (in mg/cm2/day) will be NOAELin mg/cm2 = ((dose in mg/kg bw)x (average animal weight in kg)) / Treated surface in cm2)

 

 NOAELtest* 2.4/127= NOAELmodified

 The highest dose not causing irritation/corrosion was200.45 mg/kg bw in twenty-one day dermal toxicity study in rabbits of Edwards et al.,1989, the modified dose descriptor would be

NOAELmodified =200.45 mg/kg*2.4 kg/127cm2=3.79 mg/cm2

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
Type of information:
other: published data
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
The S-allyl O-pentyl dithiocarbonate (CAS No. 2956-12-9), the subject of this dossier) is expected to exhibit very similar toxicity to Potassium butyl xanthate (CAS No.871-808-2)), which is also xanthate compound. Comparable metabolism would occur.
Qualifier:
equivalent or similar to
Guideline:
EPA OPPTS 870.8700 (Subchronic Oral Toxicity Test)
Principles of method if other than guideline:
potassium butyl xanthate was administered orally (10 mg/kg) or as air dust to rats, rabbits and dogs for 4 months.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals 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)
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
4 months
Frequency of treatment:
7 days per week
Remarks:
Doses / Concentrations:
10 mg/kg bw/day
Basis:
actual ingested
Control animals:
yes
Details on study design:
potassium butyl xanthate was administered orally (10 mg/kg) or as air dust 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.
Positive control:
no
Observations and examinations performed and frequency:
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.

Other examinations:
No
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. Some animals died during the administration.
Mortality:
mortality observed, treatment-related
Description (incidence):
tachypnoea, cyanosis, loss of hair and dermatitis. Convulsions and paralysis of the extremities were observed in some animals from week 9 of administration. Some animals died during the administration.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
. Loss of weight and increase in blood sugar and cholesterol were observed later.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
S-allyl O-pentyl dithiocarbonate (the result was read across from Potassium butyl xanthate) was administered orally (10 mg/kg) or as air dust 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.
Dose descriptor:
dose level:
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Remarks on result:
not determinable
Remarks:
no NOAEL identified
Critical effects observed:
not specified
Conclusions:
Under the condition of this study, for a period of 4 months 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.
No NOAEL was identified.
The S-allyl O-pentyl dithiocarbonate (CAS No. 2956-12-9), the subject of this dossier) is expected to exhibit very similar toxicity to Potassium butyl xanthate (CAS No.871-808-2)), which is also xanthate compound. Comparable metabolism would occur.
Executive summary:

S-allyl O-pentyl dithiocarbonate (the result was read across from Potassium butyl xanthate) was administered orally (10 mg/kg) or as air dust 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.

Endpoint:
sub-chronic toxicity: oral
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 and xanthate esters. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium or potassium 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:
yes
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).
Dithiocarbamates are related compounds to xanthates and xanthate esters. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium or potassium hydroxide: They arise from the reaction of the amine with CS2
Endpoint:
sub-chronic toxicity: oral
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:
Pentan-1-ol/Amyl alcohol is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, pentan-1-ol/Amyl alcohol need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
15 animals per sex per dose, no ophthalmological examinations
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
other: ASH/CSE
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: from a specified-pathogen-free breeding colony
- Weight at study initiation: 91.8 ± 2.1
- Diet (ad libitum): Spillers' Laboratory Small Animal Diet
- Water (ad libitum): tap-water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 1
- Humidity (%): 40 - 60
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: in appropriate concentration so that all rats received a dosage of 5 ml/kg bw/day
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13 w
Frequency of treatment:
daily
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
150 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
15
Control animals:
yes, concurrent vehicle
Details on study design:
- Rationale for selecting satellite groups: Satellite animals were included for haematological and clinical chemistry examination at 3 and 23 days.
- Doses were based on literature reports
Observations and examinations performed and frequency:
BODY WEIGHT: Yes
- Time schedule for examinations: initially, then at days 1, 2 and 6 and at intervals of not more than 1 week up to thereafter (last weighing: days 91)

FOOD CONSUMPTION CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

WATER CONSUMPTION: Yes
- Time schedule for examinations: food and water consumptions were measured over the 24-hour period preceding the day of weighing.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after final dose, the animals were killed by exsanguination from the abdominal aorta
- Anaesthetic used for blood collection: Barbiturate
- Animals fasted: Yes, the animals were deprived of food for 24 hour before sacrifice
- Parameters examined haemoglobin content, packed cell volume and counts of erythrocytes and leucocytes. Slides were prepared from all blood samples for the counting of reticulocytes and the different types of leucocytes, but the counts were confined to the controls and the animals on the highest level of treatment except at week 2, when leucocyte counts were also made on the 150-mg/kg groups.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after final dose, the animals were killed by exsanguination from the abdominal aorta
- Animals fasted: Yes, the animals were deprived of food for 24 hour before sacrifice
- Parameters examined: at week 13, serum was analysed for urea, glucose, total protein and albumin as well as for the activities of glutamic-oxalacetic transaminase, glutamic- pyruvic transaminase and lactic dehydrogenase.

URINALYSIS: Yes
- Time schedule for collection of urine: during week 2 and 6 and from the remaining rats during week 12.
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Yes, urine was collected over a 6-hour period of water deprivation from the rats about to be killed.
- Parameters were examined: the volumes and specific gravities of these samples were measured to determine the renal concentrating ability of the rats. In addition, the samples were examined for their appearance, number of cells and content of albumin, glucose, ketones, bile salts and blood. At week 6 and 12 the concentration test was extended to include measurements of the volume and specific gravity of urine produced in a 4-hr period commencing after 16 hr without water. In addition, the renal diluting capacity was investigated by measuring the volume and specific gravity of urine produced in the first 2 hr after a water load of 25 ml/kg.

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, at autopsy all the tissues were examined for gross abnormalities and the brain, heart, liver, spleen, kidneys, stomach, small intestine, caecum, adrenals, gonads, pituitary and thyroid were weighed.
HISTOPATHOLOGY: Yes, samples ot the above organs and of lung, lymph nodes, salivary gland, trachea, oesophagus, aortic arch, thymus, urinary bladder, colon, rectum, pancreas, uterus and skeletal muscle were preserved in 10% buffered formalin. Paraffin-wax sections of these tissues were stained with haematoxylin and eosin for microscopic examination, which was carried out on liver and kidney sections from all animals but on other types of tissue from only half of the control rats and from those given 1000 mg test substance/kg bw for 13 weeks.
Statistics:
Student's t test and the ranking test of White
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
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:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
No abnormalities in appearance or behaviour were seen during the study.

BODY WEIGHT AND WEIGHT GAIN, FOOD CONSUMPTION AND WATER CONSUMPTION
There were no significant differences between the treated and control rats in body weight or in food and water consumption (see table 1).

HAEMATOLOGY AND CLINICAL CHEMISTRY (see table 2)
Only isolated differences from the controls were seen in the results of the haematological studies. These included a lower total leucocyte count at week 2 in the male rats given 150 or 1000 mg test substance/kg bw/day and lower haemoglobin concentrations at week 13 in the male animals given 50 or 1000 mg/kg bw/day. Also there were higher percentages of reticulocytes in the male rats given 1000 mg/kg bw/day at week 2 and in the females at week 13, as well as a slightly lower percentage of lymphocytes at week 6 in the females given 1000 mg/kg bw/day. The results of the serum analyses were similar in test and control rats.

URINALYSIS
The urine was free from bile, blood, glucuse and ketones, while the concentration of albumin was similar in all groups. At week 6 there were lower cell counts in the urine of the male rats given 150 or 1000 mg test substance/kg bw/day, the differences being statistically significant. Some statistically significant differences were also apparent in the concentration tests at week 12; the specific gravity of the samples collected at 16-20 hour from females given 1000 mg/kg bw/day was higher than the control value and the volume was lower. After the same period on test, the male rats given 50 or 1000 mg/kg bw/day produced less urine in the 6-hour period without water. No differences from the controls were found in the dilution test nor at week 2 and 6 in the concentration tests.

ORGAN WEIGHTS (see table 3)
Examination of the organ weights showed some isolated differences at week 2, but none thereafter. The stomach weights in the males and females given 1000 mg n-amyl alcohol/kg bw/day were higher than those of the controls, but the difference was confined to the male rats when the values were related to body weight. Also, a higher heart weight was found in the female rats given the top level of treatment, but this was not evident when the figure was related to body weight. Relative to body weight, the spleens from the female rats dosed with 1000 mg/kg bw/day showed a low value, as did the female kidney weights, both at this and at the 150 mg/kg bw/day level.

GROSS PATHOLOGY
At autopsy, no abnormalities were seen at any dose level

HISTOPATHOLOGY: NON-NEOPLASTIC
On histological examination, protein casts and foci of calcification were found in the kidney tubules, particularly from the male animals, but the incidences were similar in the treated animals and their corresponding controls. The incidence of fatty change and inflammatory cell infiltration in the liver was again comparable in the control and treated rats. No histological changes related to the period or level of treatment were seen in any of the organs examined.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Critical effects observed:
not specified

Table 1: Mean body weights and food and water consumption values of rats given daily doses of 0 - l000 mg test substance/kg bw/day for l3 weeks

Dose level (mg/kg bw/day)

Body weight (g) at day

Mean food consumption (g/rat/day)

Mean water consumption (ml/rat/day)

0

34

62

91

0 (males)      

93

323

424

467

18.8

26.2

50

91

326

422

470

18.9

24.3

150

91

336

449

504

19.6

24.3

1000

96

316

426

479

18.0

24.3

 

 

 

 

 

 

 

0 (females)

91

211

256

281

14.7

20.6

50

91

211

259

286

14.9

20.5

150

89

217

268

293

15.1

21.6

1000

92

205

250

276

14.9

22.1

 

Table 2: Haematological values (aortic blood) for rats given daily doses of 0 -1000 mg test substance/kg bw/day

Sex and dose level (mg/kg bw/day)

Number of rats

Hb (g/100 ml)

PCV (%)

RBC (106/mm3)

Retics (% of RBC)

Leucocytes

Total (103/mm3)

Differential (%)

N

E

L

M

Week 2

0 (male)

5

12.7

41

5.40

1.4

7.1

11

1

85

3

150

5

12.7

41

5.80

-

5.5*

11

0

86

3

1000

5

13.0

42

5.15

2.3*

5.0*

12

1

85

2

0(female)

4

13.5

45

5.15

1.3

3.7

11

0

87

2

150

5

12.6

44

5.85

-

4.5

10

0

89

1

1000

5

13.0

44

5.74

1.0

4.6

11

1

86

2

Week 6

0 (male)

5

14.5

47

6.79

0.5

8.3

11

0

88

1

150

5

14.6

48

6.97

-

8.9

-

-

-

-

1000

5

14.0

46

6.76

0.4

5.6

7

0

91

2

0(female)

5

14.3

45

6.70

0.2

5.6

8

0

91

1

150

5

13.7

43

6.60

-

5.5

-

-

-

-

1000

5

14.1

44

6.76

0.1

6.6

18

1

79*

2

Week 13

0 (male)

14

14.1

45

6.90

0.6

5.6

17

1

80

2

50

15

13.4*

43

6.58

-

5.4

-

-

-

-

150

15

13.9

44

6.64

-

5.4

-

-

-

-

1000

15

13.6*

44

6.66

0.8

5.4

18

2

79

2

0(female)

13

14.0

43

6.56

0.3

4.7

10

1

87

2

50

14

13.5

43

6.51

-

4.4

-

-

-

-

150

14

13.8

43

6.45

-

4.4

-

-

-

-

1000

15

13.7

43

6.65

0.6*

3.9

12

1

85

2

Hb: haemoglobin, PCV: packet cell volume, RBC: red blood cells, Retics: reticulocytes,

N: neutrophils, E: eosinophils, L: lymphocytes, M: monocytes, *: significantly different

 

 

 

 

Table 3: Mean relative organ weights of rats given daily doses of 0 -1000 mg test substance/kg bw/day for 2 or 13 weeks

Sex and dose level (mg/kg bw/day)

Number of rats

Relative organ weight (g/100 g body weight)

Terminal body

weight (g)

Brain

Heart

Liver

Spleen

Kidneys

Stomach

Small intestine

Caecum

Adrenals

(mg/100g)

Gonads*

Pituitary

(mg/100g)

Thyroid

(mg/100g)

Week 2

0 (male)

5

1.04

0.45

3.59

0.36

0.88

0.62

4.75

0.47

24.24

1.25

3.5

8.0

164

150

5

0.99

0.47

3.68

0.38

0.90

0.70

4.89

0.49

25.42

1.21

3.5

6.9

164

1000

5

0.98

0.46

3.75

0.37

0.92

0.72*

4.47

0.49

27.87

1.28

4.0

6.7

164

0(female)

5

1.14

0.44

4.13

0.38

0.96

0.70

4.45

0.42

35.36

61.7

6.3

8.4

137

150

5

1.11

0.46

3.83

0.33

0.86*

0.64

4.14

0.43

35.84

60.9

6.1

9.2

144

1000

5

1.05

0.47

3.74

0.31*

0.85*

0.68

3.84

0.44

36.71

54.8

5.9

9.2

150

Week 13

0 (male)

15

0.42

0.31

2.68

0.17

0.64

0.41

2.02

0.22

15.66

0.83

2.9

4.7

546

50

15

0.42

0.30

2.73

0.18

0.63

0.42

2.19

0.21

15.05

0.81

2.6

4.8

561

150

15

0.40

0.30

2.72

0.19

0.61

0.41

2.21

0.23

14.76

0.80

2.7

4.4

491

1000

15

0.41

0.31

2.69

0.19

0.64

0.43

1.98

0.23

15.19

0.81

2.8

4.9

474

0(female)

15

0.66

0.34

2.49

0.25

0.63

0.53

2.52

0.29

28.10

54.9

5.2

7.0

270

50

15

0.66

0.34

2.49

0.24

0.65

0.53

2.53

0.31

29.45

53.2

5.3

6.5

268

150

15

0.63

0.35

2.49

0.25

0.64

0.53

2.59

0.29

27.74

54.7

5.1

6.6

276

1000

15

0.66

0.37

2.36

0.24

0.62

0.50

2.43

0.31

28.36

54.0

4.7

7.5

268

*mg/100 g body weight for female gonads; *: significantly different

CONCLUSION

Only isolated changes with no consistent pattern were found in the hematological studies, either with respect to dose-response, sex or time relationships. The reductions of hemoglobin concentration in the male rats at week 13 suggest a mild anemia, but this is not supported by other measurements. The packet cell volumes mean corpuscular hemoglobin concentrations and erythrocyte and reticulocyte counts were all within the normal limits and there were no variations in spleen weight. The low total white cell counts observed in the male animals after 2 week treatment (with 150 or 1000 mg/kg bw/day) were probably accidental findings for 2 reasons: 1) the corresponding female rats did not show a similar effect and 2) the differential white cell counts were very similar to those of the controls. The few variations observed in the reticulocyte counts were within the normal range for rats of this strain.

No specific gravity or volume measurements of the urine indicated any adverse effect on renal function in the treated groups. The two isolated reductions in relative kidney weights (after 2 weeks treatment) were neither consistent with absolute kidney weight measurements nor associated with any histopathological findings, or present after a more prolonged treatment.

The increased stomach weights found at week 2 in some rats given the top dose may be associated with a mild irritation since the test substance was administered by gastric intubation. In any case, the effect did not persist throughout the study.

The few other changes in organ weights were isolated, followed no consistent pattern and were considered to be unrelated to treatment.

The highest dose level tested can therefore be considered as the NOAEL under the conditions of the study.

Conclusions:
NOAEL of 1000 mg/kg bw/day was established for gross abnormalities and the brain, heart, liver, spleen, kidneys, stomach, small intestine, caecum, adrenals, gonads, pituitary and thyroid were weighed.
Pentan-1-ol/Amyl alcohol is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, pentan-1-ol/Amyl alcohol need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.
Endpoint:
chronic toxicity: oral
Remarks:
QSAR model
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
QSAR prediction: Accepted HESS QSAR method for chemicals properties assessment.. This method is relevant for Repeated dose oral toxicity endpoints in mammals.
Qualifier:
according to
Guideline:
other: QSAR Toolbox Version 3.3.5.17
Principles of method if other than guideline:
The profiler was developed by National Institute of Technology and Evaluation (NITE) in the contract research project “Development of Hazard Assessment Techniques by using Structure-activity Method (FY2007-FY2011)” by New Energy and Industrial Technology Development
GLP compliance:
no
Remarks:
not applicable HESS QSAR method for chemicals properties assessment.
Limit test:
no
Species:
rat
Strain:
other: QSAR model
Sex:
male/female
Route of administration:
other: QSAR model
Vehicle:
other: QSAR model
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
QSAR model
Duration of treatment / exposure:
QSAR model
Frequency of treatment:
QSAR model
Remarks:
Doses / Concentrations:

Basis:
other: QSAR model
No. of animals per sex per dose:
QSAR model
Control animals:
other: QSAR model
Details on study design:
The profiler contains category boundaries to be expected to induce similar toxicological effects in repeated dose oral toxicity. These category boundaries were developed based on repeated dose toxicity test data in the database of Hazard Evaluation Support System (HESS). Justification for each category (mechanistic or empirical information) is described.
Observations and examinations performed and frequency:
This grouping method contains simple categories for Repeated dose oral toxicity. This method is relevant for Repeated dose oral toxicity endpoints in mammals.
The database include a set of 75 chemicals that have been evaluated for their repeated dose oral toxicity potential.
Other examinations:
This grouping method contains simple categories for Repeated dose oral toxicity. This method is relevant for Repeated dose oral toxicity endpoints in mammals.
The database include a set of 75 chemicals that have been evaluated for their repeated dose oral toxicity potential.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Details on results:
In the present study, NOAEL for Repeated dose oral toxicity was 385 mg/kg bw/day (No adverse effects on the highest dose tested).
Dose descriptor:
NOAEL
Effect level:
385 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: In the present study, NOAEL for Repeated dose oral toxicity was 385 mg/kg bw/day (No adverse effects on the highest dose tested).
Critical effects observed:
not specified

See attached background material and QSAR study report

Conclusions:
In the present study, NOAEL for Repeated dose oral toxicity was 385 mg/kg bw/day (No adverse effects on the highest dose tested).This grouping method contains simple categories for Repeated dose oral toxicity. This method is relevant for Repeated dose oral toxicity endpoints in mammals.
The database include a set of 75 chemicals that have been evaluated for their repeated dose oral toxicity potential.
Executive summary:

In the (Q)SAR study, NOAEL for Repeated dose oral toxicity was 385 mg/kg bw/day (No adverse effects on the highest dose tested) for S-allyl O-pentyl dithiocarbonate. This HESS QSAR grouping method contains simple categories for Repeated dose oral toxicity.This method is relevant for Repeated dose oral toxicity endpoints in mammals. The database include a set of 75 chemicals that have been evaluated for their repeated dose oral toxicity potential.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
10 mg/kg bw/day
Study duration:
subacute
Quality of whole database:
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 and xanthate esters. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium or potassium hydroxide: They arise from the reaction of the amine with CS2
NOAEL= 10 mg/kg bw/day

In the (Q)SAR study, NOAEL for Repeated dose oral toxicity was 385 mg/kg bw/day (No adverse effects on the highest dose tested) for S-allyl O-pentyl dithiocarbonate. This HESS QSAR grouping method contains simple categories for Repeated dose oral toxicity.This method is relevant for Repeated dose oral toxicity endpoints in mammals. The database include a set of 75 chemicals that have been evaluated for their repeated dose oral toxicity potential.
NOAEL= 385 mg/kg bw/day

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
other: published data
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Potassium O-pentyl dithiocarbonate is similar to S-allyl O-pentyl dithiocarbonate . Comparable metabolism would occur.

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 the substance 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.
Remarks on result:
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
Remarks on result:
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 the substance 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. Potassium O-pentyl dithiocarbonate is similar to S-allyl O-pentyl dithiocarbonate . Comparable metabolism would occur.

Executive summary:

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

The results of this study indicate that the substance 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.

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
other: published data
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Potassium O-pentyl dithiocarbonate is similar to S-allyl O-pentyl dithiocarbonate . Comparable metabolism would occur.

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:
mouse
Strain:
Swiss Webster
Sex:
male
Details on test animals and environmental conditions:
10 male Swiss- Webster mice 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:
of 0, 23 and 252 mg/m3.
Basis:
other: actual doses
No. of animals per sex per dose:
10 male Swiss- Webster mice 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:
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.
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 mice
The results of this study indicate that the substance 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:
clinical signs
Remarks on result:
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:
body weight and weight gain
Remarks on result:
other: Higher liver to body weight ratio than controls,10 from the original group and 5/6 replacement animals died. Convulsions hyperactivity in 5/16 prior to death.
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 the substance 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.
Potassium O-pentyl dithiocarbonate is similar to S-allyl O-pentyl dithiocarbonate . Comparable metabolism would occur.

Executive summary:

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

The results of this study indicate that the substance 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.

Potassium O-pentyl dithiocarbonate is similar to S-allyl O-pentyl dithiocarbonate. Comparable metabolism would occur.

 

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
other: published data
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Potassium O-pentyl dithiocarbonate is similar to S-allyl O-pentyl dithiocarbonate . Comparable metabolism would occur.

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:
rabbit
Strain:
New Zealand White
Sex:
male
Details on test animals and environmental conditions:
4 male New Zealand White rabbits 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:
of 0, 23 and 252 mg/m3.
Basis:
other: actual doses
No. of animals per sex per dose:
4 male New Zealand White rabbits 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:
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.
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 Rabbits
The results of this study indicate that the substance 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.
Dose descriptor:
NOAEC
Effect level:
23 mg/m³ air
Based on:
test mat.
Sex:
male
Basis for effect level:
clinical signs
Remarks on result:
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: No adverse effects, only Conjunctival Eye redness,A more intense yellow brown Hair coat
Remarks on result:
other: No adverse effects, only Conjunctival Eye redness,A more intense yellow brown Hair coat
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 the substance 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.
Potassium O-pentyl dithiocarbonate is similar to S-allyl O-pentyl dithiocarbonate . Comparable metabolism would occur.

Executive summary:

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

The results of this study indicate that the substance 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.

Potassium O-pentyl dithiocarbonate  is similar to S-allyl O-pentyl dithiocarbonate . Comparable metabolism would occur.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
23 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
NOAEC of 23 mg/m3 was established based on no effects in rats.

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
other: published data
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Potassium O-pentyl dithiocarbonate is similar to S-allyl O-pentyl dithiocarbonate . Comparable metabolism would occur.

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 the substance 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.
Remarks on result:
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
Remarks on result:
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 the substance 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. Potassium O-pentyl dithiocarbonate is similar to S-allyl O-pentyl dithiocarbonate . Comparable metabolism would occur.

Executive summary:

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

The results of this study indicate that the substance 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.

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
other: published data
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Potassium O-pentyl dithiocarbonate is similar to S-allyl O-pentyl dithiocarbonate . Comparable metabolism would occur.

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:
mouse
Strain:
Swiss Webster
Sex:
male
Details on test animals and environmental conditions:
10 male Swiss- Webster mice 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:
of 0, 23 and 252 mg/m3.
Basis:
other: actual doses
No. of animals per sex per dose:
10 male Swiss- Webster mice 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:
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.
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 mice
The results of this study indicate that the substance 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:
clinical signs
Remarks on result:
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:
body weight and weight gain
Remarks on result:
other: Higher liver to body weight ratio than controls,10 from the original group and 5/6 replacement animals died. Convulsions hyperactivity in 5/16 prior to death.
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 the substance 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.
Potassium O-pentyl dithiocarbonate is similar to S-allyl O-pentyl dithiocarbonate . Comparable metabolism would occur.

Executive summary:

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

The results of this study indicate that the substance 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.

Potassium O-pentyl dithiocarbonate is similar to S-allyl O-pentyl dithiocarbonate. Comparable metabolism would occur.

 

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
other: published data
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Potassium O-pentyl dithiocarbonate is similar to S-allyl O-pentyl dithiocarbonate . Comparable metabolism would occur.

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:
rabbit
Strain:
New Zealand White
Sex:
male
Details on test animals and environmental conditions:
4 male New Zealand White rabbits 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:
of 0, 23 and 252 mg/m3.
Basis:
other: actual doses
No. of animals per sex per dose:
4 male New Zealand White rabbits 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:
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.
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 Rabbits
The results of this study indicate that the substance 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.
Dose descriptor:
NOAEC
Effect level:
23 mg/m³ air
Based on:
test mat.
Sex:
male
Basis for effect level:
clinical signs
Remarks on result:
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: No adverse effects, only Conjunctival Eye redness,A more intense yellow brown Hair coat
Remarks on result:
other: No adverse effects, only Conjunctival Eye redness,A more intense yellow brown Hair coat
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 the substance 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.
Potassium O-pentyl dithiocarbonate is similar to S-allyl O-pentyl dithiocarbonate . Comparable metabolism would occur.

Executive summary:

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

The results of this study indicate that the substance 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.

Potassium O-pentyl dithiocarbonate  is similar to S-allyl O-pentyl dithiocarbonate . Comparable metabolism would occur.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
23 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
NOAEC of 23 mg/m3 was established based on no effects in rats.

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose 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:
Dithiocarbamates are related compounds to xanthates and xanthate esters. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium or potassium 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:
200.45 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
S-allyl O-pentyl dithiocarbonate.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified

On a molecular weight scaled basis, the NOAELwould be 200.45 mg/kg bw(300x 204.35) /305.84 = 200.45mg/kg bw .

The NOAEL was 200.45 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin

Conclusions:
On a molecular weight scaled basis, the NOAELwould be 200.45 mg/kg bw(300x 204.35) /305.84 = 200.45mg/kg bw
The NOAEL was 200.45 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 and xanthate esters. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium or potassium 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
200.45 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
The NOAEL was 200.45 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 NOAELwould be 200.45 mg/kg bw(300x 204.35) /305.84 = 200.45 mg/kg bw .

The NOAEL was 200.45 mg/kg bw per day.
Dithiocarbamates are related compounds to xanthates and xanthate esters. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium or potassium hydroxide: They arise from the reaction of the amine with CS2

NOAEL = 200.45 mg/kg bw/day

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose 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:
Dithiocarbamates are related compounds to xanthates and xanthate esters. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium or potassium 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:
200.45 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
S-allyl O-pentyl dithiocarbonate.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified

On a molecular weight scaled basis, the NOAELwould be 200.45 mg/kg bw(300x 204.35) /305.84 = 200.45mg/kg bw .

The NOAEL was 200.45 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin

Conclusions:
On a molecular weight scaled basis, the NOAELwould be 200.45 mg/kg bw(300x 204.35) /305.84 = 200.45mg/kg bw
The NOAEL was 200.45 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 and xanthate esters. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium or potassium 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
3.79 mg/cm²
Study duration:
subacute
Species:
rabbit
Quality of whole database:
The generic modification from the NOAELtest (in mg/kg of body weight) to NOAELmodified (in mg/cm2/day) will be NOAELin mg/cm2 = ((dose in mg/kg bw)x (average animal weight in kg)) / Treated surface in cm2)
NOAELtest* 2.4/127= NOAELmodified
The highest dose not causing irritation/corrosion was 200.45 mg/kg bw in twenty-one day dermal toxicity study in rabbits of Edwards et al.,1989, the modified dose descriptor would be
NOAELmodified =200.45 mg/kg*2.4 kg/127cm2=3.79 mg/cm2

Additional information

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 S-allyl O-pentyl dithiocarbonate 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

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 S-allyl O-pentyl dithiocarbonate does not meet the criteria to be classified for human health hazards for Repeated dose toxicity