Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

There are conclusive but not suffcient data for the classification of substance S-allyl O-pentyl dithiocarbonate with regard to reproduction. Non-ER binder due to non-cyclic molecular structure.S-allyl O-pentyl dithiocarbonatehave a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore S-allyl O-pentyl dithiocarbonate does not cause reproductive toxicity. It is concluded that the substance S-allyl O-pentyl dithiocarbonate does not meet the criteria to be classified for human health hazards for Reproductive toxicity

Link to relevant study records

Referenceopen allclose all

Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type
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:
Carbon disulphide (CAS number 75–15–0) is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, Carbon disulphide (CAS number 75–15–0) need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Female rats were exposed to CS2 by whole body inhalation for 6 h daily for 14 days prior mating, during mating and until gestation day 19. Potential adverse effects on gonadal function, estrous cycles, conception rates, perturition and lactation of the F0 maternal generation were examined. Viability, growth and development of the F1 litters were also assessed.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River breeding Laboratories, Mischigan
- Age at study initiation: (P) 104 days
- Weight at study initiation: Females: 215-300 g
- Housing: individually, clean stainless stell wire-mesh cages suspended above cage-board till gaestation day 19; after mating the females were put to plastic maternity cages with nesting material, ground corn cob bedding
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22.8
- Humidity (%): 28-76
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
The test atmospheres was generated as vapors by introducing liquid carbon diaulfide into 1/4 J Air Atomizers (nebulizers) fitted with Model 1050 Fluid Caps and Model 84 Air Caps (Spraying Systems, Inc.). The air atomizer assemblies were located in the rear wall of the tangential turret head of each exposure chamber at a 90 degree angle to the direction of mass air flow. Liquid test material feed to the air atomizers was accomplished by use of Harvard Apparatus Co., Inc. Model 975 Compact Infmion Pumps. A positive flow of dried air was introduced to the air atomizers at a rate of approximately 6 liters per minute to aid in the complete vaporization of the test material.

- Temperature, humidity: 22 ± 2, 40-70%,
- Air flow rate: 12-15 changes/hour
Details on mating procedure:
- M/F ratio per cage: 1:1
- Proof of mating was confirmed by the presence of sperm on the vaginal smear or a vaginal copulatory plug, referred to as day 0 of gestation
- After 10 days of unsuccessful pairing replacement of first male by another male with proven fertility took place.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged as described above
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
6 h
Frequency of treatment:
daily
Details on study schedule:
The parental animals were exposed for at least 14 days and thereafter, they were paired with unexposed males. Exposure continued throughout mating until the 19th day of gestation.
- Age at mating of the mated female animals in the study: 17 weeks
Remarks:
Doses / Concentrations:
389, 777, 1554 mg/m3 (125, 250, 500 ppm)
Basis:
other: target concentrations
No. of animals per sex per dose:
15, 24 in the control group
Control animals:
yes
Parental animals: Observations and examinations:
CLINICAL OBSERVATIONS AND MORTALITY
- Time schedule: moratlity and moribundity were observed twice daily; detailed clinical observations were recorded daily during the treatment period (before and after exposure). After treatment period clinical observations were recorded weekly.

BODY WEIGHT: Yes
- Time schedule for examinations: weekly till mating; after mating on gestation days 0, 6, 9, 12, 15, and 20 and on lactation days 0, 3, 6, 9, 15 and 21.

FOOD CONSUMPTION :
- Food consumption for each animal determined: weekly, gestation or lactation body weights
Oestrous cyclicity (parental animals):
Vaginal smears were evaluated 10 days before CS2 administration and throughout the 14 day pre-pairing exposure period. During mating smearing continued until evidence of copulation.
Sperm parameters (parental animals):
not examined
Litter observations:
STANDARDISATION OF LITTERS
- yes, maximum of 10 pups/litter, 5/sex when possible randomly selected; excess pups were killed and discarded on lactation day 4.

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, physical development: pinnal detachment, incisor eruption, palpebral seperation, testicular descent, vaginal patency

GROSS EXAMINATION OF DEAD PUPS: yes
Postmortem examinations (parental animals):
SACRIFICE
- Maternal animals: All Fo female rats with viable pups were killed on lactation day 21. The females that failed to deliver were also sacrificed, on post coital day 25. Females with total litter loss were sacrificed within 24 h.

GROSS NECROPSY
- Complete gross necropsy performed including examinations of the abdominal, thoracic, and pelvic cavities

HISTOPATHOLOGY
Tissues were examined only when deemed necessary after the gross necropsy
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring were sacrificed on lactation day 42.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination)
Pinnal detachment: started on lactation day 4 and continued daily until the pup had both pinnae detached
Incisor eruption: incisors were xhecked on lactation day 9
Palpebral seperation: started on lactation day 13 and continued until both eyelids were seperated
Testicular descent: from lactation day 25, the day were the testis apperared in the scotrum was recorded
Vaginal patency: on day 30 (open vaginal lumen)

GROSS NECROPSY
- Gross necropsy performed

HISTOPATHOLOGY / ORGAN WEIGTHS
Tissues were examined only when deemed necessary after the gross necropsy
Statistics:
Two-tailed tests (significance level of 5%): Chi-square test with Yates' correction factor and one-way ANOVA with Dunett's test
Reproductive indices:
Fertility index (%): No of females paired resulting in pregnancy/total No of females paired with males
Offspring viability indices:
Each litter was examined daily for survival and all deaths were recorded. Livebirth index (%): No of viable pups at birth/No of implantation sites
Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
not examined
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not examined
Description (incidence and severity):
female animals
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): all animals survived treatment; treatment related clinical observations at 500 ppm were clear material around the eye, red material around the nose, within 1 h after completion of exposure

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): no significant effects detected on the mean weekly body weight or body weight gain and weekly food consumption (evaluated as g/animal/day and g/kg/day). The same was observed during the lactation period measuremnts. Throughout gestation body weights were significantly reduced at the highest concentration group, while food consumption appeared slightly affected at the same group during days 15-20.

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS): variations occured in all study groups; the regularity and duration of estrous were not affected by CS2 exposure

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): not affected by CS2 exposure. Female mating indices were 100% for the control group and the concentrations of 125 and 25 ppm, and 93.3% for the 500 ppm, while fertility indices were 87.5 %, 93.3%, 80% and 80%, respectively. The 80% was very common among the historical control data of the laboratory.

GESTATION: apparent signs of dystocia were observed in two females at the highest concentration group

GROSS PATHOLOGY (PARENTAL ANIMALS)
Females which failed to deliver: 3, 1, 3 and 2 animals in the control, 125, 250 and 500 ppm groups, respectively, were sacrificed on post-mating day 25 and one female of the last group on day 15. The animals were nongravid and internally normal.
Females with total litter loss: three females in the 500 ppm group, on lactation day 3. Two of them were internally normal, while one had pale eyes, kidneys and liver, as well as irregularly shaped white areas on all lobes of the liver.

Females that deliverd and killed on lactation day 21: no treatment-related findings
Dose descriptor:
NOAEC
Effect level:
250 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEC
Effect level:
500 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: reproductive function and performance
Dose descriptor:
NOAEC
Effect level:
777 mg/m³ air
Based on:
test mat.
Sex:
female
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEC
Effect level:
1 554 mg/m³ air
Based on:
test mat.
Sex:
female
Basis for effect level:
other: reproductive function and performance
Clinical signs:
no effects observed
Mortality / viability:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Histopathological findings:
not examined
VIABILITY INDICES(OFFSPRING): statistically significant increases in mortality on lactation day 0, was observed in the 500 ppm group. The mean stillbirth litter size was increased at this exposure level. Similarly pup survival was lower at this group on days 1 and 4, before selection. During lactation the numbers of pups found dead for the control, 125, 250 and 500 ppm groups were 7, 5, 6, and 38, respectively. Livebirth and gestation survival indices were comparable to the controls.

CLINICAL SIGNS (OFFSPRING): the general physical conditions in all F1 pups was similar to the controls.

BODY WEIGHT (OFFSPRING): a non statistically significant difference in mean size of live litters; still biologically significant according to the authors. No significant differences detected on mean body weights of the pups through lactation day 42.

PHYSICAL DEVELOPMENT: pinnal detachment, incisor eruption, palpebral seperation, testicular descent and vaginal patency were not affected in any of the pups, due to maternal exposure to CS2.

SEX RATIOS (OFFSPRING): not affected

GROSS PATHOLOGY (OFFSPRING): port mortem examinations of pups found dead were (in 2 pups of the 500 ppm group) dark red lungs, red foamy contents in the trachea, red fluid contents in the esophagus and red contents in the stomach.Dark red lungs and a reddened cortico-medullary junction in each kidney were noted for one pup each in the 250 and 500 pprn groups. One control pup died as a result of a water system malfunction; this pup was internally normal. With the exception of the presence or absence of milk in the stomach, all other remarkable post mortem findings involved malformations and variations. The abnormalities observed did not indicate any specific pattern of maldevelopment. Regarding the pups that were sacrificed on lactation day 42, no treatment related findings were observed.
Dose descriptor:
NOAEC
Generation:
F1
Effect level:
250 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: overall effects
Reproductive effects observed:
not specified
Conclusions:
No effects were observed on the reproductive function and reproductive performance of the animals at all concentration levels. Signs of maternal (body weight loss, dystocia) and neonatal (mortality of the pups, decreased viability, decreased litter size) toxicity were exerted by exposure to CS2 in a concentration of 500 ppm.
Carbon disulphide (CAS number 75–15–0) is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, Carbon disulphide (CAS number 75–15–0) need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.
Executive summary:

In the present study carbon disulfide vapours were administered to 15 Sprague-Dawley female rats/dose via whole body inhalation at dose levels of 125, 250 and 500 ppm (389, 777, 1554 mg/m3) for 14 days before mating, 6 h/day. Twenty- four animals were used as controls and were exposed to clean filtered air. Thereafter, they were paired with unexposed males and exposure to CS2 continued throughout mating and until the 19th day of gestation. The animals were allowed to deliver normally and they were sacrificed on lactation day 21. The pups were sacrificed on lactation day 42. Inhalation of CS2 by Fo maternal animals at a level of 500 ppm elicited maternal toxicity (clinical signs, gestational body weight and food consumption decreases and indications of dystocia) as well as neonatal toxicity (increased pup mortality, decreased pup viability and decreased live litter size). No adverse effects were noted in Fo maternal animals or F1 pups at the 125 and 250 ppm levels. No effects were observed on the reproductive function and performance of the animals at all concentration levels. Based on these results, the NOAEC for maternal toxicity and neonatal toxicity was considered to be 250 ppm (777 mg/m3), while the NOAEC for reproduction toxicity was 500 ppm (1554 mg/m3).

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
subchronic repeated dose toxicity study
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:
other: OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
15 animals per sex per dose, no ophthalmological examinations
Principles of method if other than guideline:
Groups consisting of 15 male and 15 female ASH/SCE strain rat were given daily oral intubation with 1-pentyl alcohol (reported as n-amyl alcohol for 13 weeks. Dose levels were 0 (control), 50, 150, 500, or 1000 mg/kg per day. In addition, groups of 5 males and 5 females were given daily doses of 0, 150, or 1000 mg/kg per day and then killed after 2 or 6 weeks. The 1-pentyl alcohol was diluted in corn oil in appropriate concentrations so that all rats received a dosage volume of 5 ml/kg/day. Animals were weighed initially at days 1, 2, and 6, and then weekly up to day 91 (week 13). Food and water consumption was measured over the 24-hr interval prior to the day of weighing. During week 2, 6, and 12, urine was collected over a 6-hr interval of water deprivation and subjected to urinalysis. At the end of the study, rats were fasted for 24 hr and killed by exsanguination. Blood was collected and retained for hematology and serum chemistry analysis. At necropsy, all tissues were examined for gross abnormalities and the major organs (brain, heart, liver, spleen, kidneys, stomach, small intestines, caecum, adrenals, male and female gonads, pituitary, and thyroid) were weighed. Samples of these organs as well as samples of the lung, lymph nodes, salivary gland, trachea, esophagus, aorta, thymus, urinary bladder, colon, rectum, pancreas, uterus, and skeletal muscle were preserved and prepared for microscopic examination. Liver and kidney sections from all animals were examined microscopically. All other tissues were examined from half the controls animals and from all animals that received the highest dose, 1000 mg/kg, for 13 weeks
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 (e.g. ad libitum): Spillers' Laboratory Small Animal Diet
- Water (e.g. ad libitum): tap-water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 1
- Humidity (%): 40 - 60
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
VEHICLE
- Concentration in vehicle: in appropriate concentration so that all rats received a dosage of 5 ml/kg/day
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
50, 150, 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
15
Control animals:
yes, concurrent vehicle
Parental animals: Observations and examinations:

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
Postmortem examinations (parental animals):
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.
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
no effects observed
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
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/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: no effects on reproductive organs (gross pathology, histopathology)
Clinical signs:
not examined
Mortality / viability:
not examined
Body weight and weight changes:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
Remarks on result:
not measured/tested
Reproductive 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

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/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

 

Conclusions:
No histological changes related to treatment were observed in female ovaries and uterus or male testes. The authors conclude that the no-untoward effect level is 1000 mg/kg/day.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.
Executive summary:

There were no abnormalities in appearance or behavior of rats which received doses of primary amyl alcohol of up to 1000 mg/kg/day. All animals appeared healthy throughout the study. There were no significant differences between treated and control rats in body weight or in food and water consumption. Although food consumption and body weights of males and females receiving 150 mg/kg/day were somewhat greater than those of controls and other exposure groups, but the difference was not significant at P <0.05. Administration of 1-pentyl alcohol had no significant effect on body weight gain, serum or urine analyses, or renal function. There was no consistent pattern in hematological results with respect to dose, sex, or time.

At necropsy, no abnormalities or differences in organ weights were observed in male or female gonads at any dose level, relative to controls. Male testes and female ovaries as well as the female uterus from high dose animals were examined microscopically. No histological changes related to treatment were observed in female ovaries and uterus or male testes. The authors conclude that the no-untoward effect level is 1000 mg/kg/day.

Endpoint:
two-generation reproductive toxicity
Remarks:
other: QSAR Estrogen Receptor Binding method
Type of information:
(Q)SAR
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
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 Estrogen Receptor Binding QSAR method for chemicals properties assessment.. This method is relevant for reproductive toxicity endpoints in fish and mammals.
Qualifier:
according to
Guideline:
other: QSAR Toolbox Version 3.3.5.17
Principles of method if other than guideline:
This grouping method contains simple categories for estrogen receptor (ER) binding. This method is relevant for reproductive toxicity endpoints in fish and mammals.
Estrogen receptor (ER) binding is a molecular initiating event much like protein binding. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER binding and possible subsequent endocrine disruption.

The incorporated Toolbox ER binding profiling scheme is based on structural and parametric rules extracted from literature sources and supported by experimental data . The ER-binding profiler clasifies chemicals as non binders or binders depending on molecular weight (MW) and structural characteristics of the chemicals:
1. Very strong binders: Chemicals with MW between 200 and 500 Da and two rings with a hydroxyl group connected to each of them.
2.Strong binders: Chemicals with at least one 5-or 6-members carbon ring with an unhindered hydroxyl or amino group and MW between 200 and 500 Da;
3.Moderate binders: Chemicals with at least one 5-or 6-members carbon ring with an unhindered hydroxyl or amino group and MW between 170 and 200 Da;
4. Weak binders: Chemicals with at least one 5-or 6-members carbon ring with an unhindered hydroxyl or amino group and MW less than 170 Da;

If the target chemical does not meet some of the structural and parametric requirements listed above it is classified as Non binder:
Non binder with impaired hydroxyl or amino group;
Non binder, MW more than 500 Da;
Non binders without hydroxyl or amino group;
Non-binder, non-cyclic.

GLP compliance:
no
Remarks:
not applicable. QSAR model,Estrogen Receptor Binding method, relevant for reproductive toxicity endpoints in fish and mammals.
Limit test:
no
Species:
other: fish (trout) and mammals.
Strain:
other: QSAR model
Sex:
not specified
Route of administration:
other: QSAR model
Vehicle:
other: QSAR model
Details on exposure:
Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .
Remarks:
Doses / Concentrations:

Basis:
other: QSAR model
Control animals:
not specified
Parental animals: Observations and examinations:
Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .
Clinical signs:
no effects observed
Description (incidence and severity):
QSAR model
Body weight and weight changes:
no effects observed
Description (incidence and severity):
QSAR model
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
QSAR model
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
QSAR model
Other effects:
no effects observed
Description (incidence and severity):
Test substance intake: QSAR model
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
QSAR model
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
QSAR model
Reproductive performance:
no effects observed
Description (incidence and severity):
QSAR model
S-allyl o-pentyl dithiocarbonate have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore S-allyl o-pentyl dithiocarbonate does not cause reproductive toxicity.
1.1. CAS number:
2956-12-9
1.2. Other regulatory numbers:
Not reported
1.3. Chemical name(s):
carbonodithioic acid, o-pentyl s-2-propenyl ester
s-allyl o-pentyl dithiocarbonate
o-pentyl s-prop-2-en-1-yl carbonodithioate
carbonic acid, dithio-, s-allyl o-pentyl ester
xanthic acid, pentyl-, allyl ester
1.4. Structure codes:
a. SMILES:
CCCCCOC(=S)SCC=C
1.5. Profiling results:
DNA binding by OECD
No alert found
Est rogen Receptor Binding
Non binder, non cyclic structure
OECD HPV Chemical Categories
Not categorized
Protein binding by OECD
No alert found
Protein binding potency
Not possible to classify according to these rules (GSH)
Superfragments
No superfragment
Toxic hazard classification by Cramer (original)
High (Class III)
US-EPA New Chemical Categories
Not categorized





Dose descriptor:
other: Relative ERBA (Estrogen Receptor Binding Affinity)
Effect level:
< -3 other: Log RBA(Relative Binding Affinities )
Based on:
other: Estrogen receptor (ER) binding
Sex:
not specified
Basis for effect level:
other: see 'Remark'
Remarks on result:
other: Generation: QSAR model
Clinical signs:
no effects observed
Description (incidence and severity):
QSAR model
Mortality / viability:
no mortality observed
Description (incidence and severity):
QSAR model
Body weight and weight changes:
no effects observed
Description (incidence and severity):
QSAR model
Sexual maturation:
no effects observed
Description (incidence and severity):
QSAR model
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
QSAR model
Gross pathological findings:
no effects observed
Description (incidence and severity):
QSAR model
Histopathological findings:
no effects observed
Description (incidence and severity):
QSAR model
S-allyl o-pentyl dithiocarbonate have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore S-allyl o-pentyl dithiocarbonate does not cause reproductive toxicity.
1.1. CAS number:
2956-12-9
1.2. Other regulatory numbers:
Not reported
1.3. Chemical name(s):
carbonodithioic acid, o-pentyl s-2-propenyl ester
s-allyl o-pentyl dithiocarbonate
o-pentyl s-prop-2-en-1-yl carbonodithioate
carbonic acid, dithio-, s-allyl o-pentyl ester
xanthic acid, pentyl-, allyl ester
1.4. Structure codes:
a. SMILES:
CCCCCOC(=S)SCC=C
1.5. Profiling results:
DNA binding by OECD
No alert found
Est rogen Receptor Binding
Non binder, non cyclic structure
OECD HPV Chemical Categories
Not categorized
Protein binding by OECD
No alert found
Protein binding potency
Not possible to classify according to these rules (GSH)
Superfragments
No superfragment
Toxic hazard classification by Cramer (original)
High (Class III)
US-EPA New Chemical Categories
Not categorized





Remarks on result:
other: S-allyl O-pentyl dithiocarbonate have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor
Reproductive effects observed:
not specified

This grouping method contains simple categories for estrogen receptor (ER) binding. This method is relevant for reproductive toxicity endpoints in fish and mammals.

 

Non-binder, impaired OH or NH2 group

Non-binder without OH or NH2 group

Non-binder, non-cyclic structure

Non-binder, MW > 500

Non-binder, non-cyclic structure– chemicals without cycles and MW =<500

Non-ER binder due to non-cyclic molecular structure.

 

Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .

Popular among these are the “four phase” assessment that includes Comparative Molecular Field Analysis (CoMFA) and the Common Reactivity Pattern Approach (COREPA)

Since the RE-binding is a receptor mediated event, particular organic functional groups, size and shape are critical to binding potency.

S-allyl O-pentyl dithiocarbonate have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptorand therefore S-allyl O-pentyl dithiocarbonate does not cause reproductive toxicity.

Conclusions:
Non-ER binder due to non-cyclic molecular structure S-allyl O-pentyl dithiocarbonate have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore S-allyl O-pentyl dithiocarbonate does not cause reproductive toxicity.
Executive summary:

Non-ER binder due to non-cyclic molecular structure. S-allyl O-pentyl dithiocarbonatehave a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore S-allyl O-pentyl dithiocarbonatedoes not cause reproductive toxicity.

1.1. CAS number:

2956-12-9

1.2. Other regulatory numbers:

Not reported

1.3. Chemical name(s):

carbonodithioic acid, o-pentyl s-2-propenyl ester

s-allyl o-pentyl dithiocarbonate

o-pentyl s-prop-2-en-1-yl carbonodithioate

carbonic acid, dithio-, s-allyl o-pentyl ester

xanthic acid, pentyl-, allyl ester

1.4. Structure codes:

a. SMILES:

CCCCCOC(=S)SCC=C

1.5. Profiling results:

DNA binding by OECD

No alert found

Est rogen Receptor Binding

Non binder, non cyclic structure

OECD HPV Chemical Categories

Not categorized

Protein binding by OECD

No alert found

Protein binding potency

Not possible to classify according to these rules (GSH)

Superfragments

No superfragment

Toxic hazard classification by Cramer (original)

High (Class III)

US-EPA New Chemical Categories

Not categorized

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
other: QSAR model
Type of information:
(Q)SAR
Adequacy of study:
key study
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 Estrogen Receptor Binding QSAR method for chemicals properties assessment.. This method is relevant for reproductive toxicity endpoints in fish and mammals.
Qualifier:
according to
Guideline:
other: Estrogen Receptor Binding method
Principles of method if other than guideline:
This grouping method contains simple categories for estrogen receptor (ER) binding. This method is relevant for reproductive toxicity endpoints in fish and mammals.
GLP compliance:
no
Remarks:
not applicable. QSAR model
Limit test:
no
Species:
other: fish and mammals.
Strain:
other: QSAR model
Sex:
not specified
Route of administration:
other: QSAR model
Vehicle:
other: QSAR model
Details on exposure:
Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .
Remarks:
Doses / Concentrations:

Basis:
other: QSAR model
Control animals:
not specified
Parental animals: Observations and examinations:
Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .
Clinical signs:
no effects observed
Description (incidence and severity):
QSAR model
Body weight and weight changes:
no effects observed
Description (incidence and severity):
QSAR model
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
QSAR model
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
QSAR model
Other effects:
no effects observed
Description (incidence and severity):
Test substance intake: QSAR model
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
QSAR model
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
QSAR model
Reproductive performance:
no effects observed
Description (incidence and severity):
QSAR model
No binding to Estrogen Receptor Alpha (Log RBA <-3) for the S-allyl O-pentyl dithiocarbonate (CAS# 2956-12-9)
Dose descriptor:
other: QSAR model
Effect level:
< -3 other: Log RBA
Based on:
other: Estrogen receptor (ER) binding
Sex:
not specified
Basis for effect level:
other: No binding to Estrogen Receptor Alpha (Log RBA <-3) for the S-allyl O-pentyl dithiocarbonate (CAS#2956-12-9 )
Remarks on result:
other: Generation: QSAR model
Clinical signs:
no effects observed
Description (incidence and severity):
QSAR model
Mortality / viability:
no mortality observed
Description (incidence and severity):
QSAR model
Body weight and weight changes:
no effects observed
Description (incidence and severity):
QSAR model
Sexual maturation:
no effects observed
Description (incidence and severity):
QSAR model
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
QSAR model
Gross pathological findings:
no effects observed
Description (incidence and severity):
QSAR model
Histopathological findings:
no effects observed
Description (incidence and severity):
QSAR model
No binding to Estrogen Receptor Alpha (Log RBA <-3) for the S-allyl O-pentyl dithiocarbonate (CAS# 2956-12-9) and therefore S-allyl O-pentyl dithiocarbonate does not cause reproductive toxicity.
Remarks on result:
other: No binding to Estrogen Receptor Alpha (Log RBA <-3) for the Potassium O-pentyl dithiocarbonate (PAX) (CAS# 2720-73-2)
Reproductive effects observed:
not specified

No binding to Estrogen Receptor Alpha (Log RBA <-3) for the S-allyl O-pentyl dithiocarbonate (CAS# 2956-12-9) and therefore S-allyl O-pentyl dithiocarbonatedoes not cause reproductive toxicity.

Conclusions:
No binding to Estrogen Receptor Alpha (Log RBA <-3) for the S-allyl O-pentyl dithiocarbonate (CAS# 2956-12-9) and therefore S-allyl O-pentyl dithiocarbonatedoes not cause reproductive toxicity.
Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type
Type of information:
other: published data
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
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 416 (Two-Generation Reproduction Toxicity Study)
Deviations:
yes
Remarks:
Not all required organ weights were determined. - Sperm parameters were not assessed for all animals.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, Michigan, USA
- Age at study initiation: 6 weeks
- Weight at study initiation: ♂: 144-218 g, ♀: 117-174
Route of administration:
oral: feed
Vehicle:
other: diet
Details on mating procedure:
- M/F ratio: 1:1
- Length of cohabitation: Up to 15 days
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of gestation
- After 10 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- Any other deviations from standard protocol: Litters were culled to 8 pups/litter on lactation day 4.
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
F0 parents: from study initiation until scheduled sacrifice
F1 parents: from weaning (day 22) until scheduled sacrifice
F2 pups: from weaning (day 22) until scheduled sacrifice
Duration of exposure before mating (F0 / F1 parents): 10 weeks
Frequency of treatment:
Ad libitum
Remarks:
Doses / Concentrations:
0, 72, 210, or 540 ppm, equal to 0, 3, 10, or 25 mg/kg bw per day for males and 0, 5, 13, or 32 mg/kg bw per day for females.
Basis:
nominal in diet
No. of animals per sex per dose:
30
Control animals:
yes, plain diet
Details on study design:
- Actual doses
F0 ♂:
5, 15, 37 mg/kg/day (prior to breeding)
3, 10, 25 mg/kg/day (after breeding)

F0 ♀: 6, 17, 43 mg/kg/day (prior to breeding)
5, 13, 33 mg/kg/day (gestation)
12, 33, 85 mg/kg/day (lactation)
5, 15, 37 mg/kg/day (after weaning)

F1 ♂:
6, 18, 46 mg/kg/day (prior to breeding)
3, 10, 26 mg/kg/day (after breeding)

F1 ♀:
7, 20, 51 mg/kg/day (prior to breeding)
5, 13, 32 mg/kg/day (gestation)
11, 30, 79 mg/kg/day (lactation)
5, 14, 34 mg/kg/day (after weaning)
Positive control:
none
Parental animals: Observations and examinations:
MORTALITY
- Twice daily

CLINICAL SIGNS
- Twice daily

BODY WEIGHT
- Weekly during treatment and prior to terminal sacrifice for males.
- Confirmed mated ♀ were weighed on presumed gestation Days 0, 7, 10, 14, and 20. Nursing dams were weighed on Days 1, 4, 7, 14, and 21 post partum. After weaning (day 22) once weekly until scheduled sacrifice.

FOOD CONSUMPTION
- Daily until pairing for all animals.
- Male food consumption was measured after mating again daily until scheduled sacrifice.
- Female food consumption was measured daily throughout gestation and lactation period.
- No food consumption data was obtained during the mating period.
Oestrous cyclicity (parental animals):
- Daily during mating.
Sperm parameters (parental animals):
- Only performed on males which were paired, but failed to sire a litter.
Litter observations:
- Sex-determination, pup viability, body weight gain, clinical signs, necropsy on dead pups, behavioural testing (F2)
Postmortem examinations (parental animals):
ORGAN WEIGHTS
- Yes
- Organs: testes + epididymides/ovaries, brain, pituitary gland, kidneys, liver

HISTOPATHOLOGY
- All animals from control and high-dose group.
- Tissues: Cervix, coagulating gland, epididymides, kidneys, liver, ovaries, pituitary gland, prostate, seminal vesicles, testes, uterus, vagina, vas deferens, all internal gross lesions
Postmortem examinations (offspring):
- neuropathological examination (F2)
Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
F0 (♂+♀):
- Mean body weights and body weight gains in the 540 ppm group males were reduced early in the treatment period. In females mean body weights and body weight gains in the 540 ppm group were generally reduced throughout gestation and lactation and after weaning.
- Food consumption in the 540 ppm group was generally reduced in males and prior to breeding, during gestation and lactation and after weaning in females.
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: (post-breeding intake
Remarks on result:
other: Generation: maternal (migrated information)
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: (post-breeding intake
Remarks on result:
other: Generation: neonatal (migrated information)
Dose descriptor:
NOAEL
Effect level:
25 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: (post-breeding intake)
Remarks on result:
other: Generation: reproduction (migrated information)
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
F1 (♂+♀):
- Mean pup body weights in the 540 ppm group litters were slightly reduced during lactation. Mean body weights and body weight gains in the 540 ppm group males were reduced throughout the treatment period. In females mean body weights and body weight gains in the 540 ppm group were generally reduced throughout gestation and lactation and after weaning.
- Food consumption in the 540 ppm group was generally reduced in males and prior to breeding, during gestation and lactation and after weaning in females.
F2 (♂+♀):
- Mean pup body weights in the 540 ppm group litters were slightly reduced during lactation and throughout the remainder of the study until the postnatal day 70 neuropathology evaluation.
Reproductive effects observed:
not specified

Table 7.8.1-A1         Body weight changes in reproductive toxicity study

Parameter

Genera­tion

Controls

60 ppm

180 ppm

540 ppm

Dose-response

+/–

Body weight [g]

average weight on gestation
Day 14

F 0 dams

/

348.4

/

338.6

/

356.0

/

343.8

/

F 1 dams

/

357.1

/

339.1

/

344.7

/

316.7*

/

average pup weight on lactation Day 21

F 1 pups

44.8

42.8

44.6

41.8

46.3

43.5

40.2*

37.7*

F 2 pups

40.7

39.5

41.0

39.3

44.1

41.2

38.5

36.9

* statistically significant different from control p </= 0.05

 

Conclusions:
NOAEL for maternal toxicity was 210 ppm, equal to 10 mg/kg bw per day, on the basis of reduced food consumption and body-weight gain; that for neonatal toxicity was 210 ppm, equal to 10 mg/kg bw per day, on the basis of reduced body weight; and that for reproductive and developmental neurotoxicity was 540 ppm, equal to 25 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
Executive summary:

In a two-generation study of reproductive and developmental neurotoxicity, groups of 30 male and 30 female Crl:CD BR Sprague-Dawley rats were fed ziram at concentrations of 0, 72, 210, or 540 ppm, equal to 0, 3, 10, or 25 mg/kg bw per day for males and 0, 5, 13, or 32 mg/kg bw per day for females. The parental animals received thediets from about six weeks of age for the F0generation and on day 22 postnatally for the F1generation, for at least 70 days before matingand throughout all subsequent phases of the study until termination of  the generation. All animals were observed twice daily for appearance and behaviour. Body weights and food consumption were recorded at appropriate intervals. All females were allowed to deliver and rear their pups to weaning on lactation day 21. Offspring from the pairingof the F0animals (30 pups of each sex per group) were selected to constitute the F1generation. Thirty F2pups of each sex per group were selected for testing of developmental landmarks and behaviour, neuropathological examination, and brain weight measurement. Surplus F1pups were killed and necropsied on postnatal day 28, and surplus   F2pups were killed and necropsied on postnatal day 22. The F0and F1parental animals and selected F2pups that were not allocated for  measurements underwent detailed gross necropsy; and the weights of  the brain, kidneys, liver, pituitary gland, ovaries, or testes an epididymides (F0and F1only) were recorded. Designated tissues from the controls and from F0and F1parental animals at 540 ppm and F2 pups selected for neuropathological evaluation were evaluated for histopathological changes.

 

Reproductive parameters (fertility, mating, and days between pairing and coitus, gestation, and parturition) in the F0and F1generations were not adversely affected by concentrations of 72, 210,  or 540 ppm ziram. All F0and F1parental animals survived to the scheduled necropsies, and no adverse clinical signs attributable to treatment were observed. The mean body weights and body-weight gains of F0males at 540 ppm were reduced early in the treatment period, and the mean body weights and body-weight gains of F1males at 540 ppm were generally reduced. The mean body weights and body-weight gains of F0and F1females at 540 ppm were generally reduced before  breeding, during gestation and lactation, and after weaning.

No adverse effects were seen on the body weights or body-weight gains of animals in either generation at 72 or 210 ppm. The food consumption of F0and  F1males at 540 ppm was generally reduced throughout each generation. The food consumption of F0and F1females at 540 ppm was reduced before breeding, during gestation and lactation, and after weaning of   the F0and F2generations. No adverse effects on food consumption   were observed in males or females given ziram at concentrations of 72 and 210 ppm in either generation. No treatment-related, macroscopic internal changes were found in treated F0or F1animals, and no adverse effects on organ weights were observed at any dose. No microscopic lesions attributable to treatment were observed intissues from animals at 540 ppm on histopathological examination. Microscopic examination of gross lesions seen at the scheduled necropsies of animals at 540 ppm did not reveal any adverse effects.

 

 The mean body weights of F1and F2pups in the litters of animals at 540 ppm were slightly reduced (usually statistically   significantly) during lactation and throughout the remainder of the  study until postnatal day 70 (selected F2pups). The F1and F2pup   sex ratios, live litter sizes, number of dead pups on lactation day 0,  viability indices, general physical condition, and brain weight (selected F2pups) were not adversely affected by parental treatment at any concentration. The findings at necropsy of F1and F2pups that died or were killed at the scheduled postnatal necropsies did not   suggest any correlation with parental treatment. Various indicators of physical and functional development and behavioural responses in the selected F2pups were comparable to those in controls. Neuropathological examinations on postnatal days 11 and 70 showed no   gross or microscopic treatment-related lesions in the F2pups.

The NOAEL for maternal toxicity was 210 ppm, equal to 10 mg/kg bw per day, on the basis of reduced food consumption and body-weight gain; that  for neonatal toxicity was 210 ppm, equal to 10 mg/kg bw per day, on the basis of reduced body weight; and that for reproductive and developmental neurotoxicity was 540 ppm, equal to 25 mg/kg bw per day.

 

Endpoint:
fertility, other
Remarks:
based on test type
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:
Carbon disulphide (CAS number 75–15–0) is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, Carbon disulphide (CAS number 75–15–0) need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.
Qualifier:
no guideline followed
Principles of method if other than guideline:
The present study was performed to evaluate the endocrinologic and spermatogenic effects of CS2 exposure in the rat. Male rats were exposed to 600 ppm of CS2 for 6 hr/day for 5 days/week for 10 weeks. One week before exposure and at weeks 1,4,7, and 10, males were placed with ovariectomized, hormonally primed females, and copulatory behaviours were scored. Postcopulation, the females were killed and the ejaculate was recovered from the excised uterine tract along with the semen plug. Sperm counts, sperm motility, and morphology were determined.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Long-Evans
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratory (Wilmington, Mass).
- Age at study initiation: (P) 120 days
- Housing: singly, in stainless stell hanging cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
not specified
Vehicle:
unchanged (no vehicle)
Details on mating procedure:
One week prior to exposure and at weeks 1,4,7, and 10, males were placed with ovariectomized, hormonally primed females, and copulatory behaviors were scored. Fifteen minutes postcopulation, the female was killed and the ejaculate was recovered from the excised uterine tract along with the semen plug. Sperm counts, sperm motility, and morphology were determined.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Monitored by a Baselin gas chromatograph
Duration of treatment / exposure:
6 h/d for 10 w
Frequency of treatment:
daily, 5 d/w
Remarks:
Doses / Concentrations:
0, 1870 mg/m3 (0, 600 ppm)
Basis:
nominal conc.
No. of animals per sex per dose:
24
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: a dose that does not exert neurotoxic effects was chosen; additionally, according to pilot experiments no effects were seen at 350 ppm, while at 900 ppm reduced body weight gains were recorded.
Positive control:
no
Parental animals: Observations and examinations:
A blood sample was collected for analyses of testosterone, follicle-stimulating (FSH), and luteinizing hormone (LH). At the end of the 10th week, five animals from each group were treated with either human chorionic gonadotropin (HCG, 50 IU/animal, iv) or gonadotropin-releasing hormone (GnRH, 100 ng/animalt iv), and the testosterone or gonadotropin responses were recorded over time.
Oestrous cyclicity (parental animals):
not examined, only males were tested
Sperm parameters (parental animals):
Parameters examined in male parental animals:
Sperm counts, sperm motility, and spem morphology
Litter observations:
not examined
Postmortem examinations (parental animals):
Animals were killed and one epididymis and testis were taken for histologic examination. The other epididymiswas used for determinationof sperm count. In addition to the mated animals, 10 more control and CS2-exposed non-mated animals were maintained. The animals were killed after 10 weeks of exposure and thereafter, reproductive organs were excised and weighed.
Postmortem examinations (offspring):
not examined
Statistics:
A repeated measures analysis of variance with one between factor (dose) and one within factor (weeks) was applied to the analyses of body weight, copuiatory behaviors, and sperm parameters. All significant effects were further tested by the method of Least Squares Difference (Kirk, 1968). Significance levels were set at p < 0.05 for all comparisons.
Offspring viability indices:
not examined
Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
effects observed, treatment-related
Reproductive performance:
effects observed, treatment-related
A decrease in body weight gain was observed between exposure weeks 4 to 10, that was significant in week 10.

Mount and intromission data exhibited marked variability. In general mount latency gave a decreasing trend, being signifcantly different from controls in week 10. Ejaculation latency was significantly different during weeks 4 to 10.

CS2 exposed rats elicited significant depressions on sperm counts in weeks 7 and 10, compared to controls. Motility decreased in both groups, but no significant effects were observed. 'Analysis of semen plug weights revealed significant effects (p≤ 0.05) resulting from a greater increase in absolute plug weights in the controls over weeks compared to the CS2-exposed group. This difference was not significant when analyzed as "percentage-change from baseline".

Regarding the levels of testosterone, FSH and LSH, there were no CS2-induced changes. A normal increase in FSH and LSH, following injection of GnRH and a normal increase in testosterone levels, following injection of HCG, was detected.

No CS2-exposure related effects were seen in the histopathological examinations of the epididymis and testis, as well as in the sperm counts obtained from the cauda epididymis. Regarding to the organ/body weigh ratios, the only change observed was a decrease in prostate weight.
Dose descriptor:
LOAEC
Effect level:
600 ppm
Based on:
test mat.
Sex:
male
Basis for effect level:
other: effects on the copulatory behaviour of animals; decreased mount and ejaculation latencies; decreased sperm count in the ejaculate
Dose descriptor:
LOAEC
Effect level:
1 870 mg/m³ air
Based on:
test mat.
Sex:
male
Basis for effect level:
other: effects on the copulatory behaviour of animals; decreased mount and ejaculation latencies; decreased sperm count in the ejaculate
Clinical signs:
not examined
Mortality / viability:
not examined
Body weight and weight changes:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
not examined
Remarks on result:
not measured/tested
Reproductive effects observed:
not specified
Conclusions:
In the present study, exposure of rats to CS2 via inhalation, exerted effects on the copulatory behaviours of the animals, characterized by decreased mount and ejaculation lattencies, as well as decreases in sprem counts in the ejaculate. Exposed rats had significantly reduced weight gains during the experiment. However, the authors suggest these changes were not due a direct effect of CS2 on the testis of the animals.
Carbon disulphide (CAS number 75–15–0) is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, Carbon disulphide (CAS number 75–15–0) need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.
Executive summary:

Male Long-Evans rats were exposed to CS2 via inhalation for 6 h/d, 5 d/w for 10 consecutive weeks, in a concentration of 1870 mg/m3 (600 ppm). One week prior to exposure and at weeks 1,4,7, and 10, males were placed with ovariectomized, hormonally primed females, and copulatory behaviors were scored. Postcopulation, the female was killed and the ejaculate was recovered from the excised uterine tract along with the semen plug. Sperm counts, sperm motility, and morphology were determined. A blood sample was obtained for analyses of testosterone, follicle-stimulating (FSH), and luteinizing hormone (LH). At the end of the 10th week, five animals in each group were challenged with either human chorionic gonadotropin (HCG, 50 IU/animal) or gonadotropin-releasing hormone (GnRH, 100 ng/animal), and the testosterone or gonadotropin responses were monitored over time. Animals were killed with one epididymis and testis processed for histology and a sperm count determined from the other epididymis. Animals appeared to be in good health and the only indication of systemic toxicity was a small reduction in body weight gain. Decreased mount and ejaculation lattencies, as well as depression of sperm counts in the ejaculate, indicate effects on the mating behaviour patterns. Nonetheless, the authors suggest that the decreased amounts of ejaculated sperm is due to alteration in the sperm production in the testes or sperm maintenance in the epididymides. This is also supported by the absence of histological lesions in these tissues. The findings imply that at this dose level CS2 does not exert a direct effect on the testis, but it may interfere with processes which regulate the sperm transport and the ejaculate.

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type
Type of information:
other: published data
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
Justification for type of information:
Carbon disulphide (CAS number 75–15–0) is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, Carbon disulphide (CAS number 75–15–0) need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.
Qualifier:
no guideline followed
Principles of method if other than guideline:
A non-standard test, providing information on CS2 reproductive/developmental toxicity. Pregnant rats were exposed in utero to CS2 vapours. Half of the animals were allowed to litter and a representative number of F1 generation was reared until maturity. Thereafter, they were mated within the experimental groups and produced F2 generation. Fertility of F1 generation was investigated, as well as developmental effects on F2 feneration.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 180 g
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
not specified
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
not specified
Remarks:
Doses / Concentrations:
0, 50, 100, 200 mg/m3 (16, 32, 63 ppm)
Basis:
nominal conc.
No. of animals per sex per dose:
32
Control animals:
yes
Details on study design:
no data
Parental animals: Observations and examinations:
SACRIFICE
Out of the total 32 animals tested, half were killed at the end of exposure, and the other half after delivery.
Offspring viability indices:
viability index: (pups alive on 4th day/pups alive on birth)*100, lactation index: (pups alive on 21st day/pups aline on 4th day)*100, development index: (pups alive on 45th day/pups alive on 21st day)*100
Clinical signs:
not examined
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
not examined
Other effects:
not examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, treatment-related
F0: remarkable increase in preimplantation losses at 32 and 63 ppm, although it was significant only at the highest concentration.
Dose descriptor:
NOAEC
Effect level:
32 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: number of implantation sites
Clinical signs:
not examined
Mortality / viability:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
F1 GENERATION/developmental effects
BODY WEIGHT (FETUS): significantly decreased at 32 and 63 ppm
Dose-related malformations were noted in the F1 generation, which were statistically significant at 32 and 63 ppm. The most often malformations were hydrocephalus (14.2 & 17.5%) and club foot (11.9 & 19.2%), followed by tail deformations. Oedema (6.4%) and hypognathia (6.4%) were noted only after exposure at 63 ppm (data taken from a table provided in the publication).

Histological examinations showed mild parenchymatous dystrophy and reduced glycogen content of the hepatic cells of the fetuses exposed in utero to 63 ppm. In the kidney, liver and brain tissues the consumption of O2 appeared increased. However, these results are only based on the description of the authors; no tables or figures are given in the publication. Assessment of these data is difficult.

Behavorial test results showed reduced exploratory activity and increased emotional activity, more marked in females. The findings were 90th day of life. However, these results are only based on the description of the authors; no tables or figures are given in the publication. Assessment of these data is difficult.

An impairement of viability was seen by the indices at 63 ppm (73.8%)
Dose descriptor:
NOAEC
Generation:
F1
Effect level:
16 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: fetal body weight; malformations of the offspring
Dose descriptor:
NOAEC
Generation:
F1
Effect level:
63 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: reproductive capacity
Dose descriptor:
NOAEC
Generation:
F2
Effect level:
16 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: malformations of the offspring
Reproductive effects observed:
not specified

F1 GENERATION/effects on fertility The results are reproduced here based on the description of the authors. However, no tables or figures are provided on the publication for this part: 'No impairment of the reproductive capacity of F1 was found. Ratios of fertilized to mated females and of pregnant to fertilised females in the test groups did not differ from those of the controls. No increase of pre- and postimplantation lethality and no reduction of foetal weight of F2 generation were noted. Examination of F2 foetuses, however, revealed congenital malformations of the same type and incidence as those observed in the previous generation. Postnatally, statistically significant behavioral changes similar to those registered in F1 were found in all test groups'.

Conclusions:
In utero exposure to CS2 at 32 and 63 ppm, resulted in preimplantation losses in the F0 (parents) animals and in malformations if the offspring of the F1 generation. Fertility of F1 animals, and fetal body weights of F2 animals were not affected. However, teraotegenic effects of the same type and incidence of F1 generation, were also noted in F2.
Carbon disulphide (CAS number 75–15–0) is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, Carbon disulphide (CAS number 75–15–0) need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.
Executive summary:

What follows is the original abstract of the publication

Pregnant albino rats were exposed to carbon disulphide vapour in concentrations of 50, 100 or 200 mg/m3 throughout gestation. Two successive generations (F1 and F2) were studied. Concentration levels of 100 and 200 mg/m3 produced marked dose-related impairment in the prenatal development of the F1 progeny, with increase of early embryonal lethality, reduction in foetal weight and a high incidence of malformations affecting mostly the brain and limbs. Postnatal viability, body weight, lipid and energy metabolism and behaviour were also impaired. Behavioral deviations were observed even at 50 mg/m3. After reaching sexual maturity the F1 rats were mated within their experimental groups, but no further carbon disulphide exposure was applied. The adverse effects on progeny were still detectable in the F2 generation. Structural abnormalities of the same type as those found in the F1 at 100 and 200 mg/m3 exposure were observed in their progeny and, postnatally, statistically significant behavioral changes were observed in the progeny of all test groups.

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
other: 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: MCASE/MC4PC is a knowledge-based system designed by MultiCASE, Inc. and further developed with the Informatics and Computational Safety Analysis Staff (ICSAS) of the US FDA to reveal the relationship between the structure of a chemical and its activity in a specific biological assay. This method is relevant for reproductive toxicity endpoints in rodentss.
Qualifier:
according to
Guideline:
other: MULTICASE AO1-AO7 FDA Reproductive toxicity in adult males
Principles of method if other than guideline:
Multicase
MCASE/MC4PC is a knowledge-based system designed by MultiCASE, Inc. and further developed with the Informatics and Computational Safety Analysis Staff (ICSAS) of the US FDA to reveal the relationship between the structure of a chemical and its activity in a specific biological assay (Klopman et al., 2005). MC4PC, and the predecessor software CASE (Computer Automated Structure Evaluation), were designed to find structural fragments that discriminate between active and inactive molecules, and the backbone of the software is based on the hypothesis that a relationship does exist between chemical structure and activity. Together with the ICSAS, human expert rules were developed to enhance the performance of the MC4PC quantitative structure activity relationship (SAR) software program, which reduces chemicals to 2 - 10 atom fragments and sorts the fragments in relation to biological activity or toxicity (structural alerts), lists the structural alerts linked to a query compound, and lists the structures, names, and activity of compounds in the database that are related to the query substance. The program automatically identifies molecular substructures that have a high probability of being relevant or responsible for an observed toxicological effect from a learning set containing both active and inactive molecules of diverse structure. The program selects its own descriptors from a number of possible sub-structural units and creates a dictionary of molecular descriptors. The selected descriptors are characterized either as activating (biophore) or inactivating (biophobe).

GLP compliance:
no
Remarks:
not applicable. QSAR model
Limit test:
no
Species:
other: rodent, rat and mouse
Strain:
other: QSAR model
Sex:
male
Route of administration:
other: QSAR model
Vehicle:
other: QSAR model
Analytical verification of doses or concentrations:
not specified
Remarks:
Doses / Concentrations:

Basis:
other: QSAR model
Control animals:
not specified
Clinical signs:
no effects observed
Description (incidence and severity):
QSAR model
Body weight and weight changes:
no effects observed
Description (incidence and severity):
QSAR model
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
QSAR model
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
QSAR model
Other effects:
no effects observed
Description (incidence and severity):
Test substance intake: QSAR model
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
QSAR model
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
QSAR model
Reproductive performance:
no effects observed
Description (incidence and severity):
QSAR model
The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and therefore S-allyl O-pentyl dithiocarbonate does not cause reproductive toxicity.The probability that the prediction is accurate is 80%.
Dose descriptor:
other: RP_AO1 , RP_AO4 , RP_AO7
Effect level:
80 other: % The probability that the prediction is accurate is 80%.
Based on:
other: RP_AO1 Fertility in males, rodent, RP_AO4 Fertility in males, rat, RP_AO7and Fertility in males, mouse
Sex:
not specified
Basis for effect level:
other: see 'Remark'
Remarks on result:
other: Generation: QSAR model
Clinical signs:
no effects observed
Description (incidence and severity):
QSAR model
Mortality / viability:
no mortality observed
Description (incidence and severity):
QSAR model
Body weight and weight changes:
no effects observed
Description (incidence and severity):
QSAR model
Sexual maturation:
no effects observed
Description (incidence and severity):
QSAR model
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
QSAR model
Gross pathological findings:
no effects observed
Description (incidence and severity):
QSAR model
Histopathological findings:
no effects observed
Description (incidence and severity):
QSAR model
The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and therefore S-allyl O-pentyl dithiocarbonate does not cause reproductive toxicity.The probability that the prediction is accurate is 80%.
Remarks on result:
other: The tested molecule does not contain any confirmed alerts and is assumed to be inactive. The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation
Reproductive effects observed:
not specified

Table 1. Reproductive toxicity in male adult rodents

Compound

AO1

AO2

AO3

RCA Method Expert Call (Overall)

Review expert

O-pentyl dithiocarbonic acid/Carbonodithioic acid, o-pentyl S-2-propenyl ester

-

-

-

-*

-

 

Table 2. Reproductive toxicity in male adult rats

Compound

AO4

AO5

AO6

RCA Method Expert Call (Overall)

Review expert

O-pentyl dithiocarbonic acid/Carbonodithioic acid, o-pentyl S-2-propenyl ester

-

-

-

-*

-

 

Table 3. Reproductive toxicity in male adult mice

Compound

AO7

RCA Method Expert Call (Overall)

Review expert

O-pentyl dithiocarbonic acid/Carbonodithioic acid, o-pentyl S-2-propenyl ester

+

?*

-

The probability that the prediction is accurate is 80%.

Conclusions:
The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and therefore S-allyl O-pentyl dithiocarbonate does not cause reproductive toxicity.
Endpoint:
screening for reproductive / developmental toxicity
Remarks:
other: QSAR model (MC4PC version 2.4.1.5)
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: MCASE/MC4PC is a knowledge-based system designed by MultiCASE, Inc. and further developed with the Informatics and Computational Safety Analysis Staff (ICSAS) of the US FDA to reveal the relationship between the structure of a chemical and its activity in a specific biological assay. This method is relevant for reproductive toxicity endpoints in rodentss.
Qualifier:
according to
Guideline:
other: MULTICASE AN1-AN9 FDA Reproductive toxicity in females set
Principles of method if other than guideline:
Multicase
MCASE/MC4PC is a knowledge-based system designed by MultiCASE, Inc. and further developed with the Informatics and Computational Safety Analysis Staff (ICSAS) of the US FDA to reveal the relationship between the structure of a chemical and its activity in a specific biological assay (Klopman et al., 2005). MC4PC, and the predecessor software CASE (Computer Automated Structure Evaluation), were designed to find structural fragments that discriminate between active and inactive molecules, and the backbone of the software is based on the hypothesis that a relationship does exist between chemical structure and activity. Together with the ICSAS, human expert rules were developed to enhance the performance of the MC4PC quantitative structure activity relationship (SAR) software program, which reduces chemicals to 2 - 10 atom fragments and sorts the fragments in relation to biological activity or toxicity (structural alerts), lists the structural alerts linked to a query compound, and lists the structures, names, and activity of compounds in the database that are related to the query substance. The program automatically identifies molecular substructures that have a high probability of being relevant or responsible for an observed toxicological effect from a learning set containing both active and inactive molecules of diverse structure. The program selects its own descriptors from a number of possible sub-structural units and creates a dictionary of molecular descriptors. The selected descriptors are characterized either as activating (biophore) or inactivating (biophobe).

GLP compliance:
no
Remarks:
not applicable. QSAR model
Limit test:
no
Species:
other: rodent, rat and mouse
Strain:
other: QSAR model
Sex:
female
Route of administration:
other: QSAR model
Vehicle:
other: QSAR model
Analytical verification of doses or concentrations:
not specified
Remarks:
Doses / Concentrations:

Basis:
other: QSAR model
Control animals:
not specified
Clinical signs:
no effects observed
Description (incidence and severity):
QSAR model
Body weight and weight changes:
no effects observed
Description (incidence and severity):
QSAR model
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
QSAR model
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
QSAR model
Other effects:
no effects observed
Description (incidence and severity):
Test substance intake: QSAR model
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
QSAR model
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
QSAR model
Reproductive performance:
no effects observed
Description (incidence and severity):
QSAR model
The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and therefore S-allyl O-pentyl dithiocarbonatedoes not cause reproductive toxicity.The probability that the prediction is accurate is 80%.
Dose descriptor:
other: RP_AN1,RP_AN5,RP_AN9
Effect level:
80 other: % The probability that the prediction is accurate is 80%.
Based on:
other: RP_AN1Fertility in females, rodent,RP_AN5 Fertility in females, rat, RP_AN9 Fertility in females, mouse
Sex:
not specified
Basis for effect level:
other: see 'Remark'
Remarks on result:
other: Generation: QSAR model
Clinical signs:
no effects observed
Description (incidence and severity):
QSAR model
Mortality / viability:
no mortality observed
Description (incidence and severity):
QSAR model
Body weight and weight changes:
no effects observed
Description (incidence and severity):
QSAR model
Sexual maturation:
no effects observed
Description (incidence and severity):
QSAR model
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
QSAR model
Gross pathological findings:
no effects observed
Description (incidence and severity):
QSAR model
Histopathological findings:
no effects observed
Description (incidence and severity):
QSAR model
The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and therefore S-allyl O-pentyl dithiocarbonate does not cause reproductive toxicity.The probability that the prediction is accurate is 80%.
Remarks on result:
other: The tested molecule does not contain any confirmed alerts and is assumed to be inactive. The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation
Reproductive effects observed:
not specified

Table 7. Reproductive toxicity in female adult rodents

Compound

AN1

AN2

AN3

AN4

RCA Method Expert Call (Overall)

Review expert

 

O-pentyl dithiocarbonic acid/Carbonodithioic acid, o-pentyl S-2-propenyl ester

 

-

-

-

-

-*

-

 

Table 8. Reproductive toxicity in female adult rats

Compound

AN5

AN6

AN7

AN8

RCA Method Expert Call (Overall)

Review expert

 

O-pentyl dithiocarbonic acid/Carbonodithioic acid, o-pentyl S-2-propenyl ester

 

-

-

-

-

-*

-

 

Table 9. Reproductive toxicity in female adult mice

Compound

AN9

RCA Method Expert Call (Overall)

Review expert

 

O-pentyl dithiocarbonic acid/Carbonodithioic acid, o-pentyl S-2-propenyl ester

 

-

-*

-

The probability that the prediction is accurate is 80%.

Conclusions:
The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and therefore S-allyl O-pentyl dithiocarbonate does not cause reproductive toxicity.
Endpoint:
fertility, other
Remarks:
based on test type
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:MCASE/MC4PC is a knowledge-based system designed by MultiCASE, Inc. and further developed with the Informatics and Computational Safety Analysis Staff (ICSAS) of the US FDA to reveal the relationship between the structure of a chemical and its activity in a specific biological assay. This method is relevant for reproductive toxicity endpoints in rodentss.
Qualifier:
according to
Guideline:
other: MULTICASE AP1-AP7 Sperm toxicity,mammal,rat,mouse
Principles of method if other than guideline:
Multicase
MCASE/MC4PC is a knowledge-based system designed by MultiCASE, Inc. and further developed with the Informatics and Computational Safety Analysis Staff (ICSAS) of the US FDA to reveal the relationship between the structure of a chemical and its activity in a specific biological assay (Klopman et al., 2005). MC4PC, and the predecessor software CASE (Computer Automated Structure Evaluation), were designed to find structural fragments that discriminate between active and inactive molecules, and the backbone of the software is based on the hypothesis that a relationship does exist between chemical structure and activity. Together with the ICSAS, human expert rules were developed to enhance the performance of the MC4PC quantitative structure activity relationship (SAR) software program, which reduces chemicals to 2 - 10 atom fragments and sorts the fragments in relation to biological activity or toxicity (structural alerts), lists the structural alerts linked to a query compound, and lists the structures, names, and activity of compounds in the database that are related to the query substance. The program automatically identifies molecular substructures that have a high probability of being relevant or responsible for an observed toxicological effect from a learning set containing both active and inactive molecules of diverse structure. The program selects its own descriptors from a number of possible sub-structural units and creates a dictionary of molecular descriptors. The selected descriptors are characterized either as activating (biophore) or inactivating (biophobe).

GLP compliance:
no
Remarks:
not applicable. QSAR model
Limit test:
no
Species:
other: rodent, rat and mouse
Strain:
other: QSAR model
Sex:
male
Route of administration:
other: QSAR model
Vehicle:
other: QSAR model
Analytical verification of doses or concentrations:
not specified
Remarks:
Doses / Concentrations:

Basis:
other: QSAR model
Control animals:
not specified
Clinical signs:
no effects observed
Description (incidence and severity):
QSAR model
Body weight and weight changes:
no effects observed
Description (incidence and severity):
QSAR model
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
QSAR model
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
QSAR model
Other effects:
no effects observed
Description (incidence and severity):
Test substance intake: QSAR model
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
QSAR model
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
QSAR model
Reproductive performance:
no effects observed
Description (incidence and severity):
QSAR model
The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and therefore S-allyl O-pentyl dithiocarbonate does not cause reproductive toxicity.The probability that the prediction is accurate is 80%.
Dose descriptor:
other: RP_AP1,RP_AP4,RP_AP7
Effect level:
80 other: % The probability that the prediction is accurate is 80%.
Based on:
other: RP_AP1Sperm toxicity, mammal,RP_AP4 Sperm toxicity, rat,RP_AP7 Sperm toxicity, mouse
Sex:
not specified
Basis for effect level:
other: see 'Remark'
Remarks on result:
other: Generation: QSAR model
Clinical signs:
no effects observed
Description (incidence and severity):
QSAR model
Mortality / viability:
no mortality observed
Description (incidence and severity):
QSAR model
Body weight and weight changes:
no effects observed
Description (incidence and severity):
QSAR model
Sexual maturation:
no effects observed
Description (incidence and severity):
QSAR model
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
QSAR model
Gross pathological findings:
no effects observed
Description (incidence and severity):
QSAR model
Histopathological findings:
no effects observed
Description (incidence and severity):
QSAR model
The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and therefore S-allyl O-pentyl dithiocarbonate does not cause reproductive toxicity.The probability that the prediction is accurate is 80%.
Remarks on result:
other: The tested molecule does not contain any confirmed alerts and is assumed to be inactive. The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation
Reproductive effects observed:
not specified

Table 4. Sperm toxicity in male adult rodents

Compound

AP1

AP2

AP3

RCA Method Expert Call (Overall)

Review expert

O-pentyldithiocarbonic acid/Carbonodithioic acid, o-pentyl S-2-propenyl ester

 

-

-

-

-*

-

 

Table 5. Sperm toxicity in male adult rats

Compound

AP4

AP5

AP6

RCA Method Expert Call (Overall)

Review expert

O-pentyldithiocarbonic acid/Carbonodithioic acid, o-pentyl S-2-propenyl ester

 

-

-

-

-*

-

 

Table 6. Sperm toxicity in male adult mice

Compound

AP7

RCA Method Expert Call (Overall)

Review expert

O-pentyldithiocarbonic acid/Carbonodithioic acid, o-pentyl S-2-propenyl ester

 

-

-*

-

The probability that the prediction is accurate is 80%.

Conclusions:
The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and thereforeS-allyl O-pentyl dithiocarbonate does not cause reproductive toxicity.
Endpoint:
screening for reproductive / developmental toxicity
Remarks:
other: 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: MCASE/MC4PC is a knowledge-based system designed by MultiCASE, Inc. and further developed with the Informatics and Computational Safety Analysis Staff (ICSAS) of the US FDA to reveal the relationship between the structure of a chemical and its activity in a specific biological assay. This method is relevant for reproductive toxicity endpoints in rodentss.
Qualifier:
according to
Guideline:
other: MULTICASE AQ1-AQ9 Newborn behavioral toxicity, rodent,rat,mouse
Principles of method if other than guideline:
Multicase
MCASE/MC4PC is a knowledge-based system designed by MultiCASE, Inc. and further developed with the Informatics and Computational Safety Analysis Staff (ICSAS) of the US FDA to reveal the relationship between the structure of a chemical and its activity in a specific biological assay (Klopman et al., 2005). MC4PC, and the predecessor software CASE (Computer Automated Structure Evaluation), were designed to find structural fragments that discriminate between active and inactive molecules, and the backbone of the software is based on the hypothesis that a relationship does exist between chemical structure and activity. Together with the ICSAS, human expert rules were developed to enhance the performance of the MC4PC quantitative structure activity relationship (SAR) software program, which reduces chemicals to 2 - 10 atom fragments and sorts the fragments in relation to biological activity or toxicity (structural alerts), lists the structural alerts linked to a query compound, and lists the structures, names, and activity of compounds in the database that are related to the query substance. The program automatically identifies molecular substructures that have a high probability of being relevant or responsible for an observed toxicological effect from a learning set containing both active and inactive molecules of diverse structure. The program selects its own descriptors from a number of possible sub-structural units and creates a dictionary of molecular descriptors. The selected descriptors are characterized either as activating (biophore) or inactivating (biophobe).

GLP compliance:
no
Remarks:
not applicable. QSAR model
Limit test:
no
Species:
other: rodent, rat and mouse
Strain:
other: QSAR model
Sex:
male
Route of administration:
other: QSAR model
Vehicle:
other: QSAR model
Analytical verification of doses or concentrations:
not specified
Remarks:
Doses / Concentrations:

Basis:
other: QSAR model
Control animals:
not specified
Clinical signs:
no effects observed
Description (incidence and severity):
QSAR model
Body weight and weight changes:
no effects observed
Description (incidence and severity):
QSAR model
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
QSAR model
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
QSAR model
Other effects:
no effects observed
Description (incidence and severity):
Test substance intake: QSAR model
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
QSAR model
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
QSAR model
Reproductive performance:
no effects observed
Description (incidence and severity):
QSAR model
The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and therefore S-allyl O-pentyl dithiocarbonate does not cause reproductive toxicity.The probability that the prediction is accurate is 80%.
Dose descriptor:
other: RP_AQ1,RP_AQ4,RP_AQ9
Effect level:
80 other: % The probability that the prediction is accurate is 80%.
Based on:
other: RP_AQ1 Newborn behavioral toxicity, rodent,RP_AQ4 Newborn behavioral toxicity, rat,RP_AQ9 Newborn behavioral toxicity, mouse
Sex:
not specified
Basis for effect level:
other: see 'Remark'
Remarks on result:
other: Generation: QSAR model
Clinical signs:
no effects observed
Description (incidence and severity):
QSAR model
Mortality / viability:
no mortality observed
Description (incidence and severity):
QSAR model
Body weight and weight changes:
no effects observed
Description (incidence and severity):
QSAR model
Sexual maturation:
no effects observed
Description (incidence and severity):
QSAR model
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
QSAR model
Gross pathological findings:
no effects observed
Description (incidence and severity):
QSAR model
Histopathological findings:
no effects observed
Description (incidence and severity):
QSAR model
The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and therefore S-allyl O-pentyl dithiocarbonate does not cause reproductive toxicity.The probability that the prediction is accurate is 80%.
Remarks on result:
other: The tested molecule does not contain any confirmed alerts and is assumed to be inactive. The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation
Reproductive effects observed:
not specified

Table 10.Newborn behavioral toxicity, rodent

Compound

AQ1

AQ2

AQ3

RCA Method Expert Call (Overall)

Review expert

O-pentyldithiocarbonic acid/Carbonodithioic acid, o-pentyl S-2-propenyl ester

 

-

-

-

-*

-

 

Table 11.Newborn behavioral toxicity, rat

Compound

AQ4

AQ5

AQ6

RCA Method Expert Call (Overall)

Review expert

O-pentyldithiocarbonic acid/Carbonodithioic acid, o-pentyl S-2-propenyl ester

 

-

-

-

-*

-

 

Table 12.Newborn behavioral toxicity, mouse

Compound

AQ7

RCA Method Expert Call (Overall)

Review expert

O-pentyldithiocarbonic acid/Carbonodithioic acid, o-pentyl S-2-propenyl ester

 

-

-*

-

The probability that the prediction is accurate is 80%.

Conclusions:
The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and therefore S-allyl O-pentyl dithiocarbonate does not cause reproductive toxicity.
Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
89.36 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
 The inhalation dose for the rat is converted to the oral dose using a standard breathing volume for the rat (1.15 m3/kg for 24 hours exposure.The resulting air concentration needs to be firstly corrected for 24 hlight activity (20 m3), assuming 100 % absorption for both routes.
 corrected oral NOAEL=   inhalationNOAEL
  (1554 mg/m3  ÷20m3/rat) x 1.15 m3/kg bw =89.36 mg/kg bw/day
  NOAELrat  = 89.36 mg/kg bw/day
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
1 554 mg/m³
Study duration:
subacute
Species:
rat
Effect on fertility: via dermal route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2.23 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
For dermal exposure we taken that:
-the average weight of rats is 250g (200-300g),
-the dose is applied over an area which is approximately 10% of the total body surface=0.025 kg
 corrected dermal NOAEL=   oral NOAEL
89.36 mg/kg bw/day x 0.025 kg =                  
 NOAELrat  = 2.23 mg/kg bw/day
Additional information

Oral exposure

 The inhalation dose for the rat is converted to the oral dose using a standard breathing volume for the rat (1.15 m3/kg for 24 hours exposure.The resulting air concentration needs to befirstly corrected for 24 hlight activity (20 m3), assuming 100 % absorption for both routes.

 

corrected oral NOAEL=   inhalationNOAEL

  (1554 mg/m3  ÷20m3/rat) x 1.15 m3/kg bw =89.36 mg/kg bw/day

            

 NOAELrat  = 89.36 mg/kg bw/day

Dermal exposure:

For dermal exposure we taken that:

-the average weight of rats is 250g (200-300g),

-the dose is applied over an area which is approximately 10% of the total body surface=0.025 kg

 corrected dermal NOAEL=   oral NOAEL

89.36 mg/kg bw/day x 0.025 kg =                  

 NOAELrat  = 2.23 mg/kg bw/day

Inhalation exposure:

 

Based on the results in the study of WIL Research Laboratories, Inc. 1992, the NOAEC for maternal toxicity and neonatal toxicity was considered to be 250 ppm (777 mg/m3), while the NOAEC for reproduction toxicity was 500 ppm (1554 mg/m3).

 

 Short description of key information: 

 

There are conclusive but not suffcient data for the classification of substance S-allyl O-pentyl dithiocarbonate with regard to reproduction. Non-ER binder due to non-cyclic molecular structure. S-allyl O-pentyl dithiocarbonate have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore S-allyl O-pentyl dithiocarbonate does not cause reproductive toxicity. It is concluded that the substance S-allyl O-pentyl dithiocarbonate does not meet the criteria to be classified for human health hazards for Reproductive toxicity

Effects on developmental toxicity

Description of key information

There are conclusive but not suffcient data for the classification of substance S-allyl O-pentyl dithiocarbonate with regard to Developmental toxicity / teratogenicity.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
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:
no guideline followed
Principles of method if other than guideline:
The test substance was administered at dose levels of 31.25, 64.2, 125 and 250 mg/kg bw/day as suspension in olive oil to groups of pregnant Wistar rats (21-23 animals/group) during days 7 to 15 of gestation. On gestation day 20, 14 rats from the control and high dose groups and 15 rats from the other test groups were opened under anesthesia to inspect the uterus, number of corpora lutea, number of inplants, sex ratio and number of live and dead fetuses. The other rats from each group were allowed to give natural birth, and post-natal development of the pups was examined. The assessed parameters were number of pups, mortality rate, outward abnormalities, skeletal and soft tissue abnormalities and body weight, as well as ear auricle extension, tooth bud collapse or emergence, fur emergence, eyelid opening and timing for testes descent and vagina opening. Pups were allowed to wean and the observation continued till age 10 weeks, after which animals were sacrificed and gross pathological and organ weight examinations were performed.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Japan
- Age at study initiation: females 12 weeks, males 14 weeks
- Housing: singly in aluminum pregnancy cages (Natsume Seisakusho)
- Diet: solid feed pellets (Oriental Yeast Co., MF), ad libitum
- Water: tap water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 25±1
- Humidity (%): 55±5
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light):
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: using an ultrasonic disintegrator (360W, 5 minutes) as a 20% suspension fluid in olive oil (The Japanese Pharmacopoeia).
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 2 / 5
- Length of cohabitation: overnight
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
During days 7-15 of gestation
Frequency of treatment:
Once daily
Duration of test:
Until gestation day 20 or natural labor; naturally born pups were observed until age of 10 weeks
No. of animals per sex per dose:
21-23 females/dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on the dose-range finding study
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION : Yes / No / No data
- Time schedule for examinations: daily


OTHER: spleen weights of pregnant dams were examined
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: sex ratio
Fetal examinations:
- External examinations: Yes: [all per litter ]
- Soft tissue examinations: Yes: [ca. 1/3 per litter ]
- Skeletal examinations: Yes: [ca. 2/3 per litter ]
- Head examinations: No
Statistics:
x2 test (death rate of dams), the t test (dam body weight, feed intake volume, number of corpora lutea, implant number and spleen weight, fetus number and weight, and the newborn number, body weight, and weight of important organs), and the rank sum test (fetus death rate, frequency of malformations, number of bone variations, delivery rate, suckling rate, and survival rate of newborns)
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
The 31.25 and 62.5mg/kg groups showed the same body weight increases as the control group, and no abnormalities in the normal state were seen, nor were there any examples of deaths. In the 125mg/kg group, while no change in the average weight trend was seen, minor cases of diarrhea were observed in 5 rats out of 22 rats from the 6th day after start of administration (gestation day 12) through the 8th day (gestation day 14). In the 250 mg/kg group, minor suppression of body weight increase was seen from the 2nd day after start of administration (gestation day 8), and in all cases piloerection, diarrhea, bleeding around the eyes, and debilitation were observed, with 7 rats out of 21 dying between gestation day 9 and day 13. The pregnant rats that avoided death continued to show minor suppression of body weight increase even after administration was ended.
A drop in feed intake volume was seen for the control group and for each of the ZDEC groups on the 2nd day after the start of administration (gestation day 8). The feed intake volume during the gestation period for the groups at 125 mg/kg and lower showed no major difference when compared with the control group. In the 250 mg/kg group, the feed intake volume was lower than the control group from the 2nd day after start of administration (gestation day 8) through the 6th day (gestation day 12). From the 7th day of administration, however, it showed generally the same trend as the control group.
Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
62.5 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No significant differences were found in the number of corpora lutea, implantations sites, implantation rates, live and dead fetuses, sex ratio and fetus weights between the controls and the test groups. In the external abnormality test, no abnormal fetuses were observed in the control group, and in the ZDEC groups of 125 mg/kg or less. In the 250 mg/kg group, one case of a fetus with a cleft palate was found. However, this occurrence rate was 0.6%, and was not a significant difference when compared with the control group. In the internal organs test, no abnormal fetuses were observed among the surviving fetuses. Abnormalities thought to be skeletal malformations were not observed in the control group and in the ZDEC groups of 125 mg/kg or less. In the 250 mg/kg group, one case of a fetus with a cleft palate was found (0.8%). However, this occurrence frequency of skeletal malformation fetuses was low, and was not a significant difference when compared with the control group.
Abnormalities that could be considered skeletal deformations were observed in all groups, including the control group. Cervical ribs were observed in 1.5 to 8.9% of all groups. Fetuses with shortened or split cervical arches were observed in 1.7% of the 62.5 mg/kg group and 4.2% of the 250 mg/kg group. Deformations (vestigial conditions, dual sphere conditions) of the thoracic centra were observed in 3.0 to 11.0% of all groups, split thoracic centra was observed in 2.7% of the control group, 1.6% of the 31.25 mg/kg group, 0.7% of the 62.5 mg/kg group, and 2.2% of the 250 mg/kg group. Fetuses with sternebrae abnormalities (deformation, splitting, fusion, deficiency) included 64.0% of the control group, 59.7% of the 31.25 mg/kg group, 63.6% of the 62.5 mg/kg group, 64.1% of the 125 mg/kg group, and 81.4% of the 250 mg/kg group. Lumbar ribs were observed in 31.1 to 58.5% of all groups, including the control group. Shortened pubic bones were observed in 0.8% of the 31.25 mg/kg group. Nevertheless, the occurrence rates for these skeletal deformations did not show significant differences between the control group and the ZDEC dosage groups.
For the ossification state, the bone number for the metacarpal bone, metatarsal bone, and sacro-cardal vertebrae was determined. In every case, there was no significant difference in bone number between the target group and the ZDEC dosage groups.
No significant differences in body weight were observed between the test groups and control groups up till the age of 10 weeks, when the study was terminated. For the ear auricle extension, tooth bud collapse or emergence, fur emergence, eyelid opening, and timing for testes descent and vagina opening of newborn pups, each measurement period showed no significant difference between the control group and the ZDEC dosage groups.
Remarks on result:
other: Embryotoxic / teratogenic effects:no effects
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
In the present study, the NOAEL for maternal toxicity of zinc bis(diethyldithiocarbamate) was 125 mg/kg bw/day (Based on clinical signs of toxicity and mortality at the next dose level) and the NOAEL for developmental toxicity was 250 mg/kg bw/day (No adverse effects on the highest dose tested)
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:
developmental toxicity
Type of information:
(Q)SAR
Adequacy of study:
key study
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 DART QSAR method for chemicals properties assessment.. This method is relevant for Developmental and Reproductive toxicity endpoints in mammals.
Qualifier:
according to
Guideline:
other: QSAR Toolbox Version 3.3.5.17
Principles of method if other than guideline:
This grouping method contains simple categories for Developmental and Reproductive toxicity. This method is relevant for Developmental and Reproductive toxicity endpoints in mammals.
GLP compliance:
no
Remarks:
not applicable DART QSAR method for chemicals properties assessment..
Limit test:
no
Species:
rat
Strain:
other: QSAR model
Route of administration:
other: QSAR model
Vehicle:
other: QSAR model
Details on exposure:
This grouping method contains simple categories for Developmental and Reproductive toxicity. This method is relevant for Developmental and Reproductive toxicity endpoints in mammals. The database include a set of 716 chemicals (664 positive, 16 negative, and 36 with insufficient data) that have been evaluated for their DART potential. These chemicals were grouped into 25 different categories, and 129 sub-categories, based on defined receptor binding and chemical properties, and when known, their MOA. Data is separated into two types of endpoints: developmental and reproductive toxicity. Detailed information for the effect associated with observed data is available in the metadata information of the database.
Analytical verification of doses or concentrations:
no
Details on mating procedure:
QSAR model
Duration of treatment / exposure:
QSAR model
Frequency of treatment:
QSAR model
Duration of test:
QSAR model
Control animals:
other: QSAR model
Maternal examinations:
This grouping method contains simple categories for Developmental and Reproductive toxicity. This method is relevant for Developmental and Reproductive toxicity endpoints in mammals. The database include a set of 716 chemicals (664 positive, 16 negative, and 36 with insufficient data) that have been evaluated for their DART potential. These chemicals were grouped into 25 different categories, and 129 sub-categories, based on defined receptor binding and chemical properties, and when known, their MOA. Data is separated into two types of endpoints: developmental and reproductive toxicity. Detailed information for the effect associated with observed data is available in the metadata information of the database.
Fetal examinations:
This grouping method contains simple categories for Developmental and Reproductive toxicity. This method is relevant for Developmental and Reproductive toxicity endpoints in mammals. The database include a set of 716 chemicals (664 positive, 16 negative, and 36 with insufficient data) that have been evaluated for their DART potential. These chemicals were grouped into 25 different categories, and 129 sub-categories, based on defined receptor binding and chemical properties, and when known, their MOA. Data is separated into two types of endpoints: developmental and reproductive toxicity. Detailed information for the effect associated with observed data is available in the metadata information of the database.
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
No adverse effects on the highest dose tested according the DART QSAR method for chemicals properties assessment..
This grouping method contains simple categories for Developmental and Reproductive toxicity. This method is relevant for Developmental and Reproductive toxicity endpoints in mammals. The database include a set of 716 chemicals (664 positive, 16 negative, and 36 with insufficient data) that have been evaluated for their DART potential.
Dose descriptor:
NOAEL
Effect level:
385 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Fetal body weight changes:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Basis for effect level:
other: Embryotoxic / teratogenic effects:no effects
Remarks on result:
other: No adverse effects on the highest dose tested according the DART QSAR method for chemicals properties assessment.. This method is relevant for Developmental and Reproductive toxicity endpoints in mammals.
Abnormalities:
not specified
Developmental effects observed:
not specified

See attached QSAR study report

Conclusions:
NOAEL for developmental toxicity was 385 mg/kg bw/day (No adverse effects on the highest dose tested) for S-allyl O-pentyl dithiocarbonate and does not cause developmental toxicity.
Developmental & Reproductive Toxicity (DART): Not known precedent reproductive and developmental toxic potential (DART scheme v.1.0)


Executive summary:

Profiling results:

DNA binding by OECD: No alert found

Est rogen Receptor Binding :Non binder, non cyclic structure

OECD HPV Chemical Categories \;Not categorized

Developmental & Reproductive Toxicity (DART): Not known precedent reproductive and developmental toxic potential (DART scheme v.1.0)

Endpoint:
developmental toxicity
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:
Carbon disulphide (CAS number 75–15–0) is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, Carbon disulphide (CAS number 75–15–0) need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
animals were not exposed to CS2 throught the whole gestation period, but only from gestation day 6 to 18.
GLP compliance:
not specified
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton, Research Animals, Denver, Pennsylvania
- Age at study initiation: 5.5 to 7 months
- Weight at study initiation:
- Diet (e.g. ad libitum): on a restricted basis to avoid enteritis (based on the advice of the supplier)
- Water: ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature: 65 ±5 F
- Humidity (%): 55±15
- Photoperiod (hrs dark / hrs light): 12
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
Carbon disulfide atmospheres were generated by nebulization of liquid carbon disulfide into a 1.2 cubic meter stainless steel and glass plenum. The aerosol was allowed to evaporate, and the carbon disulfide vapor was delivered to the exposure chambers. The delivery apparatus for the inhalation chambers was set up to bypass the chambers until the target concentration was reached. The target concentration used to develop subsequent exposure levels was based on the highest exposure level, and subsequent exposure levels were produced by dilution with HEPA filtered air. Chamber concentrations were controlled by adjustment of the ratio of dilution air to carbon disulfide vapor. The target concentration was produced and maintained at a stable level for approximately 15 minutes prior to incorporation into the air flow entering the exposure chambers. Carbon disulfide vapor used to obtain the target concentration bypassed the exposure chambers until the appropriate concentration was reached at which time the air flow containing the carbon disulfide vapor was routed into one of the five exposure chambers. The 0 ppm control chamber received HEPA filtered air only.
The exhaust from the exposure chambers was delivered to an activated charcoal collection system, which removed carbon disulfide vapor from the exhaust chamber air prior to venting the air to the outside.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Monitored by infrared spectrophotometry. The mean chamber concentration for each exposure level was within the required 10% relative standard deviation for both the pre-exposure and exposure periods.
Details on mating procedure:
- Impregnation procedure: natural insemination (gestation day 0) at the vendor's facility
Duration of treatment / exposure:
6 h/day for 12 days (gestation days 6-18)
Frequency of treatment:
daily
No. of animals per sex per dose:
24
Control animals:
yes
Details on study design:
- Dose selection rationale: based on dose range finding study were 100, 300, 1000 or 3000 ppm were tested. Exposure to 3000 ppm was lethal to rabbits. Surviving animals in the remaining exposure levels were euthanitized on gestation day 29, cesarean sections were performed, and uterine contents were evaluated. Exposure to 1000 ppm of carbon disulfide did not produce overt maternal toxicity, and only a transient exposure-related anoxia was suggested. However, it produced significant embryo and fetal toxicity. From these data, concentrations of carbon disulfide were selected for the main study.
Maternal examinations:
CLINICAL OBSERVATIONS: Yes
- Time schedule: at least twice a day; prior to, during and following exposure period to gestation day 29

BODY WEIGHT: Yes
- Time schedule for examinations: on gestation day 0, 5, 6, 9, 12, 15, 18, 19 and 29

HEMATOLOGY: 10 animals per group; blood was collected on gestation days 6, 8, 11 and 19; the following parameters were examined: reciculocyte count, total hematology count, white blood cell differential, methemoglobin, hematocrit, and packed cell volume (PCV).

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29; cesarian sections were performed
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: yes
- Number of late resorptions: yes
Fetal examinations:
All fetuses were examined for gross visceral , skeletal and cephalic malformations. Enhanced fetal evaluations included a double stain to evaluate skeletal and cartilaginous malformations. In addition, cephalic evaluations were conducted on all viable fetuses based on results from the dosage range-finding study.
Statistics:
ANOVA, Dunett's test, Fischer's exact test, Chi-Square test, Kruskal- Wallis test
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
see below in section 'any other information on results incl. tables'
Dose descriptor:
NOAEC
Effect level:
300 ppm
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEC
Effect level:
600 ppm
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEC
Effect level:
948 mg/m³ air
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEC
Effect level:
1 896 mg/m³ air
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Mean corpora lutea, mean crown-rump measurements, and mean number of implantations were not statistically different from the controls. Preimplantation losses were statistically different when compared to the 0 ppm control exposure level for the 100 ppm and 1200 ppm exposure groups. Because the animals were not exposed during the preimplantation period (Gestation Days 0-5), these data were not considered biologically significant. The fetal sex ratio was comparable among all treatment groups.

Postimplantation losses (resorptions and dead fetuses) in the 600 and 1200 ppm exposure groups were statistically different from the 0 ppm control exposure group. Postimplantation losses in the 600 ppm exposure group of 0.64 ± 1.00 were significantly higher when compared to the control 0 ppm exposure group. Accordingly, the number of live fetuses observed in this exposure group was statistically reduced when compared to the control group. Postimplantation loss in the 1200 ppm exposure group was 7.00 ± 3.94 as compared to the 0 ppm group loss of 0.30 ± 0.63.

Dead fetuses were observed in the 0, 100, and 600 ppm exposure groups; yet this was not considered a treatment-related finding because dead fetuses were observed in the control group, and none was observed in the 60, 300, or 1200 ppm exposure groups.

Mean fetal body weights were statistically lower in groups of 600 and 1200 ppm. Two litters of 22 in the 600 ppm group and 14 litters of 21 in the 1200 ppm group consisted of implantation sites with no live fetuses, i.e., the litters consisted exclusively of resorptions. Therefore, only 20 litters from the 600 ppm group and 7 litters from the 1200 ppm group had viable fetuses examined for visceral, skeletal, and cephalic malformations.
Visceral, skeletal and external examinations are summarized in Tables 7, 9 and 11, respectively. The total incidence of visceral and skeletal malformations was statistically higher in the 1200 ppm group (hydrocephaly, right-sided esophagus, absent right subclavian artery, swollen sublingual salivary glands, malformed stomach, small thyroid and parathyroid, abnormal caudal vertebrae, fused sternebrae, and split sternebrae). However, the incidence of any specific skeletal or visceral malformation was not significant.
Dose descriptor:
NOAEC
Effect level:
600 ppm
Based on:
test mat.
Sex:
not specified
Basis for effect level:
fetal/pup body weight changes
Abnormalities:
not specified
Developmental effects observed:
not specified

Maternal toxicity

CLINICAL OBSERVATIONS: Ataxia, labored respiration, wheezing, and tremors were observed in the 1200 ppm exposure level, as well as scant feces and low food consumption, that were clearly associated with CS2 treatment. Three animal deaths at 1200 ppm were considered treatment related.

BODY WEIGHT (Fig.1, attachment): the group mean body weight for animals at 1200 ppm was statistically lower when compared to the control. Two statistically significant reductions in cumulative weight gain for the 100 and 600 ppm exposure groups on gestation day 29, were not considered to be dose-related.

HEMATOLOGY: statistically significant changes in groups exposed to 600 & 1200 ppm, on gestation day 19, in hemoglobin and hematocrit levels. Mean corpuscular volume (on gest.day 29), mean corpuscular hemoglobin concentration (on gest. day 8), segmented neutrophils (on gest. day 19), lymphocytes (on gesta. day 29) were significantly altered in the 1200 ppm exposure level, when compared to the control. Although there some evidence of toxicity on the 600 ppm level it does not seem to be treatment related.

Conclusions:
In the study of PAI (Pathology Associates, Inc.). 1991, carbon disulfide was embryotoxic, developmentally toxic at exposure levels of 300 ppm (948 mg/m3) and above, while overt maternal toxicity was observed only at the 1200 ppm exposure level.
Carbon disulphide (CAS number 75–15–0) is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, Carbon disulphide (CAS number 75–15–0) need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.
Executive summary:

In this developmental toxicity study, pregnant rabbits in groups of 24 were exposed to 0, 60, 100, 300, 600, 1200 ppm carbon disulfide 6 hours per day on days 6-18 of gestation. In dams exposed to 1200 ppm, statistically significant decreases in maternal weight gain and clinical signs of toxicity including ataxia, low food consumption, labored respiration, wheezing, tremors, and abortion with bloody excretion involving the death of two animals, were observed. No exposure-related signs of maternal toxicity were observed in the other dose groups. Post implantation loss had a significantly higher incidence in exposure groups of 600 or 1200 ppm. Total resorption was observed in 2/22 and 14/21 litters of the 600 ppm and 1200 ppm exposure groups, respectively. Mean fetal body weight was significantly reduced in the 600 and 1200 ppm exposure groups. In the 1200 ppm group, the total incidence of skeletal and visceral malformations was significantly increased; however, no single malformation accounted for this increase. In the lower dose groups, significant increases in skeletal malformations were observed in the incidences of rudimentary 13th ribs, extra ribs, extrathoracic vertebrae, or hypoplastic pubis. The malformations in the lower dose groups did not appear to be dose-related by the authors.

Endpoint:
developmental toxicity
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:
Carbon disulphide (CAS number 75–15–0) is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, Carbon disulphide (CAS number 75–15–0) need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
CD-1
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc. (Kingston, NY)
- Age at study initiation: 8-12 weeks
- Housing: solid bottoom polypropylene or polycarbonate cages with stainless steel wire lids
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 14 days quarantine period

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-20
- Humidity (%): 52-77
- Air changes (per hr): 12-14
- Photoperiod (hrs dark / hrs light): 12
Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: overnight
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
from gestation day 6 to 15
Frequency of treatment:
daily
Duration of test:
until gestational day 20
No. of animals per sex per dose:
26 females in control group
29 females in 100 mg/kg group
28 females in 200 mg/kg group
27 females in 400 mg/kg group and 600 mg/kg group
Control animals:
yes, concurrent vehicle
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily at 1 and 4 hours post-dosing

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: uterus, liver
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: No
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: No data
Statistics:
Non-parametric statistics, Kruskal-Wallis test, ANOVA, Mann-Whitney U test, Jonckheere's test, one-tailed Fischer's exact test, two-way ANOVA design, William's test, Dunnett's test
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
During CS treatment, dams exhibited clinical signs including rough or erect coat, lethargy, postural abnormalities, hind limb paralysis and weight loss; clinical signs were most frequent and severe in the 400 and 600 mg/kg/day groups. The maternal mortality rate was 4% (1/25) for the 400 mg/kg/day group and 0% for all other dose groups. On gd 11, 15 and 20 maternal body weight was decreased across treatment groups in a dose-related manner with 400 mg/kg/day CS dams exhibiting body weights significantly below vehicle controls on gd 15 and 20, and 600 mg/kg/day CS dams exhibiting body weights significantly below controls on gd 11, 15 and 20. Measures of maternal weight gain (i.e., weight gain during treatment weight gain during gestation and absolute weight gain) as well as gravid uterine weight were also decreased in a dose-related manner. Maternal weight gain during the treatment period was significantly below controls for dams treated with 200, 400 or 600 mg/kg/day CS. Absolute weight gain was significantly below controls for the 400 and 600 mg/kg/day CS groups. Gestational weight gain was below controls for all CS-treated groups. Relative maternal liver weight was increased in a dose-related manner with statistically significant increases above vehicle control observed in the 400 and 600 mg/kg/day CS groups; absolute maternal liver weight did not differ among treatment groups.
Dose descriptor:
LOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The percentage per litter of resorbed, dead, nonlive (i.e., dead plus resorbed) or affected (i.e., nonlive plus malformed) fetuses did not differ among dose groups.
Among those litters containing live fetuses, there were no differences among dose groups in the number of live fetuses per live litter or in the proportion of males per live litter. Average fetal body weight per live litter was reduced in a dose-related manner, with CS 200, 400 and 600 mg/kg/day litters significantly below controls; males and females were equally affected on this measure. The percentage of fetuses malformed per litter, but not the proportion of litters with one or more malformed fetuses, differed significantly among treatment groups, but no clear dose-effect relationship was observed.
Dose descriptor:
NOAEL
Effect level:
> 600 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: fetotoxicity
Dose descriptor:
LOAEL
Effect level:
200 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: fetotoxicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Dam Body Weight Summary Table:

Time

Dose (in mg/kg) and Dose Group

0 (control)

100

200

400

600

 

mean

SEM

mean

SEM

mean

SEM

mean

SEM

mean

SEM

GD 00

240.3

4.45

244.7

5.2

241.5

4.37

237.5

3.32

241.2

4.85

GD 06

263.8

4.46

268.7

5.39

263.8

4.28

263.2

3.84

265.1

5.3

GD 11

279

4.61

281.4

6.06

272.3

4.53

264.1

3.99

258

4.65

GD 15

300.5

5.25

300.2

6.41

290

4.99

278.4

4.15

270.9

4.47

(bold letters show signficant change compared to control)

Dam Organ weight Summary Table:

Measurement

Obs. Time

Dose (in mg/kg) and Dose Group

0 (control)

100

200

400

600

 

 

mean

SEM

mean

SEM

mean

SEM

mean

SEM

mean

 SEM

Body Weight (Necropsy)(grams)

GD 20

354.2

5.74

348

7.49

339

5.92

322.1

4.34

318.1

5.01

Gravid Uterine Weight (grams)

GD 20

72.42

1.712

66.5

4.403

63.27

3.715

60.88

3.104

61.13

1.994

Liver Weight (grams)

GD 20

14.04

0.318

13.99

0.293

13.68

0.251

13.62

0.237

13.66

0.232

Dam Weight Change

GD 20

113.9

2.99

103.3

4.49

97.5

4.21

84.6

3.34

76.9

2.76

Corrected Weight Change for Dam

GD 20

41.5

2.89

36.8

2.31

34.2

2.42

22.5

3.22

15.2

2.62

(bold letters show signficant change compared to control)

Dam Pregnancy Status Summary Table:

Measurement

Obs. Time

Dose (in mg/kg) and Dose Group

0 (control)

100

200

400

600

No. Treated

GD 20

26

29

28

27

27

No. Removed

GD 20

1

0

1

0

0

No. Dead or Euthanized

GD 20

0

0

0

1

0

No. (%) Pregnant at Sacrifice

GD 20

23(88.5)

24(82.8)

22(78.6)

24(88.9)

27(100.0)

Fetal Body Weights Summary Table:

Measurement

Obs. Time

Dose (in mg/kg) and Dose Group

0 (control)

100

200

400

600

 

 

mean

SEM

mean

SEM

mean

SEM

mean

SEM

mean

 SEM

Body Weight (Necropsy)(grams)

GD 20

3.4

0.02

3.5

0.02

3.2

0.02

2.9

0.02

2.9

0.02

Average Number of Pups/Litter

GD 20

13.3

0.31

12.2

0.81

12.4

0.79

13.2

0.69

13.1

0.38

(bold letters show signficant change compared to control)

Conclusions:
In conclusion, Carbon disulfide (0, 100, 200, 400 or 600 mg/kg/day, po) administered on gd 6 through 15, produced dose-related maternal and fetal toxicity, but failed to increase the incidence of malformations in CD rats relative to vehicle control subjects.
Carbon disulphide (CAS number 75–15–0) is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, Carbon disulphide (CAS number 75–15–0) need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.
Executive summary:

Carbon disulfide (CS2), was evaluated for teratogenic effects in timed-pregnant CD rats. The following doses were administered: 0, 100, 200, 400 and 600 mg/kg/day in corn oil by gavage, in a volume of 5 ml/kg bw, on gestational days (gd) 6 to 15. All animals were sacrificed on gestation day 20. The gravid uterus for each dam was weighed and the number of implantation sites, and live, dead or resorbed fetuses were recorded. All live fetuses were weighed and examined for external, visceral and skeletal malformations. For the dose groups of 200, 400 and 600 mg/kg bw/day, a significant decrease in absolute maternal body weight gain was observed during treatment. Gravid uterine weights showed a dose-consistent decreasing trend; still, not significant. Larger relative liver weights were measured in the two high dose groups. Fetal body weights were decreased in rats exposed to 200 mg/kg bw/day and above.

There was no compound-related increase in malformations of the offspring.

Endpoint:
developmental toxicity
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:
Carbon disulphide (CAS number 75–15–0) is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, Carbon disulphide (CAS number 75–15–0) need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dutchland Laboratory Animals, Inc. (Denver, PA)
- Age at study initiation: at least 6 months
- Weight at study initiation: not exceeding 5 kg
- Housing: stainless steel cages with mesh flooring
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 14 days quarantine period

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-20
- Humidity (%): 52-77
- Air changes (per hr): 12-14
- Photoperiod (hrs dark / hrs light): 12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The experiment was performed with two replications. The results are a combination of both experiments.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: artificial insemination, with 0.25 ml of undiluted ejaculate
Duration of treatment / exposure:
from gestation day 6 to 19
Frequency of treatment:
daily
Duration of test:
30 days
No. of animals per sex per dose:
29 females at 0, 25 and 150 mg/kg bw/day group
30 females at 75 mg/kg bw/day group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on a preliminary toxicity study performed
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily


BODY WEIGHT: Yes
- Time schedule for examinations: daily


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 30
- Organs examined: uterus, liver
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: No data
Statistics:
Non-parametric statistics, Kruskal-Wallis test, ANOVA, Mann-Whitney U test, Jonckheere's test, one-tailed Fischer's exact test, two-way ANOVA design, William's test, Dunnett's test
Indices:
.
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
The mortality rate for treated females was 3.5% (1/29), 0% (0/26), 3.3% (1/30), and 7.1% (2/28) for the vehicle control through high dose, respectively. Maternal body weight on gd 0, gd 6 (i .e., prior to the initiation of treatment), gd 12 (i.e., midway through the treatment period) and gd 30 (i.e., immediately prior to sacrifice) did not differ significantly among treatment groups. On gd 19 (i.e., the final day of treatment) maternal body weight was decreased across treatment groups in a dose-related manner with 150 mg/kg/day CS dams exhibiting body weights significantly below vehicle controls. Maternal weight gain during treatment, maternal weight gain during gestation and gravid uterine weight were each decreased in a dose-related manner. Maternal weight gain during the treatment period was significantly below controls for dams treated with 75 or 150 mg/kg/day CS. Gestational weight gain was below controls only for the high-dose group. Absolute weight gain (i.e. maternal gestational weight gain minus gravid uterine weight) did not differ significantly among treatment groups. Both absolute and relative maternal liver weight were increased in a dose-related manner with statistically significant increases above vehicle control observed in the 75 and 150 mg/kg/day CS groups. Since maternal body weight at sacrifice did not differ among treatment groups, the increase in absolute and relative maternal liver weight appears to reflect a treatment related hepatic response, but the data collected did not allow further characterization of this response.
Dose descriptor:
LOAEL
Effect level:
75 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
25 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
The percentage per litter of resorbed, nonlive (i.e., dead plus resorbed) or affected (i.e., nonlive plus malformed) fetuses was increased in a dose-related manner, and all CS-treated groups were significantly above vehicle controls on these measures. The proportion of litters with one or more resorbed, nonlive or affected fetuses also increased in a dose-related manner, but only the high-dose group (150 mg/kg/day, CS) was significantly above vehicle controls on these measures. No statistically significant differences among treatment groups were observed in the percentage of dead fetuses (i.e., fetuses weighing „10 g with discernible digits, but showing no vital signs at uterine dissection) per litter or in the proportion of litters with one or more dead fetuses.
Among those litters containing live fetuses, there were no differences among dose groups in the proportion of males per live litter. The number of live fetuses per litter, as well as average fetal body weight per live litter, were reduced in a dose-related manner, with CS 150 litters significantly smaller than controls on both measures. The percentage of fetuses malformed per litter, but not the proportion of litters with one or more malformed fetuses, differed significantly among treatment groups and a clear dose-effect relationship was observed.
Dose descriptor:
LOAEL
Effect level:
25 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: fetotoxicity
Dose descriptor:
LOAEL
Effect level:
150 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Dose descriptor:
NOAEL
Effect level:
< 25 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: fetotoxicity
Dose descriptor:
NOAEL
Effect level:
75 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Dam Body Weights Summary Table:

Time

Dose (in mg/kg) and Dose Group

0 (control)

25

75

150

 

mean

SEM

mean

SEM

mean

SEM

mean

 SEM

GD 00

4086.3

89.3

4047

93.76

4194.6

78.52

4160.4

83.74

GD 06

4203

93.11

4098.3

101.64

4236.8

84.92

4267.2

91.7

GD 12

4234.4

94.57

4162.6

99.29

4198.2

79.34

3982.4

80.07

GD 19

4279.6

88.33

4271.7

96.95

4093.6

75.44

3934

77.37

(bold letters: significant change compared to vehicle control)

 

Organ Weight Summary Table (Dam data):

Measurement

Obs. Time

Dose (in mg/kg) and Dose Group

0 (control)

25

75

150

 

 

mean

SEM

mean

SEM

mean

SEM

mean

 SEM

Body Weight (Necropsy)(grams)

GD 30

4290

86.74

4307.4

95.08

4270

86.35

4140.8

78.86

Gravid Uterine Weight (grams)

GD 30

495.35

33.764

427.28

52.467

343.54

44.08

219.29

33.036

Liver Weight (grams)

GD 30

103.73

3.444

116.96

6.165

124.68

5.195

131.6

5.953

Dam Weight Change

GD 30

203.7

55.23

260.4

63.31

75.4

64.06

-19.6

53.04

Corrected Weight Change for Dam

GD 30

-291.6

56.41

-166.8

66.26

-268.2

66.43

-238.9

68.63

(bold letters: significant change compared to vehicle control)

 

Dam Pregnancy Status Summary Table:

Measurement

Obs. Time

Dose (in mg/kg) and Dose Group

0 (control)

25

75

150

 

 

 

 

 

 

No. Treated

GD 30

29

29

30

29

No. Removed

GD 30

0

3

0

1

No. Dead or Euthanized

GD 30

1

0

1

2

No. (%) Pregnant at Sacrifice

GD 30

27(93.1)

23(79.3)

28(93.3)

25(86.2)

 

Fetal Body Weights Summary Table:

Measurement

Obs. Time

Dose (in mg/kg) and Dose Group

0 (control)

25

75

150

 

 

mean

SEM

mean

SEM

mean

SEM

mean

SEM 

Body Weight (Necropsy)(grams)

GD 30

43.8

0.59

43.5

0.74

39

0.7

38.2

0.85

Average Number of Pups/Litter

GD 30

7.5

0.52

7.5

0.73

7

0.77

5.2

0.53

(bold letters: significant change compared to vehicle control)

All Litter Summary Table:

Measurement

Obs. Time

Dose (in mg/kg) and Dose Group

0 (control)

25

75

150

 

 

mean

SEM

mean

SEM

mean

SEM

mean

SEM 

Total Number of Corpora Lutea

GD 30

12

0.5

11

0.7

11

0.8

10

0.5

Full Resorptions per Litter (Discerned by Weight of Dead Fetus)

GD 30

0

0.1

0

0.1

0

0.1

0

0.1

Implants Only per Litter

GD 30

1

0.3

2

0.7

4

0.7

5

0.7

Mid Term Resorptions per Litter

GD 30

0

0

0

0.3

1

0.3

0

0.3

Percent Late Deaths per Litter

GD 30

1.4

0.65

0.6

0.62

1.2

0.7

1

0.69

Percent Resorptions per Litter

GD 30

8.6

2.3

16.3

4.72

16.6

4.6

28.9

6.54

Total Number of Implantations

GD 30

8

0.6

9

0.8

9

0.6

8

0.6

Dead fetuses per litter

GD 30

0

0.1

0

0

0

0.1

0

0.1

Early Resorptions per Litter

GD 30

1

0.3

1

0.4

1

0.3

2

0.5

Late Resorptions per Litter

GD 30

0

0

0

0

0

0

0

0.1

Total resorptions/litter

GD 30

1

0.3

2

0.5

1

0.4

2

0.6

 

(bold letters: significant change compared to vehicle control)

Conclusions:
In conclusion, Carbon disulfide (25, 75 or 150 mg/kg/day, po) administered on gd 6 through 19, produced dose-related maternal and fetal toxicity, and increased the incidence of malformed fetuses in New Zealand White rabbits relative to the vehicle control group. The incidence of resorptions was significantly increased at all doses tested (i.e., 12.30%, 32.47%, 41.60% and 61.16% resorbed in the vehicle through high-dose, respectively), but the incidence of malformations in the control group (5.72%) was significantly exceeded only in the high dose group (19.51% malformed fetuses per litter).
Carbon disulphide (CAS number 75–15–0) is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, Carbon disulphide (CAS number 75–15–0) need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.
Executive summary:

Carbon disulfide (CS2), was evaluated for teratogenic effects in artifically inseminated New Zealand White rabbits. The following doses were administered: 0, 25, 75 and 150 mg/kg/day in corn oil by gavage, in a volume of 1 ml/kg bw, on gestational days (gd) 6 to 19. All animals were sacrificed on gestation day 30. The gravid uterus for each dam was weighed and the number of implantation sites, and live, dead or resorbed fetuses were recorded. All live fetuses were weighed and examined for external, visceral and skeletal malformations. CS2 treatment produced dose-related maternal and fetal toxicity, and increased the incidence of malformed fetuses in New Zealand White rabbits relative to the control group. The incidence of resorptions was significantly increased at all doses tested (i.e., 12.30%, 32.47%, 41.60% and 61.16% resorbed in the vehicle through high-dose, respectively), but the incidence of malformations in the control group (5.72%) was significantly exceeded only in the high dose group (19.51% malformed fetuses per litter). The findings show that developmental toxicity might be exerted at doses lower than maternal toxicity

Endpoint:
developmental toxicity
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 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
Groups of approximately 15 pregnant female Sprague-Dawley rats were exposed via inhalation to 3900 ppm of 1-pentyl alcohol vapor for 7 hours/ day from gestation Day 1 - 19. Purity of 1-pentyl alcohol (>99%) was verified by gas chromatography. A control group of 15 females was similarly treated but exposed to air only. Food and water consumption was measured on gestation day 7, 14 and 20. Dams were weighed daily for the first week and weekly thereafter. Females were exposed in stainless steel wire mesh cages in 0.5 m3 inhalation chambers having a dynamic air flow of 0.5 cubic meter/min. Temperature was maintained at 77 +/- 2 degree F and relative humidity at 50 +/-15%. The concentration of the test material was monitored continuously using a Miran 1A infrared analyzer. The exposure concentration was verified on weekly basis by gas chromatography. On gestation day 20, dams were individually weighed and euthanized. The uterus was removed and the number of corpora lutea, implantations, resorption sites, and live fetuses were recorded. Fetuses were serially removed, examined for external malformations, weighed, and sexed. One-half of the fetuses were randomly selected, placed in 80% ethanol, and subsequently prepared and examined for skeletal malformations. The remaining fetuses were fixed in Bouin’s solution and subsequently sectioned and examined for visceral abnormalities.
Statistical methods: Data were analyzed using multivariate analysis of variance (MANOVA) and analysis of variance (ANOVA). The fiducial limit of 0.05 (two-tailed) was used as the critical level of significance for all comparisons.
GLP compliance:
no
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, MI, USA
- Weight at study initiation: 200 - 300 g
- Housing: in standard metal cages equipped with automatic water dispensers
- Diet (e.g. ad libitum): NIH-07 lab chow (Ziegler Bros., Garden, MA); ad libitum
- Water (e.g. ad libitum): tap water, ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 40 - 60
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Hinners-type chamber
- Method of holding animals in test chamber: in stainless steel wire mesh cages within the exposure chambers
- System of generating particulates/aerosols: A constant flow of test substance was mixed with a known volume of heated compressed air, resulting in instantaneous vaporization of the alcohol. This vapor-air mixture was introduced into the mainstream of the chamber airflow upstream from an orifice, and the resulting turbulence produced uniform mixing of the test chemical throughout the exposure chamber
- Temperature, humidity, pressure in air chamber: temperature of 25 ± 2°C; relative humidity of 50 ± 15%
- Air flow rate: ca. 0.5 m3/minute


TEST ATMOSPHERE
- Brief description of analytical method used: using a Miran 1A infrared-Analyzer at every hour
- Samples taken from breathing zone: no
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Charcoal tube samples were drawn 2 days/week and analyzed by gas chromatography with partial verification of these methods using spiked samples of known concentration.
Means from the continuous monitoring were equal to the target value of 14 mg/L, with standard deviations not exceeding 5% of the means. Concentrations from the secondary monitoring method (gas chromatograph analysis of samples captured on charcoal tubes) were frequently 10-20% lower than the means from the primary method. However, results from spiked samples were often similarly below the concentrations supplied. Consequently, the figures from the primary monitoring method (infrared analyzer) are cited.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: no data
- Length of cohabitation: no data
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
days 1 - 19 of gestation
Frequency of treatment:
7 h/day
Duration of test:
20 d
No. of animals per sex per dose:
15
Control animals:
yes, sham-exposed
Maternal examinations:
CAGE SIDE OBSERVATIONS: No data



DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations: weighed daily for the first week and weekly thereafter


FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No


WATER CONSUMPTION: Yes
- Time schedule for examinations: on gestation days 7, 14, 20


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: uterus with ovaries
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
Statistics:
Data were analyzed using multivariate analysis of variance (MANOVA) and analysis of variance (ANOVA); p< 0.05 was accepted as statistically significant. Three separate analyses were performed using exposure group as the independent variable. For the litter data (numbers of corpora lutea, resorptions, females per litter and males per litter, and weight of females per litter and of males per litter), a one-way ANOVA/ANOVA design was used. If a significant MANOVA was observed, individual ANOVAs were performed, and if these were significant, Bonferroni corrections were made comparing the individual exposure group with controls. A second analysis, for the weight data, used a litter per exposure group X day ANOVA. A third analysis, for the feed and water consumption data, used a litter per exposure group X week MANOVA/ANOVA design. For the ANOVAs, the probabilities of all within-litter main effects and interactions were corrected with the Greenhouse-Geisser estimate of Box's epsilon.
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Comparing to the control group maternal body weights were decreased slightly, but this difference was not statistically significant. Food consumption was decreased, but water consumption unchanged.
Dose descriptor:
NOAEC
Effect level:
14 mg/L air
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEC
Effect level:
14 mg/L air
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Number of corpea lutea, resorptions, gender ratio and fetal weights were not affected by treatment.
Small, but nonsignificant, reversible delays in ossification of caudal vertebrae, sternum, metacarpals and hindpaw phalanges were reported.
No malformations were observed.
Remarks on result:
other: Embryotoxic / teratogenic effects:no effects
Abnormalities:
not specified
Developmental effects observed:
not specified

Results:

 

1-Pentanol

Control

Mean maternal weight (g)

day 0

260 ± 22

243 ± 25

day 7

297 ± 21

262 ± 24

day 14

291 ± 23

291 ± 26

day 20

348 ± 25

354 ± 32

overall gain

88

111

 

 

 

Mean feed consumption (g)

 

 

week 1

92 ± 14

108 ± 14

week 2

110 ± 10

124 ± 12

week 3

99 ± 12

118 ± 10

overall mean

100 ± 14

117 ± 13

 

 

 

Mean water intake (g)

 

 

week 1

222 ± 33

204 ± 46

week 2

223 ± 43

276 ± 93

week 3

288 ± 45

265 ± 123

overall mean

244 ± 51

248 ± 96

 

 

 

Mean corpora lutea/litter

13 ± 3

14 ± 4

Mean resorptions/litter

0.2

0.4

Mean no. females /litter

7 ± 1

8 ± 2

Mean no. males /litter

5 ± 2

7 ± 2

 

 

 

Mean fetal weight (g)

 

 

males

3.11 ± 0.31

3.19 ± 0.2

females

3.32 ± 0.26

3.28 ± 0.27

 

Conclusions:
There were no clinical signs of toxicity noted in females exposed to 3900 ppm(14 mg/L air) 1-pentyl alcohol vapor. Overall maternal food consumption was approximately 10% lower than controls. There were no differences in water consumption between groups. Although maternal weight gain was lower, the difference was not statistically significant. There were no treatment-related effects on the number of corpora lutea per litter, mean resorptions per litter, sex ratio, or mean fetal body weights. There were no malformations observed. A small, (non-significant) delay in ossification of the caudal vertebrae, sternum (first sternal center), metacarpals, and hindpaw phalanges was observed.
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.
Executive summary:

There were no clinical signs of toxicity noted in females exposed to 3900 ppm(14 mg/L air) 1-pentyl alcohol vapor. Overall maternal food consumption was approximately 10% lower than controls. There were no differences in water consumption between groups. Although maternal weight gain was lower, the difference was not statistically significant. There were no treatment-related effects on the number of corpora lutea per litter, mean resorptions per litter, sex ratio, or mean fetal body weights. There were no malformations observed. A small, (non-significant) delay in ossification of the caudal vertebrae, sternum (first sternal center), metacarpals, and hindpaw phalanges was observed. Pentan-1-ol/Amyl alcohol is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore,pentan-1-ol/Amyl alcoholneed to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
948 mg/m³
Study duration:
subacute
Species:
rabbit
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
6.25 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
For dermal exposure we taken that:
-the average weight of rats is 250g (200-300g),
-the dose is applied over an area which is approximately 10% of the total body surface=0.025 kg
corrected dermal NOAEL= oral NOAEL
250 mg/kg bw/dayx0.025 kg =
NOAELrat = 6.25 mg/kg bw/day
Additional information

Oral exposure

In the study of Nakaura S, et al. 1984, the NOAEL for maternal toxicity of zinc bis(diethyldithiocarbamate) was 125 mg/kg bw/day (Based on clinical signs of toxicity and mortality at the next dose level) and the NOAEL for developmental toxicity was 250 mg/kg bw/day (No adverse effects on the highest dose tested)

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 for developmental toxicity was 385 mg/kg bw/day (No adverse effects on the highest dose tested) for S-allyl O-pentyl dithiocarbonate and does not cause developmental toxicity.

Developmental & Reproductive Toxicity (DART): Not known precedent reproductive and developmental toxic potential (DART scheme v.1.0)

Dermal exposure:

For dermal exposure we taken that:

-the average weight of rats is 250g (200-300g),

-the dose is applied over an area which is approximately 10% of the total body surface=0.025 kg

 corrected dermal NOAEL=   oral NOAEL

250 mg/kg bw/dayx0.025 kg =                  

 NOAELrat  = 6.25 mg/kg bw/day

 

Inhalation exposure:

In the study of PAI (Pathology Associates, Inc.). 1991, the substance was embryotoxic, developmentally toxic at exposure levels of 300 ppm (948mg/m3) and above, while overt maternal toxicity was observed only at the 1200 ppm exposure level.

 

  

Deleterious effects of short term exposure of CS2 were investigated on reproductive organs of male albino rats. Different dosages of CS2 dissolved in maruti micro reined cotton seed oil viz. 25,50,100 and 200 mg/kg body weight daily were administered intraperitoneally over a period of 30 days. Pathomorphological changes and functional impairments were observed in male reproductive organs. Significant decrease in serum testosterone levels and marked degenerative changes in testicular tissue were observed specially in 100 and 200 mg/kg CS2 treated rats. Diminution of serum testosterone levels and degeneration in Leydig ceils indicate a definite alterations in the process of steroidogenesis after CS2treatment. Pronounced changes in testicular structure indicated plausible effect on sper­matogenesis. Further, androgenic deficiency, evident by decrease in testosterone level after CS2 treatment produced alterations in epididymis.

The present observations clearly indicate effects of CS2 on the male reproduction system. Nonetheless, the relevance of the study is questionable due to the invasive route of exposure.

Carbon disulphide (CAS number 75–15–0) is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, Carbon disulphide (CAS number 75–15–0) need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.

 

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

Mutagenicity-Genetic Toxicity

Muta. Cat. 1; R46 May cause heritable genetic damage.

Muta. Cat. 2; R46 May cause heritable genetic damage.

Muta. Cat. 3; R68 Possible risk of irreversible effects.

CLP

Germ cell mutagenicity

Muta. 1A

Muta. 1B

Muta. 2

H340: May cause genetic defects <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>.

H341: Suspected of causing genetic defects <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 Mutagenicity-Genetic Toxicity