Zinc bis(diethyldithiocarbamate)

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well-conducted and reported study, published in peer-reviewed literature, minor restrictions in design and reporting, but otherwise adequate for assessment.

Data source

Reference

Reference Type:

publication

Title:

Zinc diethyldithiocarbamate. Effects of Zinc diethyldithiocarbamate on the Prenatal and Postnatal Developments of Rats.

Author:

Nakaura S, Tanaka S, Kawashima K, Takanaka A, Omori Y

Year:

1984

Bibliographic source:

Eisei Shikensho Hokoku 102, 55-61

Materials and methods

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

Test material

Test material information

Constituent 1

Reference substance name:

Zinc bis(diethyldithiocarbamate)

EC Number:

238-270-9

EC Name:

Zinc bis(diethyldithiocarbamate)

Cas Number:

14324-55-1

Molecular formula:

C10H20N2S4Zn

IUPAC Name:

zinc bis(diethyldithiocarbamate)

Details on test material:

- Name of test material (as cited in study report): ZDEC, zinc diethyldithiocarbamate
- Lot/batch No.: 20601
- Supplier: Sumimoto Chemical Co., Ltd.

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system 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):

Administration / exposure

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

Examinations

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)

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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.

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

3

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Results (fetuses)

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.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Remarks:

Developmental

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects on the highest dose tested.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified