4-[(morpholinothio)thioxomethyl]morpholine

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian germ cell study: cytogenicity / chromosome aberration

Remarks:

Type of genotoxicity: chromosome aberration

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1980

Report date:

1980

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 478 (Genetic Toxicology: Rodent Dominant Lethal Test)

Version / remarks:

FDRL Proposol No. 79062-B, further defined in FDRL Protocol 6477

GLP compliance:

yes

Type of assay:

rodent dominant lethal assay

Test material

Test material information

Constituent 1

Reference substance name:

4-[(morpholinothio)thioxomethyl]morpholine

EC Number:

237-335-9

EC Name:

4-[(morpholinothio)thioxomethyl]morpholine

Cas Number:

13752-51-7

Molecular formula:

C9H16N2O2S2

IUPAC Name:

morpholin-4-yl morpholine-4-carbodithioate

Constituent 2

Reference substance name:

Cure-Rite® 18; commercial

IUPAC Name:

Cure-Rite® 18; commercial

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Blue Spruce Farms Inc.
- Age at study initiation: not stated.
- Weight at study initiation: 307 - 329 grams mean weight at week 1.
- Assigned to test groups randomly: yes
- Fasting period before study: no
- Housing: 1 male per wire mesh cage, 2 females per cage.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 10 days


IN-LIFE DATES: From: 31 March 1980 To: 18 June 1980

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

Corn Oil.

Details on exposure:

All housed male rats were gavaged at the appropriate dose for 56 consecutive days.
Positive control animals were dosed with Triethylenemelamine via intraperitoneal injection on the last day of the treatment period.

Duration of treatment / exposure:

Male rats were dosed for 56 consecutive days before being housed with the female rats.

Frequency of treatment:

Daily

Post exposure period:

One week for males housed with two females to allow for mating. Then the two females were replaced by two more females for one week.
Thirteen days after the midpoint of each cohabitation, all females were sacrificed and subjected to uterine examination.
After the final mating period, three males per treatment group were randomly selected for necropsy.

Doses / concentrations

Remarks:

Doses / Concentrations:

Basis:
nominal conc.
0, 6.25, 12.5 and 25 mg/kg/day. TEM 0.25 mg/Kg/day

No. of animals per sex per dose:

10 males per group, in 5 groups (labelled A, B, C, D, E).

Control animals:

yes, concurrent vehicle

Positive control(s):

triethylenemelamine
- Justification for choice of positive control(s):
- Route of administration: intraperitoneal injection on last day of treatment.
- Doses / concentrations: 0.25 m/Kg/Day.

Examinations

Tissues and cell types examined:

Male rats: The following tissues were preserved - adrenals, brain, kidneys, liver, spleen, lung/main bronchi, sciatic nerve/skeletal muscle, testes, seminal vesicles, epididymides, prostate, pancreas, spinal cord, stomach, altered tissues.

Details of tissue and slide preparation:

All tissues taken from males rats were weighed except for the sciatic nerve/skeletal muscle, pancreas and spinal cord. Organ/body weight ratios were calculated for each.

Evaluation criteria:

Female rats: uterine examination to evaluate percent pregnancy, implantation per pregnancy, pre-implantation losses, early fetal deaths per pregnancy, late fetal deaths per pregnancy, and percent early fetal deaths per dam.

Statistics:

The effects of mating and treatment and their interaction were analyzed statistically at a 0.05 level of significance. Percentages and proportions were
analyzed using 95% confidence intervals or by computation of exact probabilities. Continuous data were analyzed using a one-way completely random classification analysis of variance for fixed effects. When differences were indicated, the least significant differences test was then employed
to determine which group(s) differed from the control.

Results and discussion

Test results

Sex:

male

Genotoxicity:

negative

Toxicity:

not specified

Vehicle controls validity:

valid

Negative controls validity:

not applicable

Positive controls validity:

valid

Additional information on results:

Number of implantation sites in females from the test groups were comparable to the control group. The positive control mated females had a significantly lower number of implantation sites per females.

The mean percent of pre-implantation losses were similar to the control groups and fall within accepted limits as presented by FDRL. The positive control was significantly higher.

Mean number of early fetal deaths per pregnancy and the mean percent of early fetal deaths were comparable to the control groups. The positive control was significantly higher.

Any other information on results incl. tables

Pregnancy rates overall range: 75 - 95%

Control group (corn oil) -  85%

TEM positive control      -  90%

6.25 mg/Kg Curerite 18 - 85%

12.5 mg/Kg Curerite 18 - 95%

25.9 mg/Kg Curerite 18 - 95%

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): negative
The data was judged to indicate that Cure-rite 18 failed to produced dominant lethal mutations.

Executive summary:

The present dose levels of Curerite 18 were able to produce a dose related decrease in body weight gains over the 56 day dosing period. It also showed that Curerite 18 did not alter pregnancy or early fetal deaths. The alterations in implantation and preimplantation losses were judged to be related to a decrease in fertility for this group in the first mating. This is supported by the number of implants per dam and percentage preimplantation losses per dam for the high dose group fall into the normal range of values under FDRL limits.

Therefore, Curerite 18 is considered to not produce dominant lethal mutations.