4-[(morpholinothio)thioxomethyl]morpholine

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

other: Repro/Developmental screen

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

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

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Limited
- Age at study initiation: (P) x wks; (F1) x wks
- Weight at study initiation: (P) Males:292-334 g; Females: 173-223 g; (F1) Males: x-x g; Females: x-x g
- Fasting period before study: none
- Housing:Upon arrival, the animals were housed in groups of five by sex. During the mating period, animals were housed one male to one female percage. Following evidence of successful mating, the males were returned to their original cages. The females were housed individually.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 2
- Humidity (%): 55 +/- 15%
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 18 May 2004 To: 27 June 2004

Administration / exposure

Route of administration:

oral: feed

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): Once
- Mixing appropriate amounts with (Type of food): PMI 5002

Details on mating procedure:

- M/F ratio per cage: 1/1
- Length of cohabitation: up to 14 days
- Proof of pregnancy: vaginal plug or sperm in vaginal smear
- After successful mating each pregnant female was caged (how): individually
- Any other deviations from standard protocol: no

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The concentration of OTOS in the dietary admixtures was determined by high performance liquid chromotography (HPLC) using an external standard technique

Duration of treatment / exposure:

The test material was administered in the diet throughout maturation, mating, gestation and up to Day 4 post partum

Frequency of treatment:

Continuously in the diet

No. of animals per sex per dose:

10 male and 10 female rats per dose

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale:based on available toxicity data.
- Rationale for animal assignment (if not random):randomisation procedure based on stratified bodyweights and the group mean body weights were then determined to ensure similarity between the dose groups.
- Other:

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily during normal working week and once daily on weekends and public holidays


DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations: During the maturation and mating period the parental generation animals were weighed weekly. Following mating the parental males were weighed weekly until termination. Parental generation females showing evidence of mating were weighed on Days 0,7,14 and 20 post coitum. Parental generation females with a live litter were weighed on Days 1 and 4 post partum.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

Oestrous cyclicity (parental animals):

not measured

Sperm parameters (parental animals):

Parameters examined in all adult males
:
testis weight, epididymis weigh, sperm

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no


PARAMETERS EXAMINED
The following parameters were examined in offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities,

GROSS EXAMINATION OF DEAD PUPS:
[no / yes, for external and internal abnormalities; possible cause of death was/was not determined for pups born or found dead.]

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals subject to confirmation of successful mating
- Maternal animals: All surviving animals on Day 5 post partum

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated below were weighed

Epididymides
Testes

The corpora lutea of all ovaries from pregant females were counted and the uterine implantation sites were counted.

Postmortem examinations (offspring):

SACRIFICE

These animals were subjected to postmortem examinations macroscopic on Day 5 post partum

GROSS NECROPSY
- Gross necropsy consisted of[external and internal examinations including the cervical, thoracic, and abdominal viscera.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

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:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Details on results (P0)

Administration of the test substance to male and female rats resulted in an initial reduction of food consumtpion leading to a transient reduction in bodyweight gain at 600 ppm. This is not considered to be an adverse effect as food consumptions and bodyweight gain were comprable to controls by the second week of treatment.

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

600 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Systemic Toxicity

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Details on results (F1)

There was no effect on offspring viability, growth and development.

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

ca. 600 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Reproductive Toxicity

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Administration of the test substance to male and female rats throughout maturation, mating, gestation and early lactation phases of reproduction resulted in an initial reduction in food consumption leading to a transient reduction in bodyweight gain at 600 ppm. This is not considered to be an adverse effect as food consumption and bodyweight gain were comprable to controls by the second week of treatment. There were no histopathological changes in the tissues examined. There was no effect on offspring viability, growth and development. The No Observed Adverse Effect Level for adults was 600 ppm. The No Observed Effect Level for offspring was 600 ppm.