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Toxicological information

Toxicity to reproduction

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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

Constituent 1
Chemical structure
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.