Di(morpholin-4-yl) disulphide

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

In a developmental toxicity study on 4,4'-dithiodimorpholine performed according to the OECD guideline # 414, the no observable effect level for maternal and developmental toxicity was 250 mg/kg/day. There was no evidence of teratogenic up to 500 mg/kg/day

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study (EPA)

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPP 83-3 (Prenatal Developmental Toxicity Study)

Deviations:

not specified

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles river breeding laboratories
- Age at study initiation: 84 days
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: individually in suspended wire-meash cages.
- Diet (e.g. ad libitum): purina certified rodent chow #5002, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23-26°C (mean 23+/-0.8°C)
- Humidity (%): 18-29% (mean 25+/-5.0%)
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

Constant volume of administration = 10 ml/kg bw.

Analytical verification of doses or concentrations:

yes

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1M/1F
- Length of cohabitation: not precised
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy

Duration of treatment / exposure:

Day 6-15 of gestation

Frequency of treatment:

daily

Duration of test:

1 month

Remarks:

Doses / Concentrations:
0, 50, 250 and 500 mg/kg/day
Basis:
actual ingested

No. of animals per sex per dose:

25 females / dose

Control animals:

yes, concurrent vehicle

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes, 2/daily
DETAILED CLINICAL OBSERVATIONS: Yes, 1/daily
BODY WEIGHT: Yes, on gestation days 0, 6, 9, 12, 16, 20
FOOD CONSUMPTION : Yes, Individual maternal food consumption was recorded for 24 hours in days 0, 6, 9, 12, 16 and 20 of gestation.
WATER CONSUMPTION : No
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs observed : the abdominal and thracic cavities and organs

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
- Other: Viable and dead fetuses, weight of fetuses (indiv.)

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data

Statistics:

All statistical analyses compared the treatment groups with the control group, with the levels of significance at p<0.05 and p<0.01. All mean were accompanied by standard deviations. Male-to-female fetal sex ratios and the proportions of litters with malformations were compared using Chi-square test criterion with Yates' correction for 2x2 contingency tables. The proportions of resorbed and dead fetuses and postimplantation losses were compared by the Mann-Whitney U-test to determine the significance of differences. Numbers of copora lutea, total implantations and live fetuses and mean fetal body weights were compared by analysis of variance, bartlett's test for homogeneity of variance and the appropriate t-test usinf Dunnett's multiple comparison table to determine the significance of differences.

Indices:

no data

Historical control data:

yes

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Clinical observations of yellow stained ventral or anogenital haircoat occurred in a dose related pattern at 250 and 500 mg/kg/day. Additional observations noted solely in the two high-dose groups included unkempt haircoat and respiratory rates.
No test article related postmortem findings were evident in any study group. One dam that died had a small amount of fluid in the thoracic cavity and one control dam had pus in the pericardial sac.

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, non-treatment-related

Description (incidence):

Survival was 100% at the 0, 50 and 250 mg/kg/day dosage levels. Four rats from the 500 mg/kg/day group died on study; one each on gestation days 9, 10, 11 and 15. Two of these animals had no apparent abnormalities prior to death white the other two had either brown staining on the nose and forelimbs or yellow anogenital staining on the day of death.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Treatment with the test article at 500 mg/kg/day caused slightly depressed body weight change (body weight loss or reduction in weight gain) during the first and last intervals of treatment (gestation days 6 to 9 and 12 to 16). The resulting body weight gains were retarded over both the overall treatment and gestation periods (gestation days 6 through 15 and 0 to 20, respectively).
No meaningful effects on body weights were evident at the 50 or 250 mg/kg/day dosage levels.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Mean and relative food consumption at the 500 mg/kg/day dosage level exceeded the control group on the initial day of test article administration (gestation day 6). All high-dose food intake data thereafter (gestation days 9, 12 and 16) were lower than respective control group values.
No abnormalities in food intake were evident at the 50 or 250 mg/kg/day dosage levels.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Details on maternal toxic effects:

A notable increase in mean postimplantation loss relative to concurrent and historical control values was present at the 500 mg/kg/day dosage level. The resulting mean viable fetuses was also reduced. Slight fetotoxicity was suggested in the high-dose group by a reduction in mean fetal body weights relative to the control group. High-dose values for corpora lutea, total implantations and fetal sex ratios were dot remarkable.
No toxicologically meaningful findings were evident at the 50 or 250 mg/kg/day dosage levels regarding any of the Cesarean section parameters evaluated. The mean postimplantation loss was significantly lower (p<0.01) in both treated groups than in the control group.

Key result

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

body weight and weight gain

food consumption and compound intake

mortality

Dose descriptor:

LOAEL

Effect level:

500 mg/kg bw/day

Based on:

test mat.

Remarks on result:

other: sereval adverse effects

Abnormalities:

not specified

Details on embryotoxic / teratogenic effects:

Malformations: The test article had no teratogenic effect on offspring at any dosage level. Although the number of malformed fetuses was slightly increased at the 500 mg/kg/day dosage level, the number of litters with malformations was not meaningfully different from the control group.
Developmental Variations : No biologically meaningful differences were noted in any treated group regarding the mean numbers of fetuses and litters with developmental variations.

Key result

Dose descriptor:

NOAEL

Effect level:

>= 500 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: teratogenicity

Remarks on result:

not determinable due to absence of adverse toxic effects

Abnormalities:

no effects observed

Developmental effects observed:

not specified

Conclusions:

In conclusion,when administered orally by gavage to pregnant Charles River rats, test sample was determined to be embryotoxic and fetotoxic at a dose level of 500 mg/kg/day which was also associated with maternal toxicity. There was no evidence of teratogenic affect at anydose level. The 250 mg/kg/day dosage level was considered the no observable effect level with regards to developmental toxicity.

Executive summary:

Mated female Charles River rats, consecutively assigned to one control and three treatment groups of 25 animals each, were used to determine the teratogenic potential of 4,4'-dithiodimorpholine. Dosage levels of 50, 250 and 500 mg/kg/day were administered orally by gavage as a single daily dose on days 6 through 15 of gestation at a volume of 10.0 ml/kg. The control group received the vehicle only, corn oil, on a comparable regimen. Casarean sections were performed on all surviving females on gestation day 20 and the fetuses were removed for teratologic evaluation.

Maternal toxicity was evidenced by mortality, alterations in appearance (stained anogenital haircoat) and reduced body weights and food intake at the 500 mg/kg/day dosage level. Treatment with the test article at 250 mg/kg/day caused a very small effects ( yellow stained ventral or anogenital haircoat ) and did not depress body weight growth of the dams.

At 500 mg/kg/day, the test article promoted intrauterine mortality and retarded fetal development as evidenced by observations of increased postimplancation loss and slightly depressed fetal body weights. Similar aspects of developmental toxicity were not affected at the 50 or 250 mg/kg/day dosage levels.

In conclusion, when administered orally by gavage to pregnant Charles River rats, 4,4'-dithiodimorpholine was determined to be embryotoxic and fetotoxic at a dose level of 500 mg/kg/day which was also associated with maternal toxicity. There was no evidence of teratogenic affect at any dose level. The 250 mg/kg/day dosage level was considered the no observable affect level with regards to maternal and developmental toxicity.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

250 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Schardein study is considered to be a reliable study with a klimisch score of 1.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

In a key developmental toxicity study performed according to the OECD guideline # 414 (Schardein, 1987a), mated female Charles River rats, consecutively assigned toone control and three treatment groups of 25 animals each, were used to determine the teratogenic potential of 4,4'-dithiodimorpholine (Sulfasan-R). Dosage levels of 50, 250 and 500 mg/kg/day were administered orally by gavage as a single daily dose on days 6 through 15 of gestation at a volume of 10.0 ml/kg. The control group received the vehicle only, corn oil, on a comparable regimen. Casarean sections were performed on all surviving females ongestationday20 and the fetuses were removed for teratologic evaluation. Maternal toxicity was evidenced by mortality, alterations in appearance (stained anogenital haircoat) and reduced body weights and food intake at the 500 mg/kg/day dosage level. Treatment with the test article at 250 mg/kg/day caused a very small effects (yellow stained ventral or anogenital haircoat) and did not depress body weight growth of the dams. At 500 mg/kg/day, the test article promoted intrauterine mortality and retarded fetaldevelopment as evidenced by observations of increased post-implantation loss and slightly depressed fetal body weights. Similar aspects of developmental toxicity were not affected at the 50 or 250mg/kg/daydosage levels. In conclusion, when administered orally by gavage to pregnantrats, 4,4'-dithiodimorpholine was determined to be embryotoxic and fetotoxic at a dose level of 500 mg/kg/day which was also associated with maternal toxicity. There was no evidence of teratogenic affect at any dose level. The 250 mg/kg/day dosage level was considered the no observable effect level with regards to maternal and developmental toxicity.

Mated femalerats, consecutively assigned to one control and five treatment groups of five animals each, were used in a range-finding study to determine the dosage levels of 4,4'-dithiodimorpholine (Sulfasan-R) for the developmental toxicity study (Schardein, 1987b). Dosage levels of 50, 100, 500, 1000 and 2000 mg/kg/day were administered orally by gavage as a single daily dose on days 6 through 15 of gestation at a volume of 10 ml/kg. The control group received the vehicle only, corn oil, on a comparable regimen. Uterine examinations were performed on all surviving females on gestation day 20. The mortality produced by treatment at 1000 and 2000 mg/kg/day precludes the use of these levels in a developmental toxicity study. Maternal toxicity, as demonstrated by changes in maternal appearance and behaviour and inhibited body weight gain and food intake, was evident at 500 mg/kg/day, but this was not considered excessive for a developmental toxicity study. With the exception of inhibited food intake at initiation of treatment, essentially no maternal or fetal effects were detected at 50 or 100mg/kg/day.

Justification for classification or non-classification

Based on the available data, no classification for reproduction toxicity is required for DTDM according to the Regulation (EC) No 1272/2008.

Justification: There was no evidence of teratogenic effect in the developmental toxicity study performed on rats.

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