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EC number: 201-247-9 | CAS number: 80-07-9
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2008
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Valid guideline study under GLP-conditions.
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 008
- Report date:
- 2008
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Bis(4-chlorophenyl) sulphone
- EC Number:
- 201-247-9
- EC Name:
- Bis(4-chlorophenyl) sulphone
- Cas Number:
- 80-07-9
- Molecular formula:
- C12H8Cl2O2S
- IUPAC Name:
- 1-chloro-4-(4-chlorobenzenesulfonyl)benzene
- Details on test material:
- - Name of test material: 4,4'-dichlorodiphenyl sulfone
- Physical state: white solid pellets
- Analytical purity: >98.4 %
- Batch No.: LP070811
- Storage condition: at room temperature in the dark
Constituent 1
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, Margate, Kent, UK
- Age at study initiation: approximately 8 weeks old
- Weight at study initiation: 286-361 g (males), 192-233 g (females)
- Housing: in solid floor polypropylene cages with stainless steel grid tops and softwood flake bedding (Datesand Ltd, Cheshire, UK); in groups of 5 animals/sex/cage premating, or 1 male and 1 female/cage during the mating period, or 1 mated female/cage during gestation and lactation
- Diet: pelleted diet (Rodent PMI 5002 certified diet, BCM IPS Limited, London, UK), ad libitum
- Water: mains drinking water supplied from polycarbonate bottles, ad libitum
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature: 21 ± 2 °C
- Humidity: 55 ± 15 %
- Air changes: 15 air changes/hour
- Photoperiod: 12 hours dark / 12 hours light
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- arachis oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS
The test material was prepared at the appropriate concentrations as a suspension in Arachis oil BP. The stability and homogeneity of the dose formulations were determined. Formulations were shown to be stable for at least 14 days. Samples were taken of each formulation and analysed for DCDPS concentration.
VEHICLE
- Justification for use and choice of vehicle: Arachis oil BP is a standard vehicle in studies of this type
- Concentration in vehicle: 0, 1.25, 3.75 or 12.5 mg/mL
- Amount of vehicle: a dose volume of 4 mL/kg bw was used - Details on mating procedure:
- - M/F ratio per cage: 1:1 within each dose group
- Length of cohabitation: max. 14 days
- Proof of pregnancy: vaginal plug and sperm in vaginal smear referred to as day 0 of pregnancy - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The concentration of DCDPS in the test material formulations was determined by high performance liquid chromatography (HPLC) using an external standard technique. The test material formulations were extracted with acetonitrile to give a final, theoretical test material concentration of approximately 0.1 mg/mL. Standard solutions of test material were prepared in acetonitrile at a nominal concentration of 0.1 mg/mL. The standard and sample solutions were then analysed by HPLC. The analytical method has been satisfactorily validated in terms of linearity, specificity and accuracy for the purposes of the study.
- Duration of treatment / exposure:
- 42 days
Total observation time up to 54 consecutive days (including a two week maturation phase, pairing, gestation and early lactation for females) - Frequency of treatment:
- once daily
- Details on study schedule:
- - Age at mating of the mated animals in the study: approximately 10 weeks
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 5, 15, and 50 mg/kg bw/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 10 animals
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: based on previous toxicology studies
- Positive control:
- none
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS:
- Time schedule: before dosing and up to 5 hours (workdays) or 1 hour (weekend) thereafter
BODY WEIGHT:
- Time schedule for examinations: day 1, weekly thereafter (males); weekly until mating, GD 0, 7, 14, 20, PPD 1 and 4
FOOD CONSUMPTION :
- Food consumption for each group determined and mean daily diet consumption calculated as g food/rat/day: Yes, premating and 3 weeks after and individual for females during pregnancy.
FEED EFFICIENCY:
Body weight gain/feed intake: for periods of measured feed consumption
WATER CONSUMPTION:
Visual observation only - Oestrous cyclicity (parental animals):
- A vaginal smear was prepared for each female and the stage of the oestrous cycle was recorded.
- Sperm parameters (parental animals):
- Parameters examined in the male parental generation:
testis weight, epididymis weight - Litter observations:
- All live offspring were assessed for surface righting reflex on day 1 post partum
- Postmortem examinations (parental animals):
- Full external and internal examination for macroscopic anomalies.
Organ weights: epididymes, testes, liver
Histopathology: coagulation gland, liver, ovaries, pituitary, prostate, seminal vesicles, testes, uterus/cervix, vagina - Postmortem examinations (offspring):
- Full external and internal examination for macroscopic anomalies
- Statistics:
- Standard methods such as linear regression, ANOVA, Dunntett's, Mann Whitney U test for parametric values, Chi square and Kruskall Wallis for non parametric data.
- Reproductive indices:
- All parameters as given in OECD TGD 421, i.e. pre-coital interval, mating Index, preganancy index, gestation length, parturition index, percent pre-implantation loss, percent post-implantation loss
- Offspring viability indices:
- All parameters as given in OECD TGD 421, i.e. live birth index, viability index, sex ratio plus weights and righting reflex on day 4.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
Details on results (P0)
Relevant data are summarised in tabular form in section "Any other information on results incl. tables"
MORTALITY AND CLINICAL OBSERVATIONS (PARENTAL ANIMALS)
One female treated with 15 mg/kg bw/day was killed in extremis due to a physical injury to the right ear. There were no further unscheduled deaths. No clinical signs of toxicity were noted.
BODY WEIGHT (PARENTAL ANIMALS)
Males treated with 50 mg/kg bw/day showed a reduction in cumulative body weight gain throughout the treatment period and a reduction in weekly body weight gain during the first two weeks of treatment. Sligthly lower weight gains (not reaching statistical significance) were also observed in the high dose females during the premating phase. No such effects were detected in animals of either sex treated with 15 or 5 mg/kg bw/day.
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
No adverse effect on dietary intake or food efficiency was detected.
REPRODUCTIVE FUNCTION AND PERFORMANCE (PARENTAL ANIMALS)
There was no adverse effect detected on mating or fertility. Gestation or parturition indices were not affected by the treatment with the test item.
GROSS PATHOLOGY
Enlarged livers were noted in 10/10 males and 7/10 females treated with 50 mg/kg bw/day. Liver enlargement was also seen in 8/10 males at 15 mg/kg bw/day.
ORGAN WEIGHTS
Animals of either sex from all treatment groups showed a dose related and statisitically significant increase in liver weights, both absolute and relative to terminal body weight. The increased relative epididymides and testes weights were not considered as toxicologically relevant in the absence of histological correlates.
HISTOPATHOLOGY
Centrilobular hepatocyte enlargement was seen for all animals examined of either sex in all treated groups. The incidence of the condition was statistically significant for all treatment groups. There was also a dose response for either sex in terms of the incidence of severity grades (males were more sensitive). Centrilobular hepatocyte vacuolation was also seen among mid and high dose animals, being more prevalent and statistically significant for high dose males only.
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- for adult toxicity
- Effect level:
- 15 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: Centrilobular hypertrophy at 50 mg/kg bw/day associated with vacuolation.
- Dose descriptor:
- NOAEL
- Remarks:
- for adult toxicity
- Effect level:
- 50 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: There was no clear significance for adverse histopathology up to and including the high dose level.
- Dose descriptor:
- NOAEL
- Remarks:
- toxicity to reproduction/fertility
- Effect level:
- 50 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: There were no effects on reproductive perfomance up to and including the high dose level.
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- 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)
No treatment related effects were detected.
CLINICAL SIGNS (OFFSPRING)
There were no treatment related clinical findings from birth to day 5 post partum.
BODY WEIGHT (OFFSPRING)
Mean offspring body weight gain between days 1 and 4 of lactation were statistically significantly reduced for offspring from litters treated with 50 mg/kg bw/day. No such effects were detected in offspring from litters treated with 15 or 5 mg/kg bw/day.
GROSS PATHOLOGY (OFFSPRING)
Neither the incidence, type or distribution of macroscopic findings observed at necropsy of decedent offspring nor offspring killed at scheduled termination (day 5 of age) indicated any adverse effect of maternal treatment.
OTHER FINDINGS (OFFSPRING)
The percentage of offspring who successfully showed surface righting reflex on day 1 and the type, incidence and distribution of clinical signs in the offspring to termination on day 5 of age was unaffected by maternal exposure.
Effect levels (F1)
- Dose descriptor:
- other:
- Generation:
- F1
- Effect level:
- 50 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- Remarks on result:
- other: The observed reduction of offspring growth (developmental effect) was distinct but likely to be secondary to the maternal effects, but this can not be finally assessed based on the available data.
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Body weight and body weight change for male parents
Dose level [mg/kg bw/day] |
Body weight [g] at day |
|||||||||||
1 |
8 |
15 |
22 |
29 |
36 |
43 |
||||||
0 (control) |
324 ± 16 |
363 ± 20 |
387 ± 22 |
407 ± 27 |
435 ± 27 |
459 ± 28 |
467 ± 32 |
|||||
5 |
326 ± 17 |
361 ± 26 |
383 ± 32 |
407 ± 35 |
433 ± 37 |
453 ± 42 |
463 ± 44 |
|||||
15 |
332 ± 18 |
368 ± 31 |
389 ± 41 |
410 ± 44 |
440 ± 49 |
459 ± 50 |
475 ± 48 |
|||||
50 |
327 ± 15 |
350 ± 25 |
361 ± 28 |
376 ± 26 |
397 ± 31 |
420 ± 30 |
428 ± 34 |
|||||
Dose level [mg/kg bw/day] |
Cumulative body weight change [g] relative to day 1 in week |
|||||||||||
1 |
2 |
3 |
4 |
5 |
6 |
|||||||
0 (control) |
39 ± 09 |
64 ± 10 |
83 ± 16 |
111 ± 17 |
135 ± 17 |
144 ± 22 |
||||||
5 |
35 ± 11 |
57 ± 18 |
81 ± 23 |
107 ± 24 |
127 ± 29 |
137 ± 32 |
||||||
15 |
37 ± 17 |
57 ± 28 |
78 ± 30 |
108 ± 38 |
128 ± 38 |
143 ± 35 |
||||||
50 |
23 ± 12 * |
34 ± 17 ** |
49 ± 19 ** |
70 ± 26 ** |
93 ± 24 ** |
101 ± 28 ** |
All values are mean ± standard deviation of 10 animals
* Significantly different from control group p<0.05
** Significantly different from control group p<0.01
Body weight and body weight change for female parents
Dose level [mg/kg bw/day] |
Body weight [g] at day |
|||||||||||
Maturation |
Gestation |
Lactation |
||||||||||
1 |
8 |
15 |
0 |
7 |
14 |
20 |
1 |
4 |
||||
0 (control) |
213 ± 12 |
223 ± 12 |
231 ± 20 |
239 ± 13 |
273 ± 15 |
310 ± 15 |
387 ± 25 |
292 ± 20 |
306 ± 23 |
|||
5 |
219 ± 10 |
228 ± 11 |
239 ± 13 |
244 ± 10 |
278 ± 14 |
313 ± 14 |
393 ± 23 |
293 ± 22 |
311 ± 18 |
|||
15 |
213 ± 10 |
218 ± 12 |
227 ± 16 |
234 ± 9 |
272 ± 14 |
306 ± 15 |
386 ± 20 |
283 ± 18 |
304 ± 15 |
|||
50 |
213 ± 9 |
216 ± 8 |
219 ± 12 |
227 ± 11 |
262 ± 15 |
298 ± 17 |
374 ± 22 |
276 ± 17 |
297 ± 21 |
|||
Dose level [mg/kg bw/day] |
Cumulative body weight change [g] relative to day 1 in week |
|||||||||||
Maturation |
Gestation |
Lactation |
||||||||||
Week 1 |
Week 2 |
Day 0-7 |
Day 7-14 |
Day 14-20 |
Days 1-4 |
|||||||
0 (control) |
10 ± 5 |
18 ± 12 |
34 ± 8 |
72 ± 8 |
148 ± 16 |
15 ± 10 |
||||||
5 |
9 ± 9 |
21 ± 11 |
34 ± 7 |
69 ± 8 |
149 ± 17 |
18 ± 10 |
||||||
15 |
5 ± 8 |
14 ± 14 |
38 ± 6 |
72 ± 7 |
153 ± 13 |
21 ± 9 |
||||||
50 |
3 ± 6 |
7 ± 10 |
35 ± 8 |
71 ± 12 |
148 ± 18 |
21 ± 8 |
All values are mean ± standard deviation of 10 animals except in the 15 mg/kg bw/day, where from gestation day 0 only 9 animals were counted due to sacrification of one female.
Offspring body weight and body weight change
Dose level [mg/kg bw/day] |
Offspring body weight [g] |
Offspring body weight change [g] |
||||
Day 1 |
Day 4 |
Days 1-4 |
||||
Males |
Females |
Males |
Females |
Males |
Females |
|
0 (control) |
7.3 ± 0.9 |
6.8 ± 0.8 |
10.5 ± 1.5 |
9.9 ± 1.5 |
3.2 ± 0.7 |
3.1±0.8 |
5 |
6.8 ± 0.6 |
6.4 ± 0.6 |
9.7 ± 1.3 |
9.0 ± 1.2 |
2.9±0.8 |
2.6±0.7 |
15 |
6.8 ± 0.6 |
6.6 ± 0.5 |
9.3 ± 0.9 |
8.9 ± 0.8 |
2.5±0.5 |
2.4±0.5 |
50 |
7.0 ± 0.7 |
6.6 ± 0.6 |
9.3 ± 1.3 |
8.7 ± 1.2 |
2.3±0.6 * |
2.1±0.7 ** |
All values are mean ± standard deviation of 10 animals
* Significantly different from control group p<0.05
** Significantly different from control group p<0.01
Organ weights of male parents
Dose level [mg/kg bw/day] |
Epididymis |
Testes |
Livera |
|||
0 (control) |
||||||
Absolute [g] |
1.3064 |
± 0.1098 |
3.3950 |
± 0.2470 |
16.4012 |
± 1.7257 |
Relative [%bw] |
0.2800 |
± 0.0198 |
0.7283 |
± 0.0531 |
3.5047 |
± 0.1819 |
5 |
||||||
Absolute [g] |
1.3386 |
± 0.1289 |
3.6080 |
± 0.2665 |
19.3653 |
± 2.4770** |
Relative [%bw] |
0.2898 |
± 0.0243 |
0.7836 |
± 0.0772 |
4.1678 |
± 0.2370*** |
15 |
||||||
Absolute [g] |
1.3607 |
± 0.0874 |
3.6308 |
± 0.1731 |
24.7682 |
± 3.8263*** |
Relative [%bw] |
0.2886 |
± 0.0260 |
0.7719 |
± 0.0832 |
5.2163 |
± 0.6115*** |
50 |
||||||
Absolute [g] |
1.3649 |
± 0.1020 |
3.6698 |
± 0.2512 |
26.6187 |
± 2.6710*** |
Relative [%bw] |
0.3202 |
± 0.0309** |
0.8598 |
± 0.0635*** |
6.2178 |
± 0.3991*** |
All values are mean ± standard deviation of 10 animals
a Relative liver weights were increased by 19%, 49% and 77% with increasing dose
** Significantly different from control group (p≤0.01)
*** Significantly different from control group (p≤0.001)
Liver weights of female parents
Dose level [mg/kg bw/day] |
Liver weight |
|
|
Absolute [g] |
Relative [%] |
0 (control) |
12.4936 ± 1.2942 |
4.0327 ± 0.2571 |
5 |
14.3538 ± 0.9536** |
4.5806 ± 0.3056** |
15 |
16.3069 ± 1.1555*** |
5.2461 ± 0.2861*** |
50 |
20.7629 ± 2.2841*** |
6.8772 ± 0.6932*** |
All values are mean ± standard deviation of 10 animals
** Significantly different from control group p<0.01
*** Significantly different from control group p<0.001
Applicant's summary and conclusion
- Conclusions:
- All doses induced effects in the parental generation, which were significantly adverse in male rats. No effects on reproduction/fertility were seen in this study. The observed reduction of offspring growth (developmental effect) was distinct but likely to be secondary to the maternal effects, but this can not be finally assessed based on the available data.
- Executive summary:
In a reproduction/developmental toxicity screening study (Safepharm Ltd, 2008), DCDPS (>98.4 %) in arachis oil was administered to 10 Sprague-Dawley rats/sex/dose level by oral gavage (4 mL/kg bw) at dose levels of 0 (vehicle only), 5, 15 or 50 mg/kg bw/day. Rats were dosed with DCDPS for two weeks maturation, pairing and pregnancy up to day 4 post partum, thus a total of 42 days. In the reproductive screening part of the study, there were no treatment related effects noted on mortality, clinical aspects, food and water consumption as well as food efficiency, reproductive performance/fertility and offspring litter size and viability. Males treated with 50 mg/kg bw/day showed a reduction in cumulative body weight gain throughout the treatment period and a reduction in weekly body weight gain during the first two weeks of treatment. Offspring from litters treated with 50 mg/kg bw/day showed a reduction in body weight gain considered as developmental effect. At necropsy, enlarged livers were seen in males at 15 mg/kg bw/day and in males and females at 50 mg/kg bw/day. Animals of either sex from all treatment groups showed an increase in liver weight. Dose-dependent centrilobular hepatocyte enlargement was seen in all treated groups. Centrilobular hepatocyte vacuolation was noted at 50 mg/kg bw/day being more prevalent in males. Based on these results, the NOAEL for parental toxicity was established at 15 and 50 mg/kg bw/day for male and female animals, respectively. The NOAEL for toxicity to reproduction/fertility was set at 50 mg/kg bw/day since no reproductive toxicity was seen.
This screening study is acceptable and satisfies the requirement for test guideline OECD 421.
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