Registration Dossier

Administrative data

Description of key information

The acute oral LD50 of the test material in the Sprague-Dawley CD (Crl: CD® (SD) IGS BR) strain rat was estimated to be in the range of 300 - 500 mg/kg bodyweight. The dermal LD50 value of diphenyl sulphone in Wistar rats was established to exceed 2000 mg/kg body weight.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent, UK
- Age at study initiation: eight weeks of age
- Weight at study initiation: 179 to 272 g
- Fasting period before study: an overnight fast immediately before dosing and for approximately three to four hours after dosing
- Housing: they were housed in groups of three by sex in solid-floor polypropylene cages furnished with woodflakes.
- Diet (e.g. ad libitum): free access to food, certified rat and mouse diet (code 5LF2) supplied by PMI Nutrition International, Nottingham, UK) was allowed throughout the study. The diet, drinking water and bedding were routinely analysed and were considered not to contain any contaminants that would be reasonably be expected to affect the purpose or integrity of the study.
- Water (e.g. ad libitum): ad libitum
- Acclimation period: an acclimatisation period of at least five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25°c
- Humidity (%): 30 - 70%
- Air changes (per hr): 15
- Photoperiod: 12 hrs dark / 12 hrs light, controlled by a time switch


IN-LIFE DATES: From: To:
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 - 20 mg/ml
- Amount of vehicle (if gavage): /
- Justification for choice of vehicle:/
- Lot/batch no. (if required): /
- Purity: /


MAXIMUM DOSE VOLUME APPLIED: 2000 mg/ml


DOSAGE PREPARATION (if unusual):as a suspension


CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: based on the results from this dose level further groups of fasted animals were treated at a dose level of 200 mg/kg bodyweight.
Doses:
200 - 2000 mg/kg
No. of animals per sex per dose:
3 females: 2000 mg/kg
3 males and 3 females: 2000 mg/kg
Control animals:
no
Details on study design:
- Duration of observation period following administration: the animals were observed for deaths or overt signs of toxicity 1/2, 1, 2 and 4 hours after dosing and subsequently once daily for up to 14 days.
- Frequency of observations and weighing: individual bodyweights were recorded prior to dosing and 7 and 14 days after treatment or at death.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, mortality data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
300 - 500 mg/kg bw
Mortality:
All animals treated at a dose level of 2000 mg/kg were killed in extremis one day after dosing.
No deaths were noted at a dose level of 200 mg/kg.
Clinical signs:
Signs of systemic toxicity noted in animals treated at a dose level of 2000 mg/kg were ataxia, hunched posture, lethargy, ptosis, decreased respiratory rate, laboured and gasping respiration, loss of righting reflex, exophthalmos, hypothermia and dehydration. Two animals treated with 2000 mg/kg were found comatose. No signs of systemic toxicity were noted in animals treated at a dose level of 200 mg/kg.
Body weight:
The surviving animals showed expected gains in bodyweight over the study period.
Gross pathology:
Abnormalities noted at necropsy of animals that were killed in extremis during the study were abnormally red lungs, patchy pallor of the liver, pale kidneys and haemorrhagic small intestine.
no abnormallities were noted at necropsy of animals that were killed at the end of the study.
Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral median lethal dose (LD50) of the test material in the Sprague-Dawley CD (Crl: CD® (SD) IGS BR) strain rat was estimated to be in the range of 300 - 500 mg/kg bodyweight.
The test material was classified as HARMFUL and the symbol 'Xn' and risk phrase R 22 'HARMFUL IF SWALLOWED' are required according the EU labelling reulations Commision directive 93/21/EEC
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
400 mg/kg bw
Quality of whole database:
High quality

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2001
Reliability:
1 (reliable without restriction)
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approximately 8 weeks old
- Weight at study initiation: body weight variation did not exceed +- 20% of the sex mean.
- Fasting period before study:
- Housing: individually housed in labelled polycarbonate cages (type III, height 15 cm) containing purified sawdust as bedding material (SAWI, Jelu Werk, Rosenberg, Germany). Certificates of analysis were examined and then retained in the NOTOX archives.
- Diet (e.g. ad libitum): Free acces to standard pelleted animal laboratory diet (from Altromin (code VRF 1), Lage, Germany). Certificates of analysis were examined and then retained in the NOTOX archives.
- Water (e.g. ad libitum): Free acces to tap-water. Certificates of quarterly analysis were examined and then retained in the NOTOX archives.
- Acclimation period: at least 5 days before start of treatment


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21+-3°c
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod: 12 hrs dark / 12 hrs artificial fluorescent light


IN-LIFE DATES: From: 26 september 2001 To: 10 october 2001
Type of coverage:
semiocclusive
Vehicle:
propylene glycol
Details on dermal exposure:
TEST SITE
- Area of exposure: 25 cm² for males and 18 cm² for females
- % coverage: approximately 10
- Type of wrap if used: The test substance was held in contact with the skin with a dressing, consisting of a surgical gauze patch (Surgy 1D)*, successively covered with aluminium foil and Coban flexible bandage*. A piece of Micropore tape* was additionally used for fixation of the bandages in females only.
( * manufactures: Laboratoires Stella s.a., Liege, Belgium (surgical gauze) and 3M, St. Paul, Minnesota, U.S.A. (Coban & Micropore).


REMOVAL OF TEST SUBSTANCE
- Washing (if done): the skin was cleaned of residual test substances, using water
- Time after start of exposure: 24h


TEST MATERIAL
- Amount(s) applied (volume or weight with unit):
- Concentration (if solution): 2000 mg/kg (10 ml/kg) body weight
- Constant volume or concentration used: yes
- For solids, paste formed: yes


VEHICLE
- Amount(s) applied (volume or weight with unit):
- Concentration (if solution):2000 mg/kg
- Lot/batch no. (if required):
- Purity:
Duration of exposure:
24 h
Doses:
2000 mg/kg (10 ml/kg) body weight
No. of animals per sex per dose:
5 males and 5 females (females were nulliparous and non-pregnant
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
* Mortality/viability: Twice daily. The time of death was recorded as precisely as possible.
* Body weights: Days 1 (pre-administration), 8 and 15 and at death (if found dead after day 1).
* Clinical signs: at periodic intervals on the day of dosing (day 1) and once daily thereafter, until day 15. The time of onset, degree and duration were recorded and the symptoms graded according to fixed scales:
Maximum grade 4: grading slight (1) to very severe (4)
Maximum grade 3: grading slight (1) to severe (3)
Maximum grade 1: prescence is scored (1)
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
no statistical analysis was performed
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
One male was found death on day1 and one male was found dead on day 2. No further mortality occured.
Clinical signs:
Lethargy, hunched posture, tremor, piloerection, chromodacryorrhoea, hypothermia, laboured respiration and/or uncoordinated movements were noted among the animals beteen days 1 and 8.
Scales, erythema and/or swelling were seen in the treated skin-area of the females during the observation period. Scales were seen in one male on day 3.
Body weight:
The changes noted in body weight gain in male and females were within the range expected for rats used in this type of study and were therefore considered not indcative of toxicity.
Gross pathology:
Macroscopic findings: At macroscopic post mortem examination, hemorrhagic cysts were found in the ovaries of one female. Macroscopic examination of the animals that died during the study and of the surviving animals at termination did not reveal any abnormalities.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The dermal LD50 value of DIPHENYLSULFON (DPS) in Wistar rats was established to exceed 2000 mg/kg bodyweight.
Based on these results and according to the EC criteria for classification and labelling requirements for dangerous substances and preparations (Guidelines in Commission Directive 93/21/EEC), DIPHENYLSULFON, (DPS) does not have to be classified and has no obligatory labelling requirement for dermal toxicity.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
High quality

Additional information

A key study for acute oral toxicity study was performed with diphenyl sulphone in arachid oil in the Sprague-Dawley CD rat according to OECD 423 method (SafePharm Laboratories, 2002). A group of three fasted females was treated at 2000 and 200 mg/kg body weight. All animals treated at 2000 mg/kg were killed in extremis one day after dosing; no deaths were noted at a dose level of 200 mg/kg. Signs of systemic toxicity at 2000 mg/kg were ataxia, hunched posture, lethargy, ptosis, decreased respiratory rate, 1 aboured and gasping respiration, loss of righting reflex, exophthalmos, hypothermia and dehydration. Two animals treated with 2000 mg/kg were found comatose. The acute oral median lethal dose (LD50) was estimated to be in the range of 300 - 500 mg/kg bodyweight.

A key study for acute derrmal toxicity study was performed with diphenyl sulphone in propylene glycol in the Wistar rat according to OECD 402 method (Notox, 2001). A group of 5 males and 5 females was treated on 10% of the body surface for 24h semi-occlusive exposure followed by washing. One male was found dead on day 1 and one male was found dead on day 2. Lethargy, hunched posture, tremor, piloerection, chromodacryorrhoea, hypothermia, laboured respiration and/or uncoordinated movements were noted among the animals between days 1 and 8. Scales, erythema and/or swelling were seen in the treated skin-area of the females during the observation period; scales were seen in one male on day 3. The changes noted in body weight gain in males and females were within the range expected for rats used in this type of study and were therefore considered not indicative of toxicity. At macroscopic post mortem examination, hemorrhagic cysts were found in the ovaries of one female. Macroscopic examination of the animals that died during the study and of the surviving animals at termination did not reveal any abnormalities. The dermal LD50 value of diphenyl sulphone in Wistar rats was established to exceed 2000 mg/kg body weight.


Justification for selection of acute toxicity – oral endpoint
Key study

Justification for selection of acute toxicity – dermal endpoint
Key study

Justification for classification or non-classification

Diphenyl sulphone was classified as HARMFUL and the symbol 'Xn' and risk phrase R 22 'HARMFUL IF SWALLOWED' are required according the EU labelling reulations Commision directive 93/21/EEC. According to CLP regulation (No. 1272/2008 of 16 December 2008), Category 4 classification is proposed for acute oral toxicity with signal word 'Warning' and hazard sentence H302 'Harmful if swallowed'. Based on these results and according to the EC Directive (No.93/21/EEC) and CLP (No. 1272/2008 of 16 December 2008), diphenyl sulphone does not have to be classified and has no obligatory labelling requirement for dermal toxicity.