Registration Dossier

Administrative data

Description of key information

No data on repeated dose toxicity with SDIBP is available. Therefore in accordance to Regulation (EC) No. 1907/2006 Annex XI, 1.5, a read across to sodium xylene sulphonate (CAS No. 1300-72-7),  for repeated dose toxicity was performed. The 90-day rat oral study, conducted in 1969,  is generally comparable to the OECD 408 guideline study and included the following observations: clinical signs, survival, body weight, feed consumption, gross pathology and non-neoplastic histopathology. The NOAEL was 763 mg a.i. per kilogram body weight per day  based on loss of relative weight of the spleen. The 90-day dermal study was a guideline study with mouse (OECD 411) published by the US National Institutes of Health. The NOAEL for females is 540 mg a.i./kg bw / day and the NOAEL for males is 440 mg a.i./kg bw /day based on epidermal hyperplasia.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
1968
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline not specified, but with detailed documentation
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
no functional observations or ophthalmoscopy
Principles of method if other than guideline:
Groups of 30 young rats (15 males and 15 females) were exposed by diet for 90 days to three concentrations. A control group was included. Observations were made of behavior, appearance, growth, food and water intake and a number of haematological factors. At the end of the experiment (during week 14) ten organs of each surviving rat were weighed and examined histologically for pathological changes. Liver enxyme activities were also determined.
GLP compliance:
not specified
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: CIVO-colony
- Age at study initiation: newly weaned
- Weight at study initiation: 41-60 g
- Fasting period before study: no data
- Housing: metal wire screen cages (5 to a cage)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 degrees centigrade
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data


IN-LIFE DATES: From: To: no data
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: test chemical mixed directly with stock diet


DIET PREPARATION
- Rate of preparation of diet (frequency): once a fortnight
- Mixing appropriate amounts with (Type of food): stock diet consisting of 28% yellow maize, 26% whole wheat, 10% rolled oats, 10% soybean oil meal, 8% fish meal and <5% each of meat scraps, dried whey, soybean oil, grass meal, minerals, sodium chloride and vitamin preparation.
- Storage temperature of food: room temperature


VEHICLE
- Justification for use and choice of vehicle (if other than water): no vehicle
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13 weeks / 90 days
Frequency of treatment:
in ad libitum diet
Remarks:
Doses / Concentrations:
0.2%, 1.0% and 5.0%
Basis:
nominal in diet
No. of animals per sex per dose:
15
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: previous range finding test
- Rationale for animal assignment (if not random): according to body weight
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Observations: general appearance and behaviour
- Time schedule: no data


DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations: weekly


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: No


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: weekly for the first week only


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: week 6 and week 12
- Anaesthetic used for blood collection: No data
- Animals fasted: No
- How many animals: 10 males and 10 females from each dose group
- Parameters checked in table [No.4] were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: terminally
- Animals fasted: No data
- How many animals: 10 males and 10 females from each dose group
- Parameters checked in table [No.5 and No.6] were examined.


URINALYSIS: Yes
- Time schedule for collection of urine: urinalysis from pooled samples from 10 males and 10 females from each dose group in 7th week.
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.7 and No.8] were examined.


NEUROBEHAVIOURAL EXAMINATION: No


OTHER: kidney funcion from samples of 10 males and 10 females in 13th week. Serum protein electrophoresis of 10 males and 10 females of control and high dose groups at 13 weeks. Liver enzyme activity at termination.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Dose descriptor:
NOAEL
Effect level:
> 763 - < 3 534 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified
Conclusions:
Test compound possesses a very low order of toxicity. 1% in the diet (corrresponding to a daily intake of 763 mg a.i./kg bw) was a no toxic effect level. At 5% in the diet (corresponding to 4092 mg a.i./kg bw) there were slight indications of deleterious effecs.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
763 mg/kg bw/day

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: dermal
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
February 23 - May 26, 1988
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Protocols and results reviewed and accepted by the National Toxicology Program's Board of Scientific Counselor's Technical Reports Review Subcommittee, USA National Institutes of Health. The study was used as dose finding study for a carcinogenicity study and therefore the number of endpoints was limited.
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
Deviations:
yes
Remarks:
clinical signs reported weekly; no food consumption; no ophthalmoscopy, no clinical chemisty; no haematology
GLP compliance:
yes
Limit test:
no
Test material information:
Composition 1
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Taconic Farms, Germantown, NY
- Age at study initiation: 7 weeks
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: 1 animal per cage; polycarbonate cages and stainless steel racks (rotated every 2 weeks), with heat-treatted hardwood chip bedding and spun-bonded polyester cage filters changed every week.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 19 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.5 to 23.9
- Humidity (%): 15 to 63
- Air changes (per hr): 10 minimum
- Photoperiod (hrs dark / hrs light): 12 / 12


IN-LIFE DATES: From: February 23 To: May 26, 1988
Type of coverage:
not specified
Vehicle:
ethanol
Details on exposure:
TEST SITE
- Area of exposure: clipped interscapular skin
- % coverage: no data
- Type of wrap if used: no data
- Time intervals for shavings or clipplings: once at start of study


REMOVAL OF TEST SUBSTANCE
- Washing (if done): no data


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100 microliters
- Concentration (if solution): 0, 5, 15, 44, 133 and 400 mg/mL
- Constant volume or concentration used: yes


VEHICLE
- Justification for use and choice of vehicle (if other than water): ethanol, because in water alone the test substance beaded up
- Amount(s) applied (volume or weight with unit): 100 microliters of 50% ethanol and 50% distilled water
- Concentration (if solution): 50%
- Lot/batch no. (if required): no data
- Purity: no data


USE OF RESTRAINERS FOR PREVENTING INGESTION: no data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
HPLC verification of each dose at beginning, midpoint and end of study
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
5 days per week
Remarks:
Doses / Concentrations:
17, 50, 140, 440 and 1300 mg active ingredient/kg bw for males and 20, 60, 170, 540 and 1620 mg active ingredient/kg bw for females
Basis:
analytical per unit body weight
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: wide range for screening study
- Rationale for animal assignment (if not random): random
Positive control:
no data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations were not included in the report.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly


DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: weekly


BODY WEIGHT: Yes
- Time schedule for examinations: weekly


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No


WATER CONSUMPTION: No


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: No


CLINICAL CHEMISTRY: No


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No


OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Kaplan and Meier
Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY - no treatment related effects


BODY WEIGHT AND WEIGHT GAIN - slight increase in body weight of males at highest dose


ORGAN WEIGHTS - increase in kidney weight of males but not dose dependent


GROSS PATHOLOGY - no treatment related effects


OTHER FINDINGS - epidermal hyperplasia of application site in males and females at the highest dose
Dose descriptor:
NOAEL
Effect level:
>= 440 mg/kg bw (total dose)
Sex:
male
Basis for effect level:
other: overall effects other: epidermal hyperplasia (also seen in females at highest dose)
Critical effects observed:
not specified
Conclusions:
NOAEL = 440 mg a.i./kg bw
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
440 mg/kg bw/day

Mode of Action Analysis / Human Relevance Framework

Additional information

There is no data available on repeated dose toxicity with SDIBP. A read-across was performed from sodium xylene sulphonate (CAS No. 1300-72-7), in accordance to Regulation (EC) No. 1907/2006 Annex XI, 1.5.

The 90-day oral study is generally comparable to the OECD 408 guideline study (Huntsman, 1969). In that study, the highest dose for female rats - 4092 mg active ingredient (a.i.) per kilogram body weight per day - resulted in a loss in relative weight of the spleen. The 2nd highest dose for females - 763 mg a.i. per kilogram body weight per day- had no measureable adverse effects and therefore establishes the repeat dose oral NOAEL for the test substance. The highest oral dose for male rats - 3534 mg a.i. per kilogram body weight - had no measurable adverse effects. No adverse effects were reported in the 90 day rat study. Test compound possesses a very low order of toxicity. 1% in the diet (corrresponding to a daily intake of 763 mg a.i./kg bw) was a no toxic effect level. At 5% in the diet (corresponding to 4092 mg a.i./kg bw) there were slight indications of deleterious effecs. The overall effects were determined as hematology (decreased red blood cells; decreased activity of a transaminase in serum); urinalysis (decreased specific gravity of urine); organ weights (decreased spleen weight); histopathology (minimal changes in the liver).

The dermal repeated dose study was a guideline study (similar to OECD 411) published by the US National Institutes of Health, 1998a. This 90-day dermal study is a mouse study where the highest doses for males (1300 mg active ingredient per kilogram body weight per day) and the highest dose for females (1620 mg a.i./kg bw /day) resulted in epidermal hyperplasia. No other adverse effects were observed. The NOAEL for females is 540 mg a.i./kg bw /day and the NOAEL for males is 440 mg a.i./kg bw /day which is therefore the repeat dose dermal NOAEL for the test substance. No adverse effects were reported in the 90 day mouse study.

The two important routes of exposure have been addressed. Hence no need for an inhalation repeated dose.

Category Justification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances.

Applying the category approach read-across concept to SDIBP, data will be used from a representative member of the hydrotropes category to avoid unnecessary (animal) testing. The endpoints for which the read-across approach to SDIBP is applied, are: toxicokinetics, short-term toxicity to fish, toxicity to microorganism, acute toxicity (inhalation and dermal), skin irritation/corrosivity, skin sensitisation, genetic toxicity (in vitro, in vivo), repeated-dose toxicity (oral and dermal), screening for carcinogenicity, and screening for reproductive / developmental toxicity.

Hazard assessment related key information for SDIBP:

SDIPB and the hydrotrope members exhibit similar levels of low toxicity. Acute toxicity values are above the classification limits, they are not sensitizing and show no genotoxic effects. Both exhibit neglible irritation to the skin, but are moderately irritating to the eyes (Cat 2B). Together with the chemical structure similarity and their similar chemical properties, it is deemed correct to fill the existing data gaps on mammalian toxicity of SDIPB with the data of the hydrotrope category.


Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: spleen

Repeated dose toxicity: dermal - systemic effects (target organ) other: skin

Justification for classification or non-classification

No classification is warranted for the repeated dose toxicity as indicated according to the general classification and labeling requirements for dangerous substances and preparations (Directive 67-548-EEC) or the classification, labeling and packaging (CLP) regulation (EC) No 1272/2008.

Value used for CSA (route: oral): NOAEL 763 mg/kg bw/day

Target organs: cardiovascular / hematological: spleen

Value used for CSA (route: dermal): NOAEL 440 mg/kg bw/day

Target organs: other: skin