Registration Dossier

Administrative data

Description of key information

The toxicity of the substance has been assessed by the repeated exposure over a period of 28-days by the three routes of exposure, oral, dermal and inhalation. Effects observed by oral exposure demonstrate a reduction in serum cholesterol at the highest tested dose. Furthermore, the results obtained by inhalation exposure are considered unsuitable for determination of the intrinsic hazard of the substance by inhalation due to the high proportion of mineral oil in the test sample [Test material: Product as manufactured in mineral oil solvent further diluted in mineral oil (65/35)].

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:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted to OECD guidelines to to GLP, and therefore meets the requirements for Klimisch code 1.
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
A fuctional observation battery for neurotoxicity was not performed since this test was not par of the OECD 407 guideline at the time the study was pedormed
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: 41 days
- Weight at study initiation: males, 179-215g; female 141-170g
- Housing: hanging stainless steel wire-bottom cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 14 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-23°C
- Humidity (%): 48-66%
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle
Route of administration:
oral: gavage
Vehicle:
peanut oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:Mixed weekly weight/volume in peanut oil


DIET PREPARATION
- Rate of preparation of diet (frequency): weekly

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chemical analysis of dosing solutions was conducted to confirm that they were homogeneous and met the desired concentrations.
Duration of treatment / exposure:
29 day treatment duration with a 14 day recovery period.
Frequency of treatment:
7 days/week.
Remarks:
Doses / Concentrations:
gavage doses of 0, 100, 500 or 1000 mg/kg/bw/day
Basis:
actual ingested
No. of animals per sex per dose:
6
Control animals:
yes
Details on study design:
- Dose selection rationale: Data from a pilot two week repeated dose oral study
Positive control:
No.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily


BODY WEIGHT: Yes
- Time schedule for examinations: Twice 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 data


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 AND COMPOUND INTAKE (if drinking water study): No
- Time schedule for examinations:


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Weekly
- Dose groups that were examined:


HAEMATOLOGY: Yes
- Time schedule for collection of blood: At termination
- Anaesthetic used for blood collection: No
- Animals fasted: Yes
- How many animals: All



CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At termination
- Animals fasted: Yes
- How many animals: All



URINALYSIS: Yes
- Time schedule for collection of urine: Overnight before termination
- Metabolism cages used for collection of urine: No
- Animals fasted: Yes


NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Tests applied included; parametric ANOVA with Dunnetts post-hoc test, non parametric Kruskal-Wallis and Mann-Whitney U test, Bartletts test for equal variances, Students t test and Dixons teat for rejection of outlying values
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Stained fur was observed in high dose animals, scabbed skin occurred in one control male and high dose female displayed sneezing and abnormal respiratory sounds.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One animal was sacrificed on Day 0 and one animal was found dead on Day 9, a result of probable misdosing.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No statistically significant differences were observed in mean bodyweights or body weight gains.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
A statistically significant increase in food consumption was observed in low dose males compared with controls.
Food efficiency:
no effects observed
Description (incidence and severity):
No statistically significant differences were observed in food efficiency.
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Male mean cell haemoglobin concentrations were significantly decreased compared with the controls at all dose levels. However, these were not considered to be biologically significant, as there was no dose response trend. A statistically significant increase in partial thromboplastin time was observed in mid and top dose males compared with controls. Prothrombin time was significantly increased in the mid and high dose females during the treatment period, and was significantly reduced in males in the recovery group. This were within normal limits and therefore not considered to be biologically significant. A statistically significant increase in the reticulocyte count was observed in treated males in the recovery group, however, was not considered to be biologically significant
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
A statistically significant decrease in serum cholesterol was observed in high dose males and females and persisted in females into the recovery period. These are considered to be treatment related.

Statistically significant increses were observed in alaninine aminotransferase, lactic dehydrogenase, aspartate aminotransferase, sodium, phosphorus and triglycerides were observed as well as decreases in albumin and chloride.There was no dose related trend with these changes, therfore they are not considered to be treatment related.
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
A statistically significant increase in specific gravity was observed in low dose males. Urine volume was significantly reduced in treated males in the recovery group. This was not considered to be biologically significant
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No statistically significant differences were observed.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No substance related macroscopic changes were observed.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No substance related microscopic changes were observed.
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Key result
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Mean serum cholesterol levels were significantly reduced in the 1000 mg/kg males and females at termination of dosing. this was still significantly reduced in 1000 mg/kg females at the end of the 14 day recovery period.
Critical effects observed:
not specified

Table 1: Average body weights and body weight gains during xx days of treatment

 

Dose rate (ppm)

Body Weights (g)

 

Total Weight Gain

Week 0

Week 1

Week 2

Week 3

Week 4

g               

% of control

Male

 0

195

243

286

323

352

157

181

100

196

245

298

340

374

175

191

500

200

245

289

329

362

162

181

1000

193

240

283

315

346

154

179

Female

  0

155

175

194

213

223

67

144

100

156

174

194

215

228

72

146

500

154

175

190

212

221

67

144

1000

155

174

195

212

224

69

145

 

Conclusions:
A NOAEL of 500 mg/kg bw/day was identified in this study.
Executive summary:

In a subchronic toxicity study calcium sulphonate was administered to 12 Sprague-Dawley rats/sex/dose in the control and top dose groups and 6 animals Sprague-Dawley rats/sex/dose in the low and mod dose via gavage at dose levels of 0, 100, 500 or 1000 mg/kg bw/day).

 

A decrease in serum cholesterol levels occurred in the top dose group. The LOAEL is 1000 mg/kg bw/day, based on  a decrease in serum cholesterol at the top dose.  The NOAEL is 500 mg/kg bw/day.

 

This subchronic toxicity study in the rat is acceptable and satisfies the guideline requirement for a subchronic oral study (OPPTS 870.3100; OECD 408) in rats.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
881.58 mg/m³
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
881.58 mg/m³
Study duration:
subacute
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Exposure was initiated November 28, 1987 and terminal sacrifice was December 21, 1987.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.
Qualifier:
no guideline followed
Principles of method if other than guideline:
To evaluate the potential dermal effects of OS#68022C when administered dermally to Sprague-Dawley rats over four weeks to the shaved intact dorsal skin.
GLP compliance:
yes
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
Test Animals- Source: Sixty-six CD male rats were received in good condition from Charles River Breeding Laboratories, Inc., Wilmington, Massachusetts.

- Age at study initiation: Approximately 6 weeks old

- Weight at study initiation: 140 to 172g

- Fasting period before study:Not applicable

- Housing: Individually in stain less - steel wire-mesh cages suspended above cage paper.

- Diet: The animals were allowed free access to food; basal ration, NIH Open Formula 07 Rat and Mouse Diet (certified), (Zeigler Brothers, Inc, Gardners, PA).

- Water - animals were allowed free access to tap water supplied to the test facility and monitored for contaminants at periodic intervals according to FDRL Standard Operating Procedures.

- Acclimation period: 20-day acclimation and pre test period.

ENVIRONMENTAL CONDITIONS

- Temperature Range: Not advised

- Humidity Range : Not advised

- Air changes (per hr): Not advised

- Photoperiod (hr dark / hrs light): 12 hours continuous light and 12 hours darkness

IN-LIFE DATES: The study was initiated on November 23, 1987 (first day of treatment) and the in-life phase completed on December 21, 1987.



Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
The test articles were applied undiluted to the shaved intact dorsal skin of each test animal five days per week for four weeks for a total of 20 applications.

The test articles were applied evenly by gentle inunction over the test site using a syringe and a glass rod.

The test articles were held in place with 2 layers of gauze and non irritating tape. All rats were fitted with collars to prevent ingestion of the test articles during the exposure period.

At the end of the six hour exposure period, the dressings were removed and the test sites wiped with a mineral oil gauze to remove as much unabsorbed test article as possible. These sites were then wiped with a clean, dry gauge t o remove any excess mineral oil.

Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Not applicable
Duration of treatment / exposure:
Six hour exposure period.
Frequency of treatment:
Once daily for five days per week over a four week treatment period.
Remarks:
Doses / Concentrations:
1000 mg/kg bodyweight
Basis:
nominal per unit body weight
No. of animals per sex per dose:
Five males per test article
Control animals:
other: Although not identified as such, two groups were considered to be control groups.
Details on study design:
- Dose selection rationale:

The selected route of administration was topical, since dermal contact is a likely route of exposure for the general population.

- Rationale for animal assignment (if not random):

Random

- Rationale for selecting satellite groups:

Not applicable

- Post-exposure recovery period in satellite groups:

Not applicable

- Section schedule rationale (if not random):

Random

Positive control:
No
Observations and examinations performed and frequency:
- Mortality Check:
All animals were observed for mortality and overt signs of toxicity twice daily at least 5 hours apart.

- Physical Examination: see appended Appendix 2.
All animals received a detailed physical examination weekly.

- Body Weights: see appended Appendices 3 and 4.
Individual body weights were measured on the first day of test article administration and weekly thereafter.

- Food Consumption: see appended Appendix 5.
Individual food consumption was measured weekly beginning with the first day of test article administration.

Dermal Irritation: see appended Appendix 5.
Application sites were examined for dermal irritation once daily throughout the study period.

Dermal irritation was evaluated according to the method of Draize, 1965.

Sacrifice and pathology:
See attached Pathology Report (Appendix 7):

A complete necropsy examination was conducted on all animals sacrificed at study termination.

Necropsies were performed under the supervision of a board certified veterinary pathologist.

Animals were euthanized using CO2 gas.

Gross necropsy included examination of the external surfaces and orifices, the cranial cavity, carcass, the external and cut surfaces of the brain, the thoracic, abdominal and pelvic cavities and their viscera and the cervical tissues and organs. Untreated and treated skin and all gross lesions were removed from each animal and fixed in 10% neutral buffered formalin.

Other examinations:
Microscopic examination of paraffin embedded hematoxylin and eosin stained tissue sections was performed on the treated and untreated skin and gross lesions from all animals. All tissues were examined by S.W. Thompson, D.V.M., M.S., Diplomate A.C.V.P.
Statistics:
Continuous data including body weight, body weight gain and food consumption w ere analyzed using analysis of variance (Snedecor and Cochran,
1967).
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No test article related signs of toxicity were noted throughout the 4-week treatment period.

Three instances of sores and two observations of hair loss all in the neck region were noted. These findings were attributed to the collars worn by the rats during the 6-hour exposure period.
Dermal irritation:
effects observed, non-treatment-related
Description (incidence and severity):
No dermal irritation was noted when test articles OS#65657B, OS#68022C, OS#82288, OS#82289 and OS#75788 were applied at 1000 mg/kg to the skin for five days per week for four weeks.

Pinpoint scabbed areas were noted on the skin of one animal on study on Day 13 when OS#54090A was dosed at 1000 mg/kg. No other signs of dermal irritation were noted for this test article throughout the study period.

Pinpoint scabbed areas were noted on the skin of one animal on study Days 10 through 18 when OS#82287 was dosed at 1000 mg/kg. No other signs of dermal irritation were noted for this test article throughout the study period.

All animals exhibited dermal irritation when dosed with OS#44321P. Well-defined erythema was noted for one animal on study Day 3 and a second animal on study Day 3. The other 3 animals exhibited very slight erythema on study Day 3.

Other findings noted for this group included pinpoint scabbed areas and dry flaking skin. Two animals exhibited dermal irritation for the remainder of the 26 day study period. For animal numbers 0025, 0021 and 0023, no dermal irritation was noted on study days 20, 23 and 24 through day 28 respectively.
Mortality:
no mortality observed
Description (incidence):
No deaths occurred during the study period.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No differences in mean body weight or body weight gain were noted among the eight treated groups throughout the study period.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Mean food consumption, evaluated as grams per animal per week, was comparable among the eight treated groups throughout the study period
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
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Compound-related findings were noted at necropsy for two animals treated with GS#34321Y.
Animals numbered 0022 and 0023 exhibited pinpoint scabbed areas over the site of administration. These were the same rats that exhibited dermal irritation to the end of the study period when observed during the in-life phase.
The other findings noted at necropsy were instances of sores around the neck. These findings correlate with the in-life findings of sores and hair loss for the same animals. This was attributed to the collars worn during the 6-hour dosing period and not considered treatment related.
No other findings were noted at necropsy.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Compound-related microscopic effects were noted in 3 of the 5 rats treated with OS#44321Y. The lesions were observed on the treated skin sites and consisted of minimal (rat numbers 0023 and 0025) to mild (rat number 0022) multifocal eschars. In rat number 0022, mild multifocal hemorrhages in the underlaying dermis also were noted.
Histopathological findings: neoplastic:
not examined
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
All rats exhibited minimal hyperkeratosis of the epithelium accompanied by minimal acanthosis of the epidermis at the site of test article administration. Since this finding occurred in all groups and with essentially no differences in severity, it was considered a response of the skin to repeated shaving and exposure to a foreign material.
Key result
Dose descriptor:
NOEL
Effect level:
> 1 000 other: mg/kg to the skin
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Dermal applications of OS#68022C did not elicit a test article related effect when applied at a dose level of 1000 mg/kg to the skin for five days per week over a four week treatment period
Critical effects observed:
not specified
Conclusions:
Dermal applications of OS#68022C did not elicit a test article related effect as determined by weekly observations for physical changes and skin irritation and weekly determinations of body weight and food consumption when applied at a dose level of 1000 mg/kg to the skin for five days per week over a four week treatment period

OS#54090A and OS#82287 both elicited minimal dermal irritation. These effects appeared to be transitory as they occurred in only one animal for one day (OS#54090A) and nine days (OS#82287). No treatment-related effects were noted at necropsy or microscopically.

OS#44321Y produced signs of dermal irritation in all treated animals throughout the majority of the 28 day study period.

These signs included slight to well defined erythema, pinpoint scabbed areas and dry flaking skin.

Microscopic observations of minimal to mild multifocal eschar were noted in two rats and mild multifocal hemorrhages in the underlaying dermis in one rat.

OS#44321Y was irritating when applied at 1000 mg/kg to the skin five days per week for four weeks.
Executive summary:

Dermal applications of OS#68022C did not elicit a test article related effect as determined by daily observations for physical changes and skin irritation and weekly determinations of body weights and food consumption when applied at a dose level of 1000 mg/kg to the skin for five days per week over a four week treatment period. No treatment-related effects were noted at necropsy or microscopically.

 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
K1

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: study meets the criteria for Klimisch code 1
Qualifier:
according to guideline
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Sprague Dawley CD rats, 8-9 weeks of age at initiation
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
test substance was applied undiluted to the clipped dorsal surface for periods of 6h per day of study. material was held in place by a gauze patch secured with tape. after each exposure period the treated area was wiped. the procedure was repeated daily for 28d.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
6h per day for 28d
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0, 100,300 and 1000 mg/kg bwt
Basis:
nominal per unit body weight
No. of animals per sex per dose:
5
Control animals:
yes, sham-exposed
Positive control:
none
Observations and examinations performed and frequency:
clinical observations daily
dermal reposes on days 0,1,4,7,11,14,18,21,25 and prior to blood collection on d28
body weight and food consumption during treatment and recovery
Hematology and clinical chemistry at termination of treatment and recovery
Microscopic examination on all animals
Sacrifice and pathology:
full range of evaluations performed
Statistics:
ANOVA with Dunnets test, Kruskal-Walis, Dunns summed rank test , Jonkheere test for monotonic trend, Students t test
Clinical signs:
no effects observed
Description (incidence and severity):
Low incidences of very slight erythema, desquamation and / or pinpoint scabbing were observed sporadically in all treated animals. All animals were free of edema during the study.
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
Effects on the skin were seen in all groups including control but tended to increase in male treated animals and females in the 300 and 1000 mg.kg groups, indicating a mild irritant effect of the test article
Mortality:
no mortality observed
Description (incidence):
No mortality occurred during the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weights were unremakable.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption were unremakable.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment related differences in heamatology. Differences from control were noted for several heamatology parameters including a statistically significant increase in mean % of neutrophils of 300 and 1000 mg/kg females and a decrease in mean % of lymphocytes in the 1000mg/kg females compared to controls on d28. In the absence of differences from control in absolute white blood cell counts, these findings were not considered related to treatment. There was a statistically significant decrease in mean corpuscular haemoglobin concentration in the male satellite animals from d28-42. In the absence of other significant findings these small differences were not considered clinically significant. Serum chemistry values were unremakable
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Description (incidence and severity):
Gross post mortem findings were considered incidental and unrelated to treatment. There were no alterations in organ weights that were attributed to treatment.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
There were no test material related microscopic findings noted in any group.
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
dermal irritation
Critical effects observed:
not specified
Conclusions:
No evidence of systemic toxicity via the dermal route.
Executive summary:

The test substance exhibited no evidence of systemic toxicity via the dermal route under the conditions of this study when exposed to 5 Sprague Dawley CD rats/sex/dose over a period of 28 days. A NOAEL of >1000 mg/kg bwt was established.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
5.13 mg/cm²
Species:
other: human volunteers and laboratory species
Quality of whole database:
The limitations of the IUCLID do not allow allow for clear reporting of the most sensitive endpoints required for the CSA. Local effects from sensitistion assessment in humans and laboratory species provide more sensitive endpoints for local effects than the repeat dose toxicity data, where an absence of significant responses has been observed.

Additional information

The repeat dose toxicity has been determined by subacute 28-day oral toxicity studies by oral, dermal and inhalation exposure. Based on the data available, the substance may have the potential for haemotological effects with a reduction in cholesterol observed in one of the studies by oral exposure.

Effects observed in the repeat dose inhalation toxicity study available demonstrated enlarged lungs in high and intermediate dose animals which are likely to be physical effects due to the inhalation of mineral oil [Test material: Product as manufactured in mineral oil solvent further diluted in mineral oil (65/35)] and not necessarily a direct toxicological effect of the registered substance. The data are therefore considered unsuitable for determination of the intrinsic hazard of the substance as effects due to the registered substance may well be masked by the effects due to inhalation of mineral oil mist. For example, Occupation Exposure Limits (OELs) expressed for human exposure in the work place are typically 5 mg/m³. Considering a typical intraspecies assessment factor of 10 the results demonstrate good correlation to the anticipated effect level for mineral oil mist.

In view of this it is considered justifiable, for the purposes of assessing DNELs, to extrapolate inhalation hazard from the oral exposure data available.

Oral-to-inhalation extrapolation was based on the following conditions:

(1)         the available repeated dose toxicity study on EC 274-263-7 was reliable;

(2)         the critical effect for the oral exposure were systemic, i.e., decreased serum cholesterol levels;

(3)         the considered systemic toxic effects was independent of the route of exposure;

(4)         the chemical is relatively soluble in body fluid.

RtR extrapolation may require corrections for difference in absorptions between oral (starting route) and the inhalation (extrapolation route) (Dethloff, L. Z. 1993; Gerrity T. R., 1990; Sharrat M. 1988). Rennen et al. ran a critical assessment on oral-to-inhalation route extrapolation for 215 substances with various physicochemical properties. In this study, they compared the experimentally established NOAEL for inhalation study to the values predicted from oral toxicity study by RtR extrapolation using various absorption assumptions, such as 100% oral and 100% inhalation; 100% oral and 75% inhalation; 50% oral and 100% inhalation. And they demonstrated that when using systemic effect as criterion and under assuming equal absorption, 55% of the predication were regarded as “safe extrapolation”, whereas 45% as underestimation of the level of toxicity via inhalation route. Based on this study, it is feasible to assume that equal absorption for this substance. Correcting from oral to inhalation route of exposure was based on REACH guidance R8, and the mathematic formula was described in DNEL derivations.

Furthermore, one dermal repeat dose study exists noting effects which resulted in the Study Director being unable to assign a NOAEL. Due consideration of these data has been taken, but the results are considered not representative of the toxicological effects of the substance since the observations have not been repeated in the remaining study with dermal exposure, nor following exposure by oral and inhalation routes which are generally considered to represent greater systemic exposure routes. Furthermore, effects to the testes of male rats were not been observed in the reproductive toxicity study. In consequence, although data are not available to adequately determine the cause of these effects, the fact that no similar observations have been found in any other study undertaken is considered adequate justification to regard these data as not representative of the toxicological profile of the registered substance.

Notwithstanding these effects, no further effects were observed in the studies and each study achieved a NOAEL. The data are therefore considered adequate to assess the toxicological profile of the substance and for the purposes of classification.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

Data from two studies are available with exposure by oral gavage to linear and branched alkaryl benzene sulphonates upto a maximum dose of 1000 mg/ml/day.  Relatively slight effects were observed in either study, limited to a reduction in cholesterol in serum at high dose animals only in one study.  The lowest dose at which no adverse effects were observed effects were observed is, therefore, taken as the appropriate effect level.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:

The data from only one repeat dose toxicity test by the inhalation route is available.  The test substance is, however, extremely difficult to test by this route and, due to the nature of the substance in mineral oil, any effects due to the test sample are masked by the effects of the mineral oil.  The NOAEC is, therefore, determined by extrapolation to oral exposure.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:

The data from only one repeat dose toxicity test by the inhalation route is available.  The test substance is, however, extremely difficult to test by this route and, due to the nature of the substance in mineral oil, any effects due to the test sample are masked by the effects of the mineral oil.  The NOAEC is, therefore, determined by extrapolation to oral exposure.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:

The data from two studies are available to assess dermal toxicity by repeated dose.  No systemic toxicity was observed in either study.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:

Most sensitive endpoint for local effects is not the repeat dose toxicity but sensitisation data available from examinations in human volunteers and laboratory species NOAEL  taken from sensitisation.  NOAEL extrapolated from negative responses achieved by assessment of human volunteers.

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

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: lung

Justification for classification or non-classification

Based on the NOAEL values available from these repeat dose toxicity data, the substance is considered to be not classified under CLP for these endpoints.