Registration Dossier

Administrative data

Description of key information

Subacute oral toxicity was tested according to OECD 407 method in male rats at 0.25, 0.5 and 1 % in the diet for 32 days, corresponding with average doses of 240, 510 and 960 mg test material/kg bw. Subchronic oral toxicity was furhter tested equivalent to OECD 408  method in male and female rats at 1% in the diet for 90 days,corresponding with ca. 750 mg act. ingr./kg bw.  These studies did not reveal toxicity, therefore 1% in the diet, corresponding with ca. 750 mg act.ingr./kg bw can be accepted as NOAEL.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1969
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
The study was conducted according to internationally accepted test guidelines and is considered relevant, adequate and reliable. There were some deviations from the study guidelines, however these did not affect the conclusions and the validity of the study.
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
no
GLP compliance:
no
Limit test:
yes
Species:
rat
Strain:
other: Charles River albino
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Source: Charles River Breeding Laboratories, North Wilmington, Mass.
- Age at study initiation: Not provided
- Weight at study initiation: 100g (female rats), 121g (male rats) on average
- Housing: individually in standard wire-bottomed steel rat cages
- Diet : standard rat ration blended with the appropriate amount of test material in a Hobart Mixer
Fresh diets were prepared each week. Each rat was offered an amount of diet sufficient for one
week ‘ad libitum’ feeding. However, checks were made periodically to ensure that the food jars were
not empty
- Water: No data provided
- Acclimation period: Not provided

ENVIRONMENTAL CONDITIONS
Not provided


Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: 1.0% in the feed
Taking into account a mean body weight of 250 g and a mean food consumption of 20g/rat/day
(Derelanko M.J., 2008, The Toxicologist's Pocket Handbook, Informa).
1% in the diet = 10000 mg/kg diet corresponds with 10 mg/g diet
20 g feed/rat (250g bw)/day = 80 g feed/kg bw/day = 0.8 g active ingredient/kg bw/day = 800 mg/kg bw/day.
A higher feed intake is possible, e.g. 1000 mg/kg at higher body weight and feed intake, but from a conservative viewpoint 750 mg/kg bw is taken


DIET PREPARATION
- Rate of preparation of diet (frequency): Fresh diets were prepared each week
- Mixing appropriate amounts with (Type of food): standard rat ration
- Storage temperature of food: Not provided

VEHICLE: No Vehicle
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
1.0 %
Basis:
nominal in diet
No. of animals per sex per dose:
For Aerosol A-196: 20 male and 20 female at 1.0 % and 20 male and 20 female as control
Control animals:
yes, plain diet
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily during the investigation

BODY WEIGHT: Yes
- Time schedule for examinations: day 0, 15, 30, 45, 60, 75 and 90.

FOOD CONSUMPTION : Yes

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 84 days
- Anesthetic used for blood collection No data
- Animals fasted: Yes (fasted serum glucose concentration)
- How many animals: 5 rats of each sex (=10) and 10 control
- Parameters checked in table [No. IV and V] were examined.
Hematocrit Value
Erythrocyte Count
Hemoglobin Concentration
Total Leukocyte Count
Differential Leukocyte Count


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after 84 days
- Animals fasted: Yes(fasted serum glucose concentration)
- How many animals: 5 rats of each sex (=10) and 10 control
- Parameters checked in table [No.VI and VII] were examined.
Blood Urea Nitrogen (BUN) Concentration
Serum Alkaline Phosphatase (SAP) Activity
Serum Glutamic-Pyruvic Transaminase (SGPT) Activity
Fasted Serum Glucose Concentration


URINALYSIS: Yes
- Time schedule for collection of urine: after 84 days
- Metabolism cages used for collection of urine: No data
- Animals fasted: Yes
- Parameters checked in table [No.VIII] were examined.
Glucose Concentration
Albumin Concentration
Microscopic Elements Examination
pH
Specific Gravity



NEUROBEHAVIOURAL EXAMINATION: No


OTHER: Organ Weight and Organ to Body and Organ to Brain Weight Ratios
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
ORGAN WEIGHTS: Yes
Other examinations:
Organ Weight and Organ to Body and Organ to Brain Weight Ratios (no effects)
Statistics:
Statistical analyses were conducted upon the absolute organ weights and their corresponding ratios to the weight of the body. An Analysis of Variance was conducted first and any significant effects disclosed by that treatment were further studied by “t” –tests.

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:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
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:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Dose descriptor:
NOAEL
Effect level:
ca. 750 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: No effects up to highest concenrtration
Critical effects observed:
not specified
Conclusions:
The comparisons of final body weights and total weight gains revealed no statistically significant differences between test and control animals.
No outstanding differences in food consumption were noted between test rats and control rats.
No deaths or abnormal behavioral reactions were noted among any of the animals employed in the study.
No outstanding differences between test and control rats were noted with respect to any of the blood parameters studied.
No significant differences between the urine of test rats and control rats were observed.
No outstanding differences between test and control rats were noted at the time of gross pathological examination.
There were no significant differences between the tissues of test and control rats observed upon histopathological examination.
Executive summary:

Six groups of 40 albino rats (20 male, 20 female, Charles River strain) plus 1 control group (20 male + 20 female) were fed with 1% of various test items mixed into the diet. The various test items were category members of the Sulfosuccinates Diester Group including Butanedioic acid, sulfo-, 1,4-dicyclohexyl ester, sodium salt. After 84 days 5 hematological values, 4 blood chemical values and 5 urinalysis values were measured for all animals. 40 tissues have been examined pathologically at the conclusion of the 90-days test period. Organ to body weight and organ to brain weight ratios were calculated. No significant differences in clinical blood chemistry studies and absolute organ weights have been detected. Body weights, organ to body weight ratios, hematologic studies and urinalysis were not different between test and control animals. No deaths or abnormal behavioral reactions occurred; no gross pathological findings were noted. Category members of the test item at 1% in the diet (10000 ppm equivalent to 750 mg/kg bw/day) for 90 days in rats did not result in any relevant changes in the subchronic toxicity study. The NOAEL was therefore considered to be 750 mg/kg bw/day.

The IBT Report, supplemented by the Intox report and the Validation Report of October 15, 1983, may be considered a valid study and the data and conclusions relied upon.

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1969
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
significant methodological deficiencies
Remarks:
The study was not performed under GLP, however the study was conducted according to standards of that time, therefore the study is considered to be adequate, reliable and relevant. However, there was no clinical pathology nor histopathology conducted in this study.
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
32 days exposure
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Not provided
- Age at study initiation: Not provided
- Weight at study initiation: mean weight 150-151 g
- Fasting period before study: 24 hours
- Housing: Not provided
- Diet (e.g. ad libitum): Not provided
- Water (e.g. ad libitum): Not provided
- Acclimation period: Not provided

ENVIRONMENTAL CONDITIONS
Not provided

IN-LIFE DATES: Not provided

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Not provided
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
32 days
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0.25%; 0.5%; 1.0% and 0% (control)
Basis:
other: test material nominal in diet
Remarks:
Doses / Concentrations:
240, 470 and 960 mg/kg bw
Basis:
other: test material nominal in diet
No. of animals per sex per dose:
5 males + 5 females
Control animals:
yes, concurrent no treatment
Details on study design:
Not provided
Positive control:
no
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: Initial and terminal

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption calculated as g : Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

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


OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No


Sacrifice and pathology:
GROSS PATHOLOGY: Yes for the control group and the 1.0% test group
HISTOPATHOLOGY: No
Statistics:
The method of multiple comparisons was used to evaluate food intake and weight gain data.
Covariance was used to evaluate adjusted weight gain data.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
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:
not examined
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Dose descriptor:
NOAEL
Effect level:
960 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: mean calculated
Dose descriptor:
NOAEL
Effect level:
768 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: based on 80% purity
Critical effects observed:
not specified

Table 1. SURFACTANT E-196: Summary of results of thirty-two daily doses in the diet of albino rats.

              

Concentration in diet (%)

0

0.25

0.5

1.0

Number of animals (M+F)

5+5

5+5

5+5

5+5

Mean dosage( g/kg/day)

-

0.24

0.47

0.96

Mean food intake (g)

589.1

604.7

592.1

603.5

Mean initial weight (g)

143.3

143.3

143.3

143.3

Mean weight gain (g)

102.8

114.5

108.9

107.5

Mean adjusted weight gain (g)

102.8

112.1

110.7

105.5

Number of deaths

0

0

0

0

Mean no. of days to death

-

-

-

-

 

At autopsy hydronephrosis was observed more frequently in the control than in the test animals. This condition has been observed previously in this strain of rat an it is considered to be spontaneous in nature. No relevant gross lesions were observed. Since animals at the high intake level were free of treatment-related lesions, animals from the 0.25% and 0.5% group were not autopsied. No significant interaction between sex and treatment was found, indicating that males and females were affected similarly by the treatment. Therefore, observations on males and females were combined for subsequent statistical analyses. The method of multiple comparisons was used to evaluate food intake and weight gain data. Covariance was used to evaluate adjusted weight gain data.

 

Conclusions:
There were no significant differences (p<0.05) in mean food intake, mean weight gain, or mean adjusted weight gain between the test and control
groups.
Executive summary:

Aerosol A-196 was incorporated into the diet to give concentrations of 0.25%, 0.5% and 1.0% , corresponding with 240, 470 and 960 mg test material/kg bw, and fed at these levels to groups of young rats, 5 males and 5 females per group, for 32 days. A similar group of 10 animals of both sexes served as controls. Body weight and food intake were recorded for each animal. At the end of the feeding period, the animals were killed and those from the control and 1.0% test groups were given a thorough gross autopsy.

There were no deaths during the test period and the overall appearance and behavior of both the test and control animals were good.

There were no significant differences (p<0.05) in mean food intake, mean weight gain, or mean adjusted weight gain between the test and control groups. Taking into account that the test product contained 80% active ingredient, the highest dose level corresponded with 768 mg act. ingr./kg bw and can be considered as NOAEL. Based on the fact that no histopathology neither clinical pathology was done, this study is considered to be a supporting study.

Endpoint:
chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
Read across argumentation is provided in Section 13.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
After an initial lag about a month, the rate of increase in weight of experimental animals was about the same as for the controls, although they never attained the same absolute increase
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
The red-cell picture of rats is unaffected by the continued daily ingestion of Aerosol-OT, at least in doses up to 0.9 g/kg. The total number of white cells is unaffected by the administration of Aerosol-OT.
Dose descriptor:
NOAEL
Effect level:
750 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Critical effects observed:
not specified
Conclusions:
Occasional spells of diarrhea occurred in some animals, particularly at the higher doses.
Neither the total red cell, total white cell, nor the differential counts of rats was affected by the continued administration of read-across substance Aerosol-OT. In a
special experiment, however, a very transient shift in the differential count was observed, the neutrophils being increased at the expense of the lymphocytes. However, no general trend could be decided.
Executive summary:

Groups of 10 (5 male & 5 female) Wistar rats were treated for 6 months at concentrations of 0.25, 0.5, 0.75, 1.0 and 1.25 g/kg diet, corresponding to doses of 190, 370, 550, 750 and 870 mg/kg bw/day read-across substance Aerosol-OT.

Occasional spells of diarrhea occured in some animals, particularly at the higher doses. Neither the total red cell, total white cell, nor the differential counts of rats was affected by the continued administration of read-across substance Aerosol-OT. In a special experiment, however, a very transient shift in the differential count was observed, the neutrophils being increased at the expense of the lymphocytes. However, no general trend could be decided. The dose level of 750 mg/kg was therefore considered as NOAEL.

Endpoint:
chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
disregarded due to major methodological deficiencies
Justification for type of information:
Read across argumentation is provided in Section 13.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
diarrhea and anorexia
Mortality:
mortality observed, treatment-related
Description (incidence):
diarrhea and anorexia
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
weight loss
Gross pathological findings:
no effects observed
Dose descriptor:
NOAEL
Remarks on result:
not determinable
Remarks:
no NOAEL identified
Critical effects observed:
not specified

Of 7 rabbits receiving 500 mg/kg bw/day of Aerosol-OT daily, 2 had to be sacrificed at 16 and 20 weeks, respectively, the first because of an ear infection which failed to respond to treatment, and the second as the result of an unexplained broken femur.

The deaths of 3 of the remaining animals were considered as being due to the Aerosol-OT. The symptoms were the same in all 3 - severe diarrhea and anorexia. 2 of the deaths occured during the first week of the experiment while the third animal survived for 16 weeks. In the 2 animals surviving the full 24 weeks of the experiment, short periods of diarrhea were occasionally observed. Postmortem examination of the survivors and the animals which were sacrificed revealed no pathology.

Conclusions:
Two of five rabbits which received 0.5g/kg of read-across substance Aerosol-OT daily by stomach tube survived the full 6-month period. The only manifestations of toxicity in those which died were anorexia and severe diarrhea. Diarrhea was also observed in the survivors from time to time.
Gross and microscopic examination revealed no significant pathology in any of the animals which survived the full experimental period.
Executive summary:

Seven rabbits received read-across substance Aerosol-OT daily by stomach tube in the form of a 5% solution at the dose of 500 mg/kg bw/day.

Of 7 rabbits receiving 500 mg/kg bw/day of Aerosol-OT daily, 2 had to be sacrificed at 16 and 20 weeks, respectively, the first because of an ear infection which failed to respond to treatment, and the second as the result of an unexplained broken femur.

The deaths of 3 of the remaining animals were considered as being due to the Aerosol-OT. The symptoms were the same in all 3 - severe diarrhea and anorexia. 2 of the deaths occured during the first week of the experiment while the third animal survived for 16 weeks. In the 2 animals surviving the full 24 weeks of the experiment, short periods of diarrhea were occasionally observed. Postmortem examination of the survivors and the animals which were sacrificed revealed no pathology.

Endpoint:
chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
disregarded due to major methodological deficiencies
Justification for type of information:
Read across argumentation is provided in Section 13.
Reason / purpose for cross-reference:
read-across source
GLP compliance:
no
Limit test:
no
Duration of treatment / exposure:
6 months
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Gross pathological findings:
no effects observed
Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Critical effects observed:
not specified

Three animals receiving 125 mg/kg of Aerosol-OT by stomach tube remained in good health through the entire 24 weeks of the experiment and at autopsy exhibited no pathology.

Aerosol-OT is somewhat irritating to the stomach, for in monkeys the administration doses greater than 125 mg/kg resulted in prompt regurgitation.

Conclusions:
Three animals receiving 125 mg/kg of read-across substance Aerosol-OT by stomach tube remained in good health through the entire 24 weeks of the experiment and at autopsy exhibited no pathology.
Aerosol-OT is somewhat irritating to the stomach, for in monkeys the administration doses greater than 0.125 g/kg resulted in prompt regurgitation.

Executive summary:

Three monkeys (Macacus rhesus) received read-across substance Aerosol-OT daily by stomach tube in the form of a 5% solution at the dose of 125 mg/kg bw/day (initially 250 mg/kg bw/day, but this was regurgitated).

Aerosol-OT was somewhat irritating to the stomach, for in monkeys the administration doses greater than 125 mg/kg resulted in regurgitation. The animals dosed at 125 mg/kg bw/day remained in good health through the entire 24 weeks of the experiment and at autopsy exhibited no pathology.

Endpoint:
chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
disregarded due to major methodological deficiencies
Justification for type of information:
Read across argumentation is provided in Section 13.
Reason / purpose for cross-reference:
read-across source
Sex:
not specified
Clinical signs:
no effects observed
Description (incidence and severity):
Slight regurgitation at high dose levels.
Mortality:
no mortality observed
Description (incidence):
Slight regurgitation at high dose levels.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Decreases in weight (see Table 1) are not considered as toxicity. The animals had a tendency to overeat, so during the experiment, they were given reduced but sufficient food in order to have the exact dosing regimen. Dog D-38, being in overweight at init
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Critical effects observed:
not specified

Table1. Weight changes in dogs

Dog No.

Sex

Dose (mg/kg)

Initial weight (kg)

Final weight (kg)

% changes in weight

D-27

F

250

12.0

11.6

-3.3

D-30

F

250

11.2

10.6

-5.4

D-29

M

250

15.0

14.0

-6.7

D-26

F

100

12.0

11.5

-4.2

D-36

F

100

23.9

24.0

0

D-38

M

100

8.0

6.5

-18.8

Conclusions:
Three dogs receiving 100 mg/kg and three others receiving 250 mg/kg of read-across substance Aerosol-OT daily in their food remained in good health for 6 months.
Although slight regurgitation was observed at 250 mg/kg bw/day, this was not considered to be adverse.
Executive summary:

Six dogs (2 males & 4 females) were treated for 6 months at concentrations of 100 and 250 mg/kg read-across substance via the feed.

Three dogs receiving 100 mg/kg and three others receiving 250 mg/kg of read-across substance Aerosol-OT daily in their food remained in good health for 6 months. Although slight regurgitation was observed at 250 mg/kg bw/day, this was not considered to be adverse.

The dose level of 250 mg/kg bw/day was therefore considered as NOAEL.

Endpoint:
chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
Read across argumentation is provided in Section 13.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
All dogs had a weight gain during the 1 year study
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: no

BODY WEIGHT AND WEIGHT GAIN: During the first half of the study there was moreor less steady increase in all groups. By weeks 20 to 28, mean body weights had reached a plateau and thereafter the dogs either maintained their weight or gained only slightly. All dogs had a weight gain during the 1 year study.

HAEMATOLOGY: Several non-compound related changes were present, generally at pre-dose bleedings, in both control and treatment groups.
Erythrocyte, hemoglobin and hematocrit values slightly below normal ranges indicated a mild normocytic hypochromic anemia during the pre-dose
period in several dogs in each group. Pre-dosed blood samples indicated a leukocytosis often with neutrophilia in several dogs in most groups.

CLINICAL CHEMISTRY: Also slightly decreased serum albumin values were found in some of the dogs on days -28 and -7. During the 1 year of compound administration scattered values were not within normal ranges but fit no particular pattern in relation to the dose or in relation to the duration of dosing. These variations were considered due to biological variation rather than any compound effect.

URINALYSIS: no effects

ORGAN WEIGHTS: all wihtin normal range

GROSS PATHOLOGY: no compound related changes

HISTOPATHOLOGY: NON-NEOPLASTIC: Microscopic examination did reveal focal areas of consolidation in the lung and focal lymphocytic infiltration in the thyroid of several dogs. Both of these minor tissue changes are not uncommon ion laboratory Beagles. In the myenteric plexus of the posterior colon neurons were somewhat less numerous. The histologic appearance of the myenteric plexus of the dogs in all goups was in accordance with the normal description of Schofield

HISTOPATHOLOGY: NEOPLASTIC (if applicable): no
Dose descriptor:
NOAEL
Effect level:
> 30 mg/kg bw/day (nominal)
Sex:
male/female
Critical effects observed:
not specified
Conclusions:
The chronic administration of read-across substance DSS to dogs at levels several times greater than recommended human doses did not cause any adverse effects.
Executive summary:

Four male and four female beagle dogs were given tablets with read-across test material daily (7 days/week) for 1 year at the dose of 30 mg read-across substance docusate sodium/kg bw/day did not cause any adverse effects.

Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
An OECD 408 (90-day study) has been started 2016 based on ECHA Communication number CCH-D-2114330559-45-01/F. The results will be provided as soon as possible with an update of the dossier.
Adequacy of study:
supporting study
Study period:
from 2016/2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
An OECD 408 (90-day study) has been started 2016 based on ECHA Communication number CCH-D-2114330559-45-01/F. The results will be provided as soon as possible with an update of the dossier.
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
water
Analytical verification of doses or concentrations:
yes
Control animals:
yes
Dose descriptor:
other:
Remarks on result:
other: An OECD 408 (90-day study) has been started 2016 based on ECHA Communication number CCH-D-2114321066-61-01/D. The results will be provided as soon as possible with an update of the dossier.
Critical effects observed:
not specified

An OECD 408 (90-day study) has been started 2016 based on ECHA Communication number CCH-D-2114330559-45-01/F. The results will be provided as soon as possible with an update of the dossier.

Executive summary:

An OECD 408 (90-day study) has been started 2016 based on ECHA Communication number CCH-D-2114330559-45-01/F. The results will be provided as soon as possible with an update of the dossier.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
750 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Klimisch 2

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: dermal
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: dermal
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Subacute toxicity

Feeding the registered substance (80% purity) for 32 days at concentrations of 0.25, 0.5 and 1 % in the diet of young male albino rats resulted in no significant signs of toxicity (American Cyanamid Company, 1969). These concentrations corresponded with mean test item intake of about 240, 470 and 960 mg/kg bw, respectively. Appearance and behaviour of the animals were normal, and at sacrifice and autopsy at the conclusion of the feeding period, there was no gross pathology that could be attributed to ingestion of the test item. Administration of test item up to 1% in the diet for 32 days in rats did not result in any relevant changes in the subacute toxicity study. Taking into account that the test item contained 80% active ingredient, the highest dose level corresponded with a NOAEL of 768 mg act.ingr./kg bw.

Subchronic and chronic toxicity 

In a key subchronic oral repeated dose toxicity study with the registered substance, six groups of 40 albino rats (20 males, 20 females) plus 1 control group (20 males, 20 females) were fed with 1% of various test items mixed into the diet . The various test items were category members of the Sulfosuccinates Diester Group including Butanedioic acid, sulfo-, 1,4-dicyclohexyl ester, sodium salt (Plank et al., 1969). After 84 days hematological values, blood chemical values, urinalysis values were measured for all animals, and tissues were examined pathologically at the conclusion of the 90-days test period. Organ to body weight and organ to brain weight ratios were calculated. No significant differences in clinical blood chemistry studies and absolute organ weights have been detected. Body weights organ to body weight ratios, hematologic studies and urinalysis were not different between test and control animals. No deaths or abnormal behavioral reactions occurred; no gross pathological findings were noted. Administration of category members at 1% in the diet (10000 ppm equivalent to ca.750 mg/kg body weight/day) for 90 days in rats did not result in any relevant changes in the subchronic toxicity study. The NOAEL was therefore considered 750 mg act. ingr./kg bw/day.

The validity of the study was supported by additional audits on the raw data and histopathological evaluation. Although deficiencies were detected compared to current standards, the study was concluded to be valid and reliable.

In a supporting study, groups of 10 (5 male & 5 female) Wistar rats were treated for 6 months at concentrations of 0.25, 0.5, 0.75, 1.0 and 1.25 g/kg diet, corresponding to doses of 190, 370, 550, 750 and 870mg/kg bw/day. Occasional spells of diarrhea occurred in some animals, particularly at the higher doses. Neither the total red cell, total white cell, nor the differential counts of rats was affected by the continued administration . The dose level of 750 mg/kg was confirmed as NOAEL (Literature, Benaglia et al. 1943).

Other studies were also available from literature in various species (Literature, Benaglia et al. 1943 and Case et al., 1977) in dogs, rabbits and Rhesus monkeys. The other species were considered to be less appropriate due to the gastrointestinal tensioactive local irritation by which systemic effects could not be fully evaluated.

 

General assessment and conclusion

- The fact that no relevant target organ changes were seen up to highest concentration of 1% in diet for both 32 and 90 days, allows to conclude that corresponding intake of 750 mg/kg bw is NOAEL.

- Further information supporting the safety of the test substance is provided in the read across justification for the Diester category, showing that all substances in the group had a NOAEL of at least 750 mg/kg bw (justification with data matrix separately attached in Section 13).

A new 90 -day repeated dose toxicity study in rats was requested based on ECHA Communication number CCH-D-2114321066-61-01/D. The results will be provided as soon as possible with an update of the dossier.Docusate sodium was used as read across substance for the registration of potassium 1,2-bis(2-ethylhexyloxycarbonyl)ethanesulphonate (CAS 7491-09-0). Based on information gaps in the old 90 -day study, ECHA requested a new subchronic toxicity (90 -day) study in rats by oral route. The new study with docusate sodium will be conducted for both the registrations of bothpotassium 1,2-bis(2-ethylhexyloxycarbonyl)ethanesulphonate and docusate sodium.


Justification for classification or non-classification

As there were no changes observed in the repeated dose toxicity studies up to 1% in the diet (corresponding to >750 mg act. ingr./kg bw/day), classification is not warranted according to the EC Directive (No.93/21/EEC) and CLP (No. 1272/2008 of 16 December 2008).