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Description of key information

No data is available on the product Sodium diisobutylnaphthalenesulphonate (ANS DIB; C8-alkyl naphthalene sulfonate) itself. Evaluation is based on read-across to the comparable C7-alkyl naphthalene sulfonate ANS IP and other substances in the Alkyl Naphthalene Sulfonates (ANS) category. Acute toxicity testing (OECD 423) of Bis(1-methylethyl)-, methyl naphthalenesulfonate, sodium salt (ANS IP) resulted to an Oral LD50 cut-off 500mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
2016-10-21 to 2016-12-20
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
See chapter 13 for support for read-across within the category of Alkyl Naphthalene Sulfonates (ANS).
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
(Bayerisches Landesamt für Gesundheit und Lebensmittelsicherheit, München, Germany)
Test type:
acute toxic class method
Specific details on test material used for the study:
Name: Naphthalenesulfonic acid, bis(1-methylethyl)-, methyl derivs., sodium salt
CAS No.: 68909-82-0
Batch No.: 1452486
Physical State: powder
Colour: tan
pH Value: 7.5 – 10 in 5% solution
Purity: 100%
Expiry Date: 07 June 2021
Storage Conditions: at room temperature
Safety Precautions: The routine hygienic procedures were sufficient to assure personnel health and safety.
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
Housing and Feeding Conditions
- Full barrier in an air-conditioned room
- Temperature: 22 +/- 3 °C
- Relative humidity: 55 +/- 10%
- Artificial light, sequence being 12 hours light, 12 hours dark
- Air change: 10 x / hour
- Free access to Altromin 1324 maintenance diet for rats and mice
- Free access to tap water, sulphur acidified to a pH value of approximately 2.8 (drinking water, municipal residue control, microbiological controls at regular intervals)
- The animals were kept in groups in IVC cages, type III H, polysulphone cages on Altromin saw fibre bedding
- Certificates of food, water and bedding are filed for two years at BSL Munich and afterwards archived at Eurofins Munich
- Adequate acclimatisation period (at least five days) under laboratory conditions

Route of administration:
oral: gavage
Vehicle:
other: Aqua ad injectionem (AlleMan Pharma, lot no. 605070, expiry date: 04/2019)
Details on oral exposure:
The animals were marked for individual identification by tail painting.
Prior to the administration a detailed clinical observation was made of all animals. Only healthy animals were used.
Prior to the administration food was withheld from the test animals for 16 to 19 hours (access to water was permitted). Following the period of fasting the animals were weighed and the test item was administered. Food was provided again approximately 4 hours post dosing.
The test item was administered at a single dose by gavage using a feeding tube.
The test item was administered at a dose volume of 10 mL/kg body weight.

Doses:
The starting dose was selected to be 2000 mg/kg body weight. Compound related mortality was recorded for 3 animals of step 1. Based on these results and according to the acute toxic class method regime, a second step was performed at a dose of 300 mg/kg body weight. No compound related mortality was recorded for any animal of step 2. Based on these results and according to the acute toxic class method regime, a third step was performed at a dose of 300 mg/kg body weight. No compound-related mortality was recorded for any animal of step 3. Based on these results and according to the acute toxic class method regime no further testing was required.
No. of animals per sex per dose:
3 per step (3 steps performed)
Control animals:
no
Details on study design:
The surviving animals were observed for 14 days after dosing for general clinical signs, morbidity and mortality.
Weight Assessment
The animals were weighed on day 1 (prior to the administration) and on days 8 and 15.
Clinical Examination
A careful clinical examination was made several times on the day of dosing (at least once during the first 30 minutes and with special attention given during the first 4 hours post-dose). As soon as symptoms were noticed they were recorded. Thereafter, the animals were observed for clinical signs once daily until the end of the observation period. All abnormalities were recorded.
Cageside observations included changes in the skin and fur, eyes and mucous membranes. Also respiratory, circulatory, autonomic and central nervous systems and somatomotor activity and behaviour pattern were examined. Particular attention was directed to observations of tremor, convulsions, salivation, diarrhoea, lethargy, sleep and coma.
Pathology
The animals which were found dead during the observation period were necropsied at retrieval.
At the end of the observation period the surviving animals were sacrificed with an overdosage of pentobarbital injected intraperitoneally at a dosage of 250-400 mg/kg bw.
All animals were subjected to gross necropsy. All gross pathological changes were recorded and the tissues were preserved for a possible histopathological evaluation. The preserved tissues of which no histopathological evaluation was made will be discarded 3 months after the release of the final report unless otherwise agreed upon with the sponsor.
Evaluation of Results
Results were interpreted according to OECD Guideline 423, Annex 2 and GHS.
Individual reactions of each animal were recorded at each time of observation.
Toxic response data were recorded by dose level.
Nature, severity and duration of clinical observations were described.
The body weight changes were summarised in a tabular form.
Necropsy findings were described.

Statistics:
According to OECD guidelines, the biological relevance of the results is the criterion for the interpretation of results, a statistical evaluation of the
results is not regarded as necessary.
Key result
Sex:
female
Dose descriptor:
LD50 cut-off
Effect level:
ca. 500 mg/kg bw
Based on:
act. ingr.
Remarks on result:
other: Limit dose testd: 2000 mg/kg body weight
Mortality:
All animals treated with the test item at a dose of 2000 mg/kg were found dead on test day 1. All remaining animals survived until the end of the study without showing any signs of toxicity.
Clinical signs:
The most relevant clinical findings in the animals treated with the test item at a dose of 2000 mg/kg bw were reduced spontaneous activity, prone position, hunched posture, piloerection and half eyelid-closure.
Body weight:
Throughout the 14-day observation period, the weight gain of the surviving animals was within the normal range of variation for this strain.
Gross pathology:
Macroscopic findings of surviving animals:
At necropsy, no treatment-related macroscopic findings were observed in any animal of any step.
Macroscopic findings of animals not having survived until the end of the observation period:
Necropsy revealed blood in parts of the gastrointestinal tract.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Under the conditions of the present study, the median lethal dose of Naphthalenesulfonic acid, bis(1-methylethyl)-, methyl derivs., sodium salt after a single oral administration to female rats, observed over a period of 14 days is 500 mg/ kg bw (LD50 cut-off).
Executive summary:

Summary Results

One group of three female WISTAR Crl: WI(Han) rats was treated with the test item by oral gavage administration at a dosage of 2000 mg/kg body weight. The test item was suspended with the vehicle aqua ad injectionem (sterile water) at a concentration of 0.2 g/mL and administered at a dose volume of 10 mL/kg.

Two further groups, each of three female WISTAR Crl: WI(Han) rats, were treated with the test item by oral gavage administration at a dosage of 300 mg/kg body weight. The test item was suspended with the vehicle aqua ad injectionem (sterile water) at a concentration of 0.03 g/mL and administered at a dose volume of 10 mL/kg.

All animals used in the study after their entrance at BSL were allowed to acclimatise to the laboratory conditions for at least 5 days. The animals were observed on delivery, on inclusion in the study and before administration for mortality/morbidity and other clinical signs. All animals were examined for clinical signs several times on the day of dosing and once daily until the end of the observation period. Their body weights were recorded on day 1 (prior to the administration) and on days 8 and 15.All animals were necropsied and examined macroscopically.

Results per Step

Step Sex / No. Starting Dose (mg/kg bw) Number of Animals Number of Intercurrent Deaths
1 Female / 1 - 3 2000 3 3
2 Female / 4 - 6 300 3 0
3 Female / 7 - 9 300 3 0

bw = body weight

All animals treated with the test item at a dose of 2000 mg/kg were found dead on test day 1. All remaining animals survived until the end of the study without showing any signs of toxicity.

The most relevant clinical findings in the animals treated with the test item at a dose of 2000 mg/kg bw were reduced spontaneous activity, prone position, hunched posture, piloerection and half eyelid-closure.

Throughout the 14-day observation period, the weight gain of the surviving animals was within the normal range of variation for this strain.

Macroscopic findings of surviving animals:

At necropsy, no treatment-related macroscopic findings were observed in any animal of any step.

Macroscopic findings of animals not having survived until the end of the observation period:

Necropsy revealed blood in parts of the gastrointestinal tract.

 

LD50:                                      500mg/kg bw

Species/strain:                     WISTAR Crl: WI(Han) rats

Vehicle:                                  Aqua ad injectionem (sterile water)

Number of animals:            3 per step / 3 steps performed

Method:          OECD 423, EC 440/2008, Method B.1 tris, OPPTS 870.1100

Conclusion

Under the conditions of the present study, a single oral application of the test item Naphthalenesulfonic acid, bis(1-methylethyl)-, methyl derivs., sodium salt to rats at a dose of 2000 mg/kg body weight was associated with signs of toxicity and mortality.

Under the conditions of the present study, a single oral application of the test item Naphthalenesulfonic acid, bis(1-methylethyl)-, methyl derivs., sodium salt to rats at a dose of 300 mg/kg body weight was associated with no signs of toxicity or mortality.

The median lethal dose of Naphthalenesulfonic acid, bis(1-methylethyl)-, methyl derivs., sodium salt after a single oral administration to female rats, observed over a period of 14 days is:

LD50cut-off (rat):500mg/ kg bw

According to Annex I of Regulation (EC) 1272/2008 the test item Naphthalenesulfonic acid, bis(1-methylethyl)-, methyl derivs., sodium salt has obligatory labelling requirement for toxicity and is classified into Category 4.

According to GHS (Globally Harmonized Classification System) the test item Naphthalenesulfonic acid, bis(1-methylethyl)-, methyl derivs., sodium salt has obligatory labelling requirement for toxicity and is classified into Category 4.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
500 mg/kg bw
Quality of whole database:
Recent guideline study under GLP. Results are sufficient for classification purposes.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No data is available on the product Sodium diisobutylnaphthalenesulphonate (ANS DIB; C8-alkyl naphthalene sulfonate) itself. Evaluation is based on read-across to the comparable C7-alkyl naphthalene sulfonate ANS IP and other substances in the Alkyl Naphthalene Sulfonates (ANS) category. See chapter 13 for support for read-across within the category of Alkyl Naphthalene Sulfonates (ANS).

 

Oral:

The acute toxicity of Bis(1-methylethyl)-, methyl naphthalenesulfonate, sodium salt (ANS IP; C7-alkyl naphthalene sulfonate) by oral route was tested in a guideline study (OECD 423, Acute Toxic Class) under GLP. In a step-wise process, three groups of 3 female rats were dosed byoral gavage. The first three animals received 2000 mg/kg bw (10 mL/kg bw of 200 mg/mL). All were found dead on test day 1. Necropsy revealed blood in parts of the gastrointestinal tract. The next two groups of 3 females received 300 mg/kg bw (10 mL/kg bw of 30 mg/mL). All animals survived until the end of the study without showing any signs of toxicity and no treatment-related macroscopic findings were observed at necropsy after 14-day observation period.

These results indicate a LD50 between 300 and 2000 mg/kg bw. According to evaluation criteria of the Acute Toxic Class method, the LD50 cut-off is 500mg/kg bw.

This is a conservative approximation considering that repeated dosing with 700 mg/kg bw in reproduction screening studies (males 28 days, females up to 54 days) resulted to a mortality rate of 1/6 (female on PND 3) in the range finder study and 5/20 (3 females and 2 males all during first week) in the full study.

 

The low acute toxicity by oral route is further confirmed in comparable naphthalene sulfonate sodium salt products involving a somewhat higher average alkyl substitution (C10-13-alkylnaphthalene sulfonate), involving both high and low nonene substitution levels (ANS N). Overall, reports on the products with high and low nonene substituted show comparable, relatively low acute toxicity. The data suggests a slightly higher acute oral toxicity for the low-nonene product. For purpose of classification, the data point at an LD50 in range 2000-5000 for both pure C10-13- alkyl naphthalene sulfonate substances.

In comparison to these, Bis(1-methylethyl)-, methyl naphthalene sulfonate, sodium salt (C7-alkyl naphthalene sulfonate) with lower average alkyl chain length substitution seems to show a somewhat higher toxicity with LD50 below 2000 mg/kg bw.

 

Dermal:

Acute and repeated dose testing via oral route on ANS IP show that C7-alkyl naphthalene sulfonate is of relative low systemic toxicity.Although the acute testing with ANS IP resulted to a LD50 cut-off value of 500 mg/kg, lethality was only seen following 2000 mg/kg, and necropsy of dead animals revealed blood in parts of the gastrointestinal tract, suggestive for local effects rather than systemic toxicity. This is confirmed in the repeated dose toxicity study where some mortality was seen following dosing at 700 mg/kg bw where the effects in the stomach (ulceration, erosion) might have contributed to the morbidity. Also the NOAEL is based on local effects, and close examination shows that the only effects observed at 200 mg/kg are a slight lower BW compared to control (-6%) in males, and an increased combined effects in stomach upon histopathological examinations in males. Also should be considered that C7 Naphthalene Sulfonate is not expected to easily pass the skin in view of its ionised form at physiological conditions, and as the substance is irritating to skin, and effects will be characterized by irritation rather than systemic toxicity.

 

The product itself is a powder and is only applied industrially in formulation steps involving high control of exposures with the application of PPE, especially considering that the substance is classified as irritating to the skin. Also the indicated end use only involves professional applications. As the substance is irritating to skin, and is of relatively low acute toxicity, and in practice dermal absorption from a dry powder is limited, further testing for acute toxicity via the skin is not considered to bring more relevant hazard information.

 

The comparable C10-13-alkyl naphthalene sulfonate (ANS N (‘High nonene’) and ANS N (‘Low nonene’) also showed low acute dermal toxicity. However, contrary to C7-alkyl naphthalene sulfonate, it was found to be corrosive to the skin, and dermal testing resulted to desquamation, fissuring, eschar formation and exfoliation. No mortality occurred at 2000 mg/kg bw level.

 

 

Inhalation:

Testing of Sodium diisobutylnaphthalenesulphonate (ANS DIB) for acute inhalation toxicity is not appropriate. The vapour pressure of the test substance was determined to be 1.7 × 10-4Pa at 25 °C. Due to the very low vapour pressure inhalation of vapours leading to irritation of airways will not occur. Also the particle size is also mostly above respiratory size with aD50of 20.6 µm. The product itself is only applied industrially in formulation steps involving high control of exposures. Also the indicated end use only involves professional applications. Testing for acute toxicity by inhalation route is therefore generally not needed according to REACH regulation (EC) 1907/2006 (Annex VIII, point 8.5, column 2).

Furthermore, testing would also not be justified because of animal welfare reasons based on severe effects especially on mucosal epithelium. C7-alkyl naphthalene sulfonate (ANS IP) has proven to be irritating to skin showing low to no recovery, cat.1 damaging to the eyes and showing irritating and corrosive potential as based on local effects in stomach following acute and repeated oral, whereas otherwise systemic toxicity is low.

Justification for classification or non-classification

The results from the study according to the Acute Toxic Class method clearly results to an LD50 between 300 and 2000 mg/kg bg bw, requiring CLP classification to Category 4, H302: Harmful if swallowed.

No actual testing for dermal toxicity is performed, but considering general systemic toxicity following oral route, where effects are characterised by local effects on gastro-intestinal system, and further expected limited dermal absorption (compared to oral)in view of its ionised form at physiological conditions,and in practice dermal absorption from a dry powder is limited, systemic toxicity via dermal route is not expected, and further testing for acute toxicity via the skin is not considered to bring more relevant hazard information.

 

Based on its physical appearance as solid there is no need for classification for aspiration hazard.

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