Benzenesulfonic acid, 4-C10-13-sec-alkyl derivs., compds. with 2-propanamine

Endpoint summary

Description of key information

Oral toxicity:

In an acute oral toxicity study (fixed dose) fasted young adult female Wistar rats (one per dose) were given a single oral dose of  benzenesulfonic acid, 4-C10-13-sec-alkyl derivs.-, compd. with 2-propanamine (97%) at doses of 300 or 2000  mg/kg bw. No effects on the animals were seen at both dose levels, and therefore, the main study was performed with the higher dose of 2000 mg/kg bw. No adverse effects were seen and the oral LD50 is likely to be higher than 2000 mg/kg bw.

Dermal toxicity:

No studies on the toxic potential of the LAS-IPA itself after acute dermal exposure to this target substance were available. Therefore, the acute toxic effects of LAS-IPA on the skin were evaluated employing a read-across approach with IPA (2-propanamine) and LAS-Na (sodium 4-undecylbenzenesulfornate).

Acute dermal toxicity assay (according to OECD TG 402) with IPA resulted in an LD50 greater than 400 mg/kg bw. No further doses were tested. With lack of further information, it was not possible to use this study for classification.

The clipped skin on the backs of five male and five female rats were exposed to 2000 mg/kg LAS Na (limit dose) under an occlusive dressing for 24 hours and observed for another 14 days (according to OECD TG 402). Results indicate slight erythema and slight oedema but no acute mortality. The dermal LD50 is > 2000 mg/kg.

Based on these results, it can be inferred that LAS IPA is not acutely toxic after oral or dermal administration.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

Deviations:

no

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratoties UK Ltd.
- Age at study initiation: 8 -12 weeks
- Housing: up to 4 animals/group, suspended solid-floor polypropylene cages furnished with woodflakes
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 30-70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: no vehicle used

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

In the absence of toxicity data of the test material a dose of 300 mg/kg bw was applied initially to one animal. Since no mortality was observed 1 more animal was used to test the higher dose of 2000 mg/kg bw. No mortality was detected; four aditional animals were treated with a single gavage dose of 2000 mg/kg bw.

Doses:

300 and 2000 mg/kg bw

No. of animals per sex per dose:

One animal tested at 300 mg/kg bw, five animals treated with 2000 mg/kg bw.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 0.5, 1, 2 and 4 h post-treatment and daily for 14 days. Morbity/mortality checks twice per day. Weighing on Day 0, Day 7 and Day 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross necropsy.

Statistics:

not required

Preliminary study:

No toxic effects were seen in the sighting study at 300 mg/kg bw.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality observed

Clinical signs:

other: No signs of toxicity

Gross pathology:

No abnormalities detected

Interpretation of results:

GHS criteria not met

Conclusions:

In an acute oral toxicity study in female rats conducted according to OECD 420, no mortality and sign of toxicity occurred at 300 and 2000 mg/kg bw. Based on the results and in accordance with OECD guideline 420 the LD50 was determined to be higher than 2000 mg/kg bw. Thus, the classification of benzenesulfonic acid, 4-C10-13-sec-alkyl derivs.-, compd. with 2-propanamine (1:1) for acute oral toxicity according to the CLP regulation 1272/2008 is not warranted.

Executive summary:

In an acute oral toxicity study (fixed-dose procedure, OECD 420), one female Wistar rat and then five female Wistar rats were treated with a single dose of 300 mg/kg bw and 2000 mg/kg bw of benzenesulfonic acid, 4-C10-13-sec-alkyl derivs, compd. with 2-propanamine (1:1) (97% purity), by oral gavage respectively, and were observed for 14 days.

All animals survived until the end of the study. The sighting study at 300 mg/kg bw did not show any toxic effects. Therefore, the main study was performed with the higher dose of 2000 mg/kg bw. There were no treatment related clinical signs, necropsy findings or changes in body weight. Based on the results and in accordance with OECD guideline 420 the LD50 value was determined to be higher than 2000 mg/kg bw. Therefore, classification for acute oral toxicity according to the CLP regulation 1272/2008 is not warranted.

This acute oral study is classified as acceptable. It satisfies the guideline requirement for an acute oral study (OECD 420) in rats. 

Reference 2

Endpoint:

acute 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 approach - see read-across justification in section 13.

Reason / purpose for cross-reference:

read-across source

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: F. Winkelmann
- Weight at study initiation: 123 g female, 146 g male
- Fasting period before study:
- Housing: 1-5 animals in Makrolon cages,
- Diet (e.g. ad libitum): R10 Alleidiaet fuer Ratten, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 4-8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 1 degree C
- Humidity (%): 60 +/- 5
- Air changes (per hr): 15/hr
- Photoperiod (hrs dark / hrs light): 12 hrs light/12 hrs dark

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 12.5-19.9% in water

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

Doses:

LAS doses of 1075, 1220, 1360, 1710 or a control
Note that all doses are corrected for 86% activity. The original doses were 1250, 1415, 1580 and 1990 mg/kg.

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

Body weight and other signs were measured on days 7 and 14.
Animals were observed for 14 days after dosing.
Necropsies were performed at the end of the study.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 080 mg/kg bw

Based on:

test mat.

Mortality:

Virtually all animals died in doses of 1220 mg/kg and above.

Clinical signs:

other: Symptoms beginning about 30 minutes past application included diarrhea, squatting attitude, breathing difficulties, nose bleeding, ataxia, and lethargy. These symptoms had disappeared in surviving animals by 120 hours.

Gross pathology:

In the animals that died before the end of the study, red mucous was seen in the stomach and intestine. In the surviving animals, hyperemia of the stomach was noted, along with abnormalities of the stomach, liver, spleen, kidneys, and the peritoneum.

Table 1: Mortality

Dose (mg/kg)	Sex	Mortality
1075	Male	0
	Female	4
1220	Male	5
	Female	3
1360	Male	4
	Female	5
1710	Male	5
	Female	5

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The acute oral LD50 in rats was shown to be 1080 mg/kg. According to EU GHS guidelines, the test substance is classified as Category 4.

Executive summary:

This study examined the oral toxicity of the test substance in rats. Groups of 5 male and 5 female rats were exposed orally to 0, 1075, 1220, 1360, or 1710 mg/kg of test substance. The animals were then monitored for 14 days for mortality and clinical signs. All animals showed signs of toxicity. Mortality was seen at all dose levels, with 4 of 10 animals at the lowest dose level dying. All animals at the highest dose level died. The acute oral LD50, when adjusted for activity was 1080 mg/kg.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The oral LD50 of LAS IPA is higher than 2000 mg/kg bw. The whole database is sufficient to fully address this endpoint.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

According to REACH Regulation substances other than gases shall be tested through one more route except for the oral for acute toxicity (inhalation or demal). The dermal route was considered more appropriate for Benzenesulfonic acid, 4-C10-13-sec-alkyl derivs.-, compd. with 2-propanamine, and therefore the requirement for acute inhalation toxicity is waived.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read-across to K1 study therefore K2 is the maximum Klimisch value.

Justification for type of information:

Read-across approach - see read-across justification in section 13.

Reason / purpose for cross-reference:

read-across source

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: CFY (remote Sprague Dawley origin)

Sex:

male/female

Details on test animals or test system and environmental conditions:

Rats were in a weight range of 210 to 239 g prior to dosing on day 1 and approximately six to eight weeks of age. All the rats were acclimated to the experimental environment for a period of 15 days prior to study initiation. Animals were housed in individual metal cages with wire mesh floors. Standard diet and water were provided ad libitum. Each animal was identified by cage number and ear punching.

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: back
- % coverage: 10%
- Type of wrap if used: Gauze held in place with an impermeable plastic dressing

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Treated area of skin were washed in warm water and blotted dry with absorbent paper
- Time after start of exposure: At the end of 24 hours exposure

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw

Duration of exposure:

24 hours

Doses:

2000 mg/kg (undiluted)

No. of animals per sex per dose:

5

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed soon after dosing and then at frequent intervals for the remainder of day 1. On subsequent days the animals were observed once in the morning and again at the end of the experimental day. The treated areas were examined daily for signs of dermal irritation and assessed according to the standard scoring system for erythema, eschar and oedema
- Necropsy of survivors performed: yes
- Clinical signs including body weight
- Other examinations performed: macroscopic post-mortem examination of internal organs.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was observed exposure to 2000 mg/kg of the undiluted test material.

Clinical signs:

other: There were no signs of systemic reaction. Well defined or slight erythema and slight oedema were observed at all test sites after removal of the occlusive dressings. These reactions were unresolved before progressive hardening of the skin was first detec

Gross pathology:

All terminal autopsy findings were normal.

Interpretation of results:

GHS criteria not met

Conclusions:

In an acute dermal toxicity study in rats conducted according to OECD 402 with sodium 4-undecylbenzenesulfonate, no mortality and no necropsy findings were observed at 2000 mg/kg bw. Signs of toxicity were seen during the observation period. Based on the results and in accordance with OECD guideline 402 the LD50 was determined to be higher than 2000 mg/kg bw. Therefore, classification of sodium 4-undecylbenzenesulfonate for acute dermal toxicity according to the CLP regulation 1272/2008 is not warranted.

Executive summary:

In an acute dermal toxicity study five Wistar rats per sex were dermally exposed to undiluted sodium 4-undecylbenzenesulfonate (purity not specified) for 24 hours to 10% of the surface area of rat backs at a dose of 2000 mg/kg bw. Animals then were observed for 14 days.

All animals survived until the end of the study. There were no signs of systemic reaction. Well defined or slight erythema and slight oedema were observed at all test sites after removal of the occlusive dressings. These reactions were unresolved before progressive hardening of the skin was first detected on day 4. All test sites were entirely covered by scab formation from day 7. Sloughing from the scabbed skin began at various times between day 7 and day 12 and was completed before test termination. Low body weight gains or loss of bodyweight were recorded for one male and three female rats on day 8. Two of the same females and a third female rat also showed low body weight gains between days 8 and 15. Finally, at necropsy, all terminal autopsy findings were normal.

Based on the results and in accordance with OECD guideline 402 the LD50 value was determined to be higher than 2000 mg/kg bw. Therefore, classification for acute dermal toxicity according to the CLP regulation 1272/2008 is not warranted.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The calculated oral LD50 of LAS IPA (molar basis) is >2000 mg/kg bw. The database is sufficient to fully address this endpoint.

Additional information

Oral toxicity

Oral toxicity:

LAS Na

A study comparable to OECD guideline 401 found an acute oral LD50 of 1080 mg/kg. According to EU GHS guidelines, the test substance is a Category IV toxicant.

The supporting studies examined the oral toxicity for various concentrations of the test substance (75%, 65% and 60%) in rats. The studies followed the same test protocol and methods as the key study. The effects and symptoms observed with the key study for the test substance were also observed in the supporting study. The acute oral LD50’s determined for the concentrations were 1600 mg/kg, 2190 mg/kg and 2760 mg/kg for 75%, 65% and 60% actives, respectively. According to CLP-Regulation, the test substance is a Category IV toxicant (H302: Harmful if swallowed) at concentrations equal to or greater than 65%, while it is not classified at lower concentrations.

IPA

Based on data from a single publication (Myers & Ballantyne, 1997), the oral LD50 of IPA is <173 mg/kg bw), when tested in Wistar rats orally by gavage. The animals suffered from lung hemorrhage, kidney and adrenal congestion, gastric and intestinal hemorrhage, and ulceration. Most surviving animals did not show any significant gross pathological signs. Compared to the LD50 for LAS-IPA (> 2000 mg/kg bw), this LD50 is much lower. This substantial difference between the two LD50s can be explained by the reactive nature of the alkyl amine (IPA), due to its strong basicity, as well as ability to engage in e.g. Maillard reactions. Adverse effects observed after a single oral administration of IPA are primarily attributable to the alkyl amine itself and not to the ammonium cation (IPA+). The normalized LD50 of IPA to LAS-IPA is <1130 mg/kg bw. Nonetheless, since no exact values are available for both LAS-IPA and IPA making a comparison is difficult. To a certain extent differences in LD50s can be also explained by the variability in toxicity testing.

It is therefore considered appropriate to base the acute oral toxicity endpoint and classification decision on the LD50 derived in the recent study performed with the substance LAS-IPA itself.

 

Justification for classification or non-classification

Based on the findings of a reliable acute oral toxicity study conducted on the substance and a reliable acute dermal toxicity study on a read-across substance, classification is not justified. Based on the available data, LAS-IPA classification for acute oral or dermal toxicity according to the CLP regulation 1272/2008 is not warranted.