C8-18 alkylampho(di)propionates

Endpoint summary

Description of key information

In 3 acute oral toxicity studies in rats and mice, conducted prior to current standards but equivalent to OECD 401, the LD50 (oral) was determined to be > 5000 mg/kg. In an acute dermal toxicity study with rats, performed according to OECD 402 and GLP, a LD50 (dermal) of > 5189.5 mg/kg bw was determined. These LD50's correspond to LD50's of > 2000 mg/kg, when expressed as solid content (for comparison purposes).

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Quality of whole database:

The 3 available studies have Klimisch score 2.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

August 16, 2012 - November 23, 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: This study has been performed in accordance with OECD 402 (1987), EU Method B.3 (2008), EPA OPPTS 870.1200 (1998) and according to GLP principles.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

(1987)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Version / remarks:

(2008)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Version / remarks:

(1998)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nohsan, Notification No. 8147, April 2011; including the most recent partial revisions

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Wistar strain, Crl:WI (Han)

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: Young adult animals (approx. 10 weeks old)
- Weight at study initiation: Body weight variation was within +/- 20% of the sex mean.
- Housing (during the acclimatization period): group housed in Makrolon cages
- Housing (after application): Individually housed in labeled Makrolon cages
- Diet: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany)
- Water: Free access to tap water.
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 24
- Humidity (%): 40 to 70
- Air changes (per hr): approx 15
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

- Clipping: One day before exposure (Day -1) an area of approximately 5x7 cm on the back of the animal was clipped
- Application: The test substance was applied in an area of approx. 10% of the total body surface, i.e. approx. 25 cm² for males and 18 cm² for females. The test substance was held in contact with the skin with a dressing, consisting of a surgical gauze patch (Surgy 1D), successively covered with aluminum foil and Coban elastic bandage. A piece of Micropore tape was additionally used for fixation of the bandages in females only.
- Frequency: Single dosage, on Day 1.
- Washing: Following application, dressings were removed and the skin cleaned of residual test substance using tap water.

Duration of exposure:

24 hours

Doses:

5189.5 mg/kg bw (expressed as registered substance) which corresponds to 2000 mg/kg bw expressed as solid content

No. of animals per sex per dose:

5

Control animals:

not required

Details on study design:

- Dose volume: 4.85 mL/kg bw (Density: approx. 1.07 g/mL)
- Dosage preparation: The test substance was dosed undiluted. Correction was made for the solid content of the test substance (a correction factor of 2.59 was used)
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/Viability: Twice daily
Body weights: Days 1 (pre-administration), 8 and 15
Clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15.
- Necropsy of survivors performed: At the end of the observation period, all animals were sacrificed by oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded.
- Other examinations performed: none.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 189.5 mg/kg bw

Based on:

test mat.

Remarks:

(aqueous solution)

Remarks on result:

other: Aqueous solution with a solid content of 38.56%

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

other: expressed as solid content

Mortality:

No mortality occurred

Clinical signs:

other: - Flat posture was shown by one male on Day 1. Chromodacryorrhoea was shown by one male and one female on Day 1 - Focal erythema (grade 1) was seen on the treated skin-area of all males on Days 2 and 3

Gross pathology:

- Pelvic dilation of the kidneys, reddish foci on the thymus or discolouration of the thymus were shown by three males
- Macroscopic examination of the other animals did not reveal any abnormalities

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

In an acute dermal toxicity study with rats, performed according to OECD/EC test guidelines, a LD50 of > 5189.5 mg/kg bw was determined.

Executive summary:

The acute dermal toxicity of the substance was determined in the rat, in accordance with OECD 402 (1987), EU Method B.3 (2008), EPA OPPTS 870.1200 (1998) and according to GLP principles. The substance was administered to five Wistar rats of each sex by a single dermal application at 2000 mg/kg body weight (expressed as solid content) for 24 hours (a correction factor of 2.59 was used). The dose corresponded to 5189.5 mg/kg bw for the registered substance.

No mortality occurred. Flat posture was shown by one male on Day 1. Chromodacryorrhoea was shown by one male and one female on Day 1. Focal erythema (grade 1) was seen on the treated skin-area of all males on Days 2 and 3. The changes noted in body weight gain in males and females were considered not indicative of toxicity. Pelvic dilation of the kidneys, reddish foci on the thymus or discolouration of the thymus were observed by three males. Macroscopic examination of the other animals did not reveal any abnormalities. The dermal LD50 value of the substance in Wistar rats was established to exceed 5189.5 mg/kg bw, which corresponds to > 2000 mg/kg body weight expressed as solid content.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 189.5 mg/kg bw

Quality of whole database:

The study has Klimisch score 1

Additional information

Oral

The acute oral toxicity in rats and mice has been investigated in 3 studies, conducted prior to current standards but equivalent to OECD 401:

Method	Reliability	Results	Result (expressed as solid content)
(1) Standard (equivalent to OECD 401; in mice)	2	< 21400 mg/kg bw (ca. 36% solids)	< 7704 mg/kg bw
(2) Standard (equivalent to OECD 401, limit test; in rats)	2	> 5350 mg/kg bw (ca. 38% solids)	> 2033 mg/kg bw
(3) Standard (equivalent to OECD 401; in mice)	2	> 24075 mg/kg bw (ca. 38% solids)	> 9148 mg/kg bw

In the second study no mortalities occurred, at a dose of 5 mL/kg bw.

Based on the results of the available studies, the oral LD50 was determined to be > 5000 mg/kg bw and > 2000 mg/kg bw, when expressed as solid content for comparison purposes.

Inhalation

There is no experimental study available by the inhalation route. Based on the low acute toxicity properties by the oral and dermal routes, there is a low toxicological concern by the inhalation route. The substance is manufactured, marketed and used as aqueous solution. In addition the substance has a low volatility potential due to low vapour pressure of the surfactant fraction (main constituent) and both major constituents of toxicological interest in the substance have a low Henry’s law constant supporting a very low release from water.

No aerosol formation is expected during manufacturing and normal handling of the substance as produced. The registered substance is then formulated in industrial setting, and then further diluted to very low concentrations before end-use application, with a low likelihood of exposure to aerosols of an inhalable size during typical uses.

Using the methanol content in the substance, and the uncertainty on the surfactant properties by inhalation, an Acute Toxicity Estimate can be derived according to CLP regulation EC No.1272/2008 and shows the substance does not require classification for the inhalation route (see below). Therefore this endpoint is adequately assessed.

Dermal

The acute dermal toxicity of the substance was determined in the rat, in accordance with OECD 402 (1987), EU Method B.3 (2008), EPA OPPTS 870.1200 (1998) and according to GLP principles. The substance was administered to five Wistar rats of each sex by a single dermal application at 2000 mg/kg body weight (expressed as solid content) for 24 hours. The dose corresponded to 5189.5 mg/kg bw for the registered substance (an aqueous solution). No mortality occurred. Flat posture was shown by one male on Day 1. Chromodacryorrhoea was shown by one male and one female on Day 1. Focal erythema was seen on the treated skin-area of all males on Days 2 and 3. Pelvic dilation of the kidneys, reddish foci on the thymus or discolouration of the thymus were shown by three males. Macroscopic examination of the other animals did not reveal any abnormalities. The dermal LD50 value of the substance in Wistar rats was established to exceed 5189.5 mg/kg bw, which corresponds to > 2000 mg/kg body weight expressed as solid content, for comparison purposes.

Justification for selection of acute toxicity – oral endpoint
There are 3 acute oral toxicity studies available, all having Klimisch score 2. As all these reliable studies showed a low acute oral toxicity in rats and mice, resulting in a LD50 of above 5000 mg/kg as the lowest LD50 for the registered substance, no specific study is selected.

Justification for selection of acute toxicity – inhalation endpoint
There is no experimental study available by the inhalation route. Based on the low acute toxicity properties by the oral and dermal routes, there is a low toxicological concern by the inhalation route (see discussion). The Acute Toxicity Estimate for the inhalation route is > 20 mg/L.

Justification for selection of acute toxicity – dermal endpoint
Reliable study conducted according to current standards.

Justification for classification or non-classification

CLP

As the acute oral and dermal LD50's of the substance were determined to be >5000 mg/kg bw, the substance does not need to be classified for acute oral and dermal toxicity in accordance with the CLP Regulation. The substance has been tested as such with all the constituents in the acute oral and acute dermal studies; the test results overrule the classification for acute oral and dermal toxicity based on the methanol content.

However, because of the methanol content in the substance, the specific target toxicity following a single exposure cannot be excluded, thus the CLP classification related to the methanol content was applied using the specific concentration limits of Annex VI (STOT SE 2; H371: 3% ≤ C < 10%): STOT SE 2, H371 (all routes; target organs: optical nerve, central nervous system).

Because no experimental results are available by the inhalation route, the classification was also assessed based on methanol content and as a mixture. Considering the Annex VI classification of methanol, Acute Tox. 3, H331, the converted Acute tox point estimate to be used in the ATEmix calculation is 3 mg/L [CLP regulation EC No.1272/2008, Table 3.1.2]. In the absence of experimental data on the surfactant fraction, it is considered of unknown toxicity in the estimate calculation, as a worst case (although unlikely, based on the available data). Based on surfactant content (max. 45%), methanol content (max. 6%) and using the equation as mentioned under 3.1.3.6.2.3. in the CLP Regulation, the ATEmix for the UVCB substance is derived as: ATEmix = (100–45)*3/6 = 27.5 mg/L.

Based on CLP criteria, and the maximum methanol content, the registered UVCB substance is therefore not classified for acute inhalation toxicity in accordance with the CLP Regulation.

Conclusion for Acute toxicity

CLP: STOT SE 2, H371

DSD: Xn; R20; Xn; R68/20/21/22