Amines, N-C10-16-alkyltrimethylenedi-, reaction products with chloroacetic acid

Endpoint summary

Description of key information

Acute oral toxicity: LD50 (rat, female) > 300 mg/kg bw; LD50 cut-off 500 mg/kg bw (OECD 423)
Acute inhalation toxicity: no relevant route of exposure
Acute dermal toxicity: LD50 (rat) > 2000 mg a.i./kg bw (OECD guideline 402 + extrapolation from acute oral toxicity study/toxicokinetic data)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

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:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

1996

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Version / remarks:

2001

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

other: Wistar outbred rat / Crl: (WI) WU BR

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Germany
- Age at study initiation: 9 – 10 weeks
- Weight at study initiation: 167 – 177 g
- Fasting period before study: yes, overnight
- Diet: standard laboratory diet, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 13 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3
- Humidity (%): 30-70
- Air changes (per hr): ca. 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 30 mg/mL aqueous suspension of the test substance

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Only a single dose level of 300 mg/kg bw of the test substance was examined. Because the test material has been verified as corrosive to skin, any treatment of the animals with standard dose of 2000 mg/kg bw was anticipated to result in extreme pain and distress to the animals. Moreover, the corrosive and surface active effect of the test substance on the gastro-intestinal tract would prevent a meaningful evaluation of the systemic toxic properties

Doses:

300 mg/kg bw

No. of animals per sex per dose:

6

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations of clinical signs within 1 hour and within 4 hours after dosing and subsequently in surviving animals at least once daily throughout an observation period of 14 days; body weight was recorded immediately before dosing on day 0, and of the surviving animals on days 3, 7 and 14 of the study
- Necropsy of survivors performed: yes

Key result

Sex:

female

Dose descriptor:

LD50 cut-off

Effect level:

500 mg/kg bw

Based on:

act. ingr.

Mortality:

One female was found dead on day 1, 27 hours after dosing, showing sluggishness, encrusted nose, piloerection and a soiled fur prior to its death. No other mortality was observed during the study.

Clinical signs:

other: Clinical signs generally observed after dosing consisted of sluggishness, vocalization, encrustated nose and piloerection.

Body weight:

other body weight observations

Remarks:

Apart from a slight dip in body weight on day 3, the surviving animals gained weight during the 14-day study. The one animal found dead showed body weight lass.

Gross pathology:

Examination at necropsy of the animals did not reveal distinct treatment-related gross alterations.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The oral LD50 (rat, female) of the registration substance was determined to be between 300 and 2000 mg a.i/kg bw. According to the criteria laid down in Regulation (EC) No 1272/2008 as well as the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations the registration substance is classified for Acute oral toxicity, Category 4.

Executive summary:

The acute oral toxicity of the registration substance (99.4% a.i.) was tested in female Wistar rats according to EC method B.1 tris (1996) and OECD guideline 423 (2001). Two groups of 3 female rats received 300 mg/kg bw of test substance by gavage. After exposure the animals were observed for clinical signs, mortality, body weight and gross pathology for 14 days.

One female was found dead on day 1, 27 hours after dosing, showing sluggishness, encrusted nose, piloerection and a soiled fur prior to its death. No other mortality was observed during the study.

Clinical signs generally observed after dosing consisted of sluggishness, vocalization, encrustated nose and piloerection.

Over the 14 day study period the surviving animals gained weight, apart from a light reduction in body weight on day 3. The one animal found dead showed body weight loss.

Examination at necropsy of the animals did not reveal distinct treatment-related gross alterations.

Since 5 out of 6 animals survived the 300 mg/kg bw application of the test substance, the LD50 is estimated to be between 300 and 2000 mg/kg bw. A 2000 mg/kg bw dose level was not examined because of the corrosivity of the test material. The LD50 cut-off is 500 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

> 300 mg/kg bw

Quality of whole database:

The available information comprises an adequate and reliable study, and is thus sufficient to fulfil the standard information requirements set out in Annex VII-VIII, 8.5, of Regulation (EC) No 1907/2006.

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

1987

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Ico rat / OFA.SD (IOPS Caw)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Iffa-Credo, Les Oncins, 69210 L’Arbresle, France
- Age at study initiation: 5–7 weeks
- Weight at study initiation: 203–277 g
- Housing: individually
- Diet: pelleted complete maintenance diet, ad libitum
- Water: filtered drinking water, ad libitum
- Acclimation period: 10 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- % coverage: approx. 10% of the total body surface.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 1.98 mL/kg

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw (20% aqueous solution, "product by process")

No. of animals per sex per dose:

Preliminary study: Two groups with 2 males and 2 females
Main study: 5 males and 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
clinical signs: Observations were made within 15 minutes after administration, then 1, 2 and 4 hours later and daily for the 14 day study period.
body weight: the body weight of each animal was recorded immediately before dosing on day 1, and on day 8 and 15.
- Necropsy of survivors performed: yes

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 400 mg/kg bw

Based on:

act. ingr.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks:

as manufactured (20% aqueous solution)

Mortality:

No deaths occurred.

Clinical signs:

other: See 'Remarks'

Body weight:

other body weight observations

Remarks:

The body weight changes of the treated animals were rather identical to that of non-treated rats, housed under the same conditions.

Gross pathology:

No abnormality was noted upon necropsy.

Interpretation of results:

study cannot be used for classification

Conclusions:

The dermal LD50 (rat, male/female) of registration substance was >2000 mg/kg bw (as test material), corresponding to > 400 mg/kg bw as active ingredient.

Executive summary:

The acute dermal toxicity of the registration substance was tested in Sprague-Dawley rats according to OECD guideline 402 (1987). A dose of 2000 mg/kg bw test item was applied once by the cutaneous route. No deviations from the methods prescribed by the guideline were reported.

Administration of the test material caused no mortality among the test animals.

Therefore, the LD50 was established above the limit dose of 2000 mg/kg bw in terms of test item as manufactured, corresponding to 400 mg a.i./kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The available information comprises adequate and reliable information, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, of Regulation (EC) No 1907/2006.

Additional information

Acute oral Toxicity

The acute oral toxicity of Amines, N-C10-16-alkyltrimethylenedi-, reaction products with chloroacetic acid (99.4% a.i.) was tested in female Wistar rats according to EC method B.1 tris (1996) and OECD guideline 423 (2001). Two groups of 3 female rats received 300 mg/kg bw of test substance by gavage. After exposure the animals were observed for clinical signs, mortality, body weight and gross pathology for 14 days.

One female was found dead on day 1, 27 hours after dosing, showing sluggishness, encrusted nose, piloerection and a soiled fur prior to its death. No other mortality was observed during the study.

Clinical signs generally observed after dosing consisted of sluggishness, vocalization, encrustated nose and piloerection.

Over the 14 day study period the surviving animals gained weight, apart from a light reduction in body weight on day 3. The one animal found dead showed body weight loss.

Examination at necropsy of the animals did not reveal distinct treatment-related gross alterations.

Since 5 out of 6 animals survived the 300 mg/kg bw application of the test substance, the LD50 is estimated to be between 300 and 2000 mg/kg bw. A 2000 mg/kg bw dose level was not examined because of the corrosivity of the test material. The LD50 cut-off is 500 mg/kg bw.

This is supported by the following data:

The acute oral toxicity of registration substance (20% aqueous solution) was tested in Sprague Dawley rats. 4 Groups of 10 animals, 5 male and 5 female rats, received single oral doses of 1953, 3125, 5000 or 8000 mg/kg bw of the test item by gavage. Animals were then observed for 14 days. Although not a guideline study, the method used was consistent to OECD guideline 401 in all important aspects. Death was noted between two hours after dosing and day 6. There were deaths among rats dosed with 3125 mg/kg bw and at all higher dose levels. All rats receiving 8000 mg/kg bw died. On the day of treatment piloerection were observed in all of the 10 test animals of all dose groups. Further frequently occurred symptoms were hunched posture and lethargy in animals of the middle dosed groups. All surviving animals of the middle dosed groups (3125 and 5000 mg/kg bw) appeared normally on day eight after treatment.

The LD50 in terms of test material (20% aqueous solution) was calculated at 3300 mg/kg bw for males, 4318 mg/kg bw for females and 3783 mg/kg bw for combined sexes.

These values correspond to 660 mg a.i./kg bw for males, 863.6 mg a.i./kg bw for females and 756.6 mg a.i./kg bw for combined sexes.

 

Acute inhalation toxicity

The active substance is a 20% aqueous solution of the active matter (“product by process”), from which the active ingredient is not volatile (vapour pressure < 1.9 × 10–4 Pa). The active substance is neither a powder nor is it to be included in powdery preparations. Furthermore, the substance is not intended to be applied in a manner leading to generation of aerosols, particles or droplets in the inhalable size range (MMAD < 50 µm). Therefore, the generation of data on the inhalation toxicity is not considered to be required.

 

Acute dermal toxicity

The acute dermal toxicity of the registration substance (20% aqueous solution) was tested in Sprague-Dawley rats according to OECD guideline 402 (1987). A dose of 2000 mg/kg bw test item was applied once by the cutaneous route. No deviations from the methods prescribed by the guideline were reported.

Administration of the test material caused no mortality among the test animals. Therefore, the LD50 was established above the limit dose of 2000 mg/kg bw in terms of test item as manufactured, corresponding to 400 mg a.i./kg bw.

Although the substance has only been tested at 400 mg a.i./kg bw, the consideration of all available data on acute dermal toxicity, acute oral toxicity, toxicokinetics and dermal penetration leads to the conclusion, that the dermal LD50 will be > 2000 mg a.i./kg bw and thus no classification for acute dermal toxicity will be required.

For classification and labelling purposes, the dermal LD50 has been extrapolated from the oral LD50 based on experimental toxikokinetic data for both routes of exposure.

The oral LD50 was determined to be 660 mg/a.i./kg bw.

In an ADME study in rat according to OECD Guideline 417, the oral absorption of registration substance was determined to be 34%.

The Guidance on Information requirements and Chemical Safety Assessment, R.7c (Nov. 2012) states: “In practice, an adjustment in oral toxicity factor (to account for absorbed dose in the dermal exposure pathway) is recommended when the following conditions are met: (1) the toxicity value derived from the critical study is based on an administered dose (e.g., delivery in diet or by gavage) in its study design; (2) a scientifically defensible database demonstrates that the GI absorption of the chemical in question, from a medium (e.g., water, feed) similar to the one employed in the critical study, is significantly less than 100% (e.g., <50%). A cut-off of 50% GI absorption is recommended to reflect the intrinsic variability in the analysis of absorption studies. Thus, this cut-off level obviates the need to make comparatively small adjustments in the toxicity value that would otherwise impart on the process a level of accuracy that is not supported by the scientific literature.”

Thus, 50% oral absorption should be assumed.

The dermal absorption was investigated in an in vitro study with human skin according to OECD Guideline 428. The systemically available dose was determined to be 0.6±0.6% of the applied substance in accordance with the definition given in the Guidance on Information requirements and chemical safety assessment, R.7c.

Based on these data, the dermal LD50 of the registration substance can be assumed to be >2000 mg a.i./kg bw.

 

There are no data gaps in acute toxicity. Even though there is no information on acute toxicity in humans, there is no reason to believe that the results obtained in experimental animals would not be relevant for human health.

Justification for classification or non-classification

According to the criteria laid down in Regulation (EC) No 1272/2008, the registration substance is classified with Hazard Category 4 for acute oral toxicity (H302: harmful if swallowed). No classification for acute dermal toxicity is required.