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Administrative data

Description of key information

The oral LD50 of all Etheramines at similar chain length is within the range of 300-2000 mg/kg bw, with LD50 cut-off value of 500 mg/kg body weight. Similar results can be expected for the Etheramine C10i and its acetate. There is no data available on acute toxicity via inhalation or dermal route.

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 from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
03 August 2010 to 24 August 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
Available data from Etheramine C13i are considered to be applicable for C10i-etheramine as well. The structure of Etheramine C13i only differs from that of Etheramine C10i, in that the alkyl chain is only 2 carbons longer. This only has limited effects on physical properties, whereas chemical behaviour, reactivity and metabolism are the same. With alkylamines in general, the corrosive properties tend to increase with shortening of the alkyl chain. Therefore the results obtained from Etheramine C13i are therefore also expected to be of similar severity for Etheramine C10i. (See for more information endpoint summary Ch.7.1 Toxicokinetics)
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
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
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000, including the most recent partial revisions.
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Species:
rat
Strain:
other: Crl:WI (Han)
Sex:
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. 8-9 weeks old)
- Weight at study initiation: Body weight variation was within +/- 20% of the sex mean.
- Housing: Group housing of 3 animals per cage in labeled Macrolon cages (MIV type; height 18 cm.) containing
sterilized sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage-enrichment
(Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom).
- Diet (e.g. ad libitum): Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest,
Germany).
- Water (e.g. ad libitum): Free access to tap water.
- Acclimation period: The acclimatization period was at least 5 days before the start of treatment under laboratory
conditions.
- Health inspection: A health inspection was performed prior to treatment, to ensure that the animals were in a
good state of health.
Results of analysis for diet (nutrients and contaminants), sawdust, paper and water were assessed and did not
reveal any findings that were considered to have affected the study integrity. All certificates and results of analysis
are retained in the NOTOX archives.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.5 - 21.5ºC
- Humidity (%): 46 - 79%
Temporary deviations from the maximum level of relative humidity occurred. Laboratory historical data do not indicate an effect of the deviations.
- Air changes (per hr): approximately 15 air changes per hour- Photoperiod (hrs dark / hrs light): 12 hours artificial
fluorescent light and 12 hours darkness per day.

IN-LIFE DATES: From: 03 August 2010 to 24 August 2010
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
GAVAGE METHOD: plastic feeding tubes.

Frequency: single dosage, on Day 1.

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg (10 mL/kg) body weight.

DOSAGE PREPARATION: The test substance was dosed undiluted as delivered by the sponsor.

CLASS METHOD
- Rationale for the selection of the starting dose: Based on anticipated mortality at the next higher dose.
Doses:
300 mg/kg (0.36 mL/kg) body weight
2000 mg/kg (2.38 mL/kg) body weight.
Dose volume calculated as dose level (g/kg) / density (g/mL)
No. of animals per sex per dose:
300 mg/kg: 6 (2 groups of three females in a stepwise manner)
2000 mg/kg: 3
Control animals:
no
Details on study design:
The toxicity of the test substance was assessed by stepwise treatment of groups of 3 females. The first group was treated at a dose level of 300 mg/kg. The absence or presence of mortality of animals dosed at one step determined the next step, based on the test procedure defined in the guidelines. The onset, duration and severity of the signs of toxicity were taken into account for determination of the time interval between the dose groups.

Animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test
substance. Water was available ad libitum.
- 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 and at death (if found dead or sacrificed after Day 1).
Clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15. The
symptoms were graded according to fixed scales and the time of onset, degree and duration were recorded.
- Necropsy of survivors performed: yes
- Other examinations performed: none.
Statistics:
No statistical analysis was performed (The method used is not intended to allow the calculation of a precise LD50
value).
Sex:
female
Dose descriptor:
LD50
Effect level:
300 - 2 000 mg/kg bw
Based on:
test mat.
Mortality:
The incidence of mortality was as follows, presented in chronological order of treatment:
Dose level Mortality Sex Date of treatment
300 mg/kg 1/3 females 03 August 2010
300 mg/kg 0/3 females 10 August 2010
2000 mg/kg 3/3 females 17 August 2010

The decedents and moribund animals were found dead or sacrificed in moribund condition on Day 4 (300 mg/kg) or between days 2 and 3 post-treatment (2000 mg/kg).
Clinical signs:
Clinical signs observed during the study period were as follows:
Dose level Clinical signs
300 mg/kg Hunched posture, piloerection, lethargy, labored respiration, rales, watery discharge from the eye, chromodacryorrhoea and/or salivation (all animals).
2000 mg/kg Restless behaviour, lethargy, hunched posture, uncoordinated movements, shallow respiration, piloerection, diarrhoea, salivation, chromodacryorrhoea, lean appearance and/or ptosis (all animals).

The surviving animals at 300 mg/kg had recovered from the symptoms by Day 6.
Body weight:
Weight loss was observed for the female at 300 mg/kg found dead on Day 4 and for two females at 2000 mg/kg found dead/sacrificed on Day 3. Surviving females at 300 mg/kg showed normal body weighty gain.
Gross pathology:
The following macroscopic post mortem findings were recorded:
Dose level Macroscopic findings
300 mg/kg : Cannibalism and irregular surface of the forestomach (female found dead).
2000 mg/kg : Gelatinous gastro-intestinal tract (one animal) or beginning stage of autolysis (one animal).
Interpretation of results:
Category 4 based on GHS criteria
Remarks:
Migrated information
Conclusions:
The oral LD50 value of 3-(Isotridecyloxy)-1-propane amine in Wistar rats was established to be within the range of 300-2000 mg/kg body weight. According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 500 mg/kg body weight.
Executive summary:

The acute oral toxicity of 3-(Isotridecyloxy)-1-propane amine in the rat was studied according to the Acute Toxic Class Method.

Initially, 3-(Isotridecyloxy)-1-propane amine was administered by oral gavage to three female Wistar rats at 300 mg/kg body weight. In a stepwise procedure additional groups of females were dosed at 2000 mg/kg body weight. All animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed on the day of death or after terminal sacrifice (Day 15).

 

The incidence of mortality was as follows, presented in chronological order of treatment:

300 mg/kg       1/3

300 mg/kg       0/3

2000 mg/kg     3/3

The decedents and moribund animals were found dead or sacrificed in moribund condition on Day 4 (300 mg/kg) or between days 2 and 3 post-treatment (2000 mg/kg).

Clinical signs observed during the study period were as follows:

300 mg/kg: Hunched posture, piloerection, lethargy, labored respiration, rales, watery discharge from the eye, chromodacryorrhoea and/or salivation (all animals).

2000 mg/kg: Restless behaviour, lethargy, hunched posture, uncoordinated movements, shallow respiration, piloerection, diarrhoea, salivation, chromodacryorrhoea, lean appearance and/or ptosis (all animals).

The surviving animals at 300 mg/kg had recovered from the symptoms by Day 6.

 

Weight loss was observed for the female at 300 mg/kg found dead on Day 4 and for two females at 2000 mg/kg found dead/sacrificed on Day 3. Surviving females at 300 mg/kg showed normal body weighty gain.

 

The following macroscopic post mortem findings were recorded:

300 mg/kg : Cannibalism and irregular surface of the forestomach (female found dead).

2000 mg/kg : Gelatinous gastro-intestinal tract (one animal) or beginning stage of autolysis (one animal).

 

The oral LD50 value of 3-(Isotridecyloxy)-1-propane amine in Wistar rats was established to be within the range of 300-2000 mg/kg body weight.

According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 500 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
500 mg/kg bw
Quality of whole database:
All studies are guideline (OECD 423, ACT) studies performed under GLP. Cross-reading validity is high, as various similar structures all lead to similar results.

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

Acute oral toxicity:

No data is available on 1-Propanamine, 3-((C9-11-iso-,C10-rich)alkyloxy)-acetate (Etheramine C10i-Acetate). The substance Etheramine C10i-Acetate is produced by neutralising Etheramine C10i with acetic acid. Etheramine C10i-Acetate consists for almost 80% (78%) of Etheramine C10i. Etheramine C10i is a strong base with a pKa of about 9.9. When Etheramine C10i-Acetate dissolves in water or physiological media, the solid structure of the salt is broken up by water molecules surrounding the charged particles namely, the positive Etheramine C10i and negative acetate ions. As the acetate is not considered to contribute significantly to the toxicity, the information available on the Etheramine itself can be used for the evaluation. For justification for cross-reading to C10i-etheramine, see IUCLID chapter 13 'Support Cross-reading - EA acetate 20150304.pdf'.

 

On Etheramine C10i itself no data is available, but there is sufficient data available on vey similar products for an adequate evaluation.

 

Etheramine C13i was tested for acute oral toxicity according to acute toxic class method.

The incidence of mortality:

Dose level

Mortality (day)

Sex

Clinical signs

300 mg/kg

1/3 (4)

females

Hunched posture, piloerection, lethargy, laboured respiration, rales, watery discharge from the eye, chromodacryorrhoea and/or salivation (all animals). Full recovery day 6.

300 mg/kg

0/3

females

2000 mg/kg

3/3 (2-3)

females

Restless behaviour, lethargy, hunched posture, uncoordinated movements, shallow respiration, piloerection, diarrhoea, salivation, chromodacryorrhoea, lean appearance and/or ptosis (all animals).

 

The oral LD50 was established to be within the range of mg/kg body weight, with LD50 cut-off value of 500 mg/kg body weight.

 

Available data from similar alkyl-etheramines show comparable results. They are all (very) corrosive substances. With alkylamines in general the corrosive properties tend to increase with shortening of the alkyl chain, which is also reflected in a generally observed tendency of higher acute oral toxicity.

Also in the case of the alkyl ether amines, the highest toxicity is observed for the Etheramine C8(branched), where the LD50 was determined at about 200 mg/kg based on the observed mortality of 2/4 animals at that dose level. In literature an acute oral LD50 for Etheramine C8(branched) of 310 mg/kg bw is reported. (Smyth HF, Carpenter CP, Weil CS, 1951, Range-finding toxicity data: List IV, A M A Arch Ind Hyg Occup Med 4(2), 119-22.)

 

 

Acute toxicity of comparable etheramines:

Substance

Alkyl chain

LD50 (mg/kgbw)

Etheramine C13i

branched C13

500 (between 300 -2000)

3-(C12-15-alkyl)oxypropylamine

C12-15

500 (between 200-2000)

3-octyl/decyloxypropylamine

C8-10

500 (between 200-2000)

3-(2-ethylhexyl)oxypropylamine

branched C8

about 200; Lit: 320

 

From the above it is concluded that Etheramine C10i can be expected to lead to similar results when tested for acute oral toxicity, leading to a LD50 between 300-2000 mg/kg with LD50 cut-off of 500 mg/kg bw. Testing for acute oral toxicity with this corrosive substance cannot be expected to contribute to better or different data and therefore scientifically not justified.

 

Support from QSAR (TOPKAT) supports the finding that LD50 increases with chain-length, but also that branching results to an (expected slight) increase of LD50 compared to linear alkyl chains. (See attached graph)

In evaluation of the above listed data for conclusion for acute oral toxicity of Etheramine C10i-acetate:

- The presence of acetate will have a possible mitigating effect on the severe corrosive properties of etheramines. However, as the effects are not (only) brought about by pH (see evaluation for dermal corrosion), the substance is still to be considered corrosive.

- Due to the presence of acetate, the substance contains less than 80% of the etheramine itself.

Based on these arguments, the acute oral toxicity of Etheramine C10i-acetate can be expected to be lower than that of Etheramine C10i. However, as the acute oral LD50 of Etheramine C10i is at the lower end of the 300-2000 mg/kg band, the acute oral LD50 of the acetate salt cannot expected to be above 2000 mg/kg.

 

Acute dermal toxicity:

Etheramine C10i is corrosive to the skin. Testing for acute dermal toxicity is therefore not justified. Toxicity following dermal exposure is characterised by local tissue damage, rather than the result of percutaneously absorbed material. For corrosive substances, the use of protective gloves and other equipment, such as face shields, aprons and good work practices are mandatory. Consequently, the occurrence of substantial dermal exposure of amounts comparable to the levels for acute oral toxicity is unlikely.

 

Acute inhalation toxicity:

Etheramine C10i-Acetateis a fluid with a boiling point of 340°C. Etheramine C10i has avapour pressure of 0.72 Pa at 20°C and for the acetate salt it can be expected to be much lower.The use is limited to industrial manufacture and formulation and doesnot result in the forming of aerosols, particles or droplets of an inhalable size. Exposure to humans via the inhalation route will be unlikely to occur.

The substance is classified as corrosive and no acute toxicity testing should normally be conducted. As the substance is corrosive, symptoms of local respiratory irritation are expected, which should limit the systemic uptake of amounts needed for systemic toxicity considering the relatively low acute oral toxicity.

Justification for classification or non-classification

The acute oral LD50 of Etheramine C10i-acetate can be expected to be within the range of 300-2000 mg/kg bw. Hence the product should be classified according to GHS for acute toxicity as Cat.4, with hazard statement H302: Harmful if swallowed.

Acute dermal testing with corrosive materials is not justified. As a consequence no classification can be made for acute dermal toxicity. Effects will be characterised by local tissue damage. Systemic uptake via skin is likely to be very limited.

No classification for acute dermal toxicity is therefore indicated.

 

Also for acute inhalation toxicity information for classification is lacking, and is testing not justified.