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Description of key information

Acute oral toxicity: LD50 > 2000 mg/kg bw, rat, OECD Guideline 423, GLP compliant
Acute dermal toxicity: LD50 > 2000 mg/kg bw, rabbit, OECD Guideline 402, GLP compliant; read-across MDEA-Esterquat C16-18 and C18 unsatd.
Acute inhalation toxicity: inhalation is no relevant route of exposure

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
Study period:
2009-02-02 to 2009-02-20
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study, GLP
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
30 May 2008
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
adopted 17 December 2001
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 223-240 g
- Fasting period before study: 16-19 hours
- Housing: Semi-barrier in an air conditioned room. The animals were kept in groups in IVC cages, type III H, polysulphone
cages on Altromin saw fiber bedding
- Diet (e.g. ad libitum): ad libitum (Altromin 1324 maintenance diet)
- Water (e.g. ad libitum): ad libitum (tap water)
- Acclimation period: 20 - 24 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 55 ± 10
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 2009-02-02 To: 2009-02-20
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 10 % w/w
- Amount of vehicle (if gavage): 20 mL/kg bw
- Justification for choice of vehicle: non-toxic characteristics
- Lot/batch no. (if required): B. Braun Melsungen, lot 7494A191, expiry date: November 2010
- Purity: aqua ad injectionem

MAXIMUM DOSE VOLUME APPLIED: 20 mL/kg bw

DOSAGE PREPARATION (if unusual): The test item was ground to a fine dust with the help of a mortar. Then it was dissolved while stirring and heated up approx. 70 °C in the vehicle.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
6 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 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). Thereafter, the animals were observed for clinical signs once daily until the end of the observation period. The animals were weighed on day 0 (prior to the administration) and on days 7 and 14.
- Necropsy of survivors performed: yes
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
act. ingr.
Remarks on result:
other: no mortalities
Mortality:
No deaths occured during the study
Clinical signs:
other: no signs of toxicity
Gross pathology:
With the exception of acute injection of blood vessels in the abdominal region, which is due to the euthanasia injection, no special gross pathological changes were recorded for any animal of the two steps.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: other: CLP, EU GHS (Regulation (EC) 1272/2008)
Conclusions:
Under the conditions of the present study, the oral LD50 of MDEA Esterquat C18 satd. in female rats is > 2000 mg/kg bw.
Executive summary:

In an acute oral toxicity study according to OECD guideline 423, adopted 17 December 2001 and EU Method B.1 tris (30 May 2008), 6 female, fasted, 8-12 weeks old Wistar strain rats were given a single oral dose of MDEA Esterquat C18 satd. in water (10% w/w) by gavage at the limit dose of 2000 mg/kg bw and observed for 14 days.

All animals survived until the end of the study period. No clinical signs were observed in any animal at any observation timepoint. The body weight of the animals was within the range commonly recorded for this strain and age. No test substance related macroscopic findings were recorded at necropsy.

Oral LD50 (rat, females) > 2000  mg/kg bw

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

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:
1986-03-26 to 1986-04-04
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study, GLP
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harald Schriever, Kaninchenfarm
- Age at study initiation: Not available
- Weight at study initiation: 2.02 - 3.28 kg
- Fasting period before study: Not available
- Housing: Single caging in battery of cages size: 40 cm high, 45 cm wide, 50 cm long with paper roll disposal system
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: At least 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 +/- 2 degree C
- Humidity (%): 50-85%
- Air changes (per hr): Not available
- Photoperiod (hrs dark / hrs light): 12 hours daily, light-dark cycle


IN-LIFE DATES: From: 1986-03-26 To: 1986-04-04
Type of coverage:
occlusive
Vehicle:
other: Oleum arachidis
Details on dermal exposure:
TEST SITE
- Area of exposure: Dorsal trunk
- % coverage: 15 X 10 cm
- Type of wrap if used: The treated area was covered with gauze pads and the body was wrapped into a rubberized cloth.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): If necessary, with lukewarm water
- Time after start of exposure: 24 hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- Concentration (if solution): 40% a.i.
- Constant volume or concentration used: no
- For solids, paste formed: no


VEHICLE
- Amount(s) applied (volume or weight with unit): Not available
- Concentration (if solution): Not available
- Lot/batch no. (if required): Not available
- Purity: Not available
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw (male/female)
No. of animals per sex per dose:
3 males and 3 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Daily for observations and Body weights were taken on first and fourteenth day
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
None
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
act. ingr.
Remarks on result:
other: No mortality was observed
Mortality:
No mortality
Clinical signs:
other: The test substance did not induce any clinical-toxicological symptoms. Slight to moderate erythema and mainly moderate edema were observed at the treatment sites up to day 3 which resolved afterwards.
Gross pathology:
Necropsies performed on all animales at termination exhibited no gross pathological findings.
Other findings:
- Organ weights: None
- Histopathology: None
- Potential target organs: None
- Other observations: None

Skin assessments made at 24 hrs, 3, 7 and 14 days revealed that 2 mg/kg MDEA-Esterquat produced moderate skin irritation. Slight (3/6 rabbits) to moderate (3/6 rabbits) erythema and moderate edema at the 24 hour reading; slight (5/6 rabbits) to moderate (1/6 rabbits) erythema and slight (3/6 rabbits) to moderate (3/6 rabbits) at day 3. These skin responses resolved at day 7. No atonia, desquamation, fissuring, eschar or exfloliation was observed in the animals in this study.

Erythema and Edema observations at Treated Site

 Animal # Erythema (24 hr)  Edema (24 hr) Erythema (3 days)   Edema (3days)  Erythema (7days)  Edema (7 days) Erythema (14 days)    Edema (14 days) 
 93 (M) 2  2  1 2  0  0  0  0 
 72 (M) 1 1  1  0  0 0  0  0 
 83 (M)  1 2  1  2  0  0  0  0 
 791 (F) 2  2  2  1  0  0  0  0 
 792 (F) 2  2  1  1  0  0  0  0 
799 (F)   1  2  1  2  0  0  0  0 
                 
                 
Interpretation of results:
Toxicity Category V
Remarks:
Migrated information Criteria used for interpretation of results: other: GHS Regulation EC No 1272/2008
Conclusions:
MDEA-Esterquat C16-18 and C18 unsatd. is practically non - toxic.
Executive summary:

In an acute dermal toxicity study (comparable to OECD guideline 402), groups of 3 male and female New Zeeland White rabbits were dermally exposed to MDEA-Esterquat C16-18 and C18 unsatd.  (40 % a.i) in oleum arachidis for 24 hours to10 x 15 cm of body surface area at doses of 2000 mg/kg bw.  Animals then were observed for14 days.

 

Dermal LD50              Males              > 2000 mg/kg bw

                                  Females          > 2000 mg/kg bw

                                  Combined      > 2000 mg/kg bw

 

No mortality occurred in this limit test.

 

MDEA-Esterquat C16-18 and C18 unsatd.  is practically non – toxic in this study.

There were no treatment related clinical signs, necropsy findings or changes in body weight.

 

Slight (1) to moderate (2) erythema and mainly moderate (2) edema with partly decreased intensity were observed at the treatment sites from 24 hours up to the 72 hours after treatment and were fully reversible within 7 days. The mean score were 1.3 for erythema and 1.75 for edema (after 24 and 72 hours). The applied scores of 1 and 2 for erythema and edema were comparable to the scores of the Draize method.

 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

Acute oral toxicity

In an acute oral toxicity study according to OECD guideline 423, adopted 17 December 2001 and EPA OPPTS 870.1100 (Acute Oral Toxicity) EPA 712-C-02-190, December 2002, 6 female, fasted, 8-12 weeks old Wistar strain rats were given a single oral dose of MDEA Esterquat C18 satd. in water (10% w/w) by gavage at the limit dose of 2000 mg/kg bw and observed for 14 days.

All animals survived until the end of the study period. No clinical signs were observed in any animal at any observation timepoint. The body weight of the animals was within the range commonly recorded for this strain and age. No test substance related macroscopic findings were recorded at necropsy. The oral LD50 for female rats was > 2000 mg/kg bw.

Also the source substance used for read-across for the endpoints irritation, sensitisation, mutagenicity and developmental toxicity, MDEA-Esterquat C16-18 and C18 unsatd., was of equally low oral toxicity as demonstrated by the following studies on rats and mice:

In an acute oral toxicity study comparable to OECD Guideline 401 (24. Feb. 1987, now deleted) rats were dosed once with 10 000 mg/kg bw MDEA-Esterquat C16-18 and C18 unsatd.  and observed for 14 days. No mortality occurred in this limit test. There were no treatment related clinical signs, necropsy findings or changes in the body weight.

The second study with mice was performed as an Irwin dose-range finding study with oral application of 316, 1000, 3160 and 10 000 mg/kg bw of MDEA-Esterquat C16-18 and C18 unsatd.  and with an observation period of 7 days. All mice dosed with 10 000 mg /kg bw showed slight apathy between 10 and 20 minutes after dosing. In addition, one animal in this group showed further indication of CNS depression when observed at 30 and 90 minutes after treatment. This animal appeared normal during the observations performed at 150 and 300 minutes; however it died overnight between day one and day two. No other treatment related clinical signs, were recorded in the remaining animals at any time during the study. Necropsy was not performed after study termination; changes in body weights were not recorded.

Acute dermal toxicity

Testing of acute dermal toxicity of MDEA Esterquat C18 satd. is scientifically not justified according to REACH Regulation Annex XI 1 as reliable and relevant in vivo data from a structurally related substance and a QSAR calculation with the target substance are used to fulfill this information requirement.

In an acute dermal toxicity study according to OECD Guideline 402 (24 April 2002) New Zealand White rabbits were dermally exposed to MDEA-Esterquat C16-18 and C18 unsatd. (40 % a.i.) in oleum arachidis. Treatment occurred on an area of 10 x 15 cm of body surface at doses of 2000 mg/kg bw for 24 hours. Animals were observed for 14 days afterwards.

No mortality occurred in this limit test. There were no treatment related clinical signs, necropsy findings or changes in body weight. Slight to moderate erythema and mainly moderate edema with partly decreasing intensity were observed at the treatment sites up to day 3 and were fully reversible within 7 days. MDEA-Esterquat C16-18 and C18 unsatd. is practically non-toxic based on the dermal LD50 of > 2000 mg/kg bw determined in this study.

Justification for read-across

For details on substance identity, toxicokinetics and detailed toxicological profiles, please refer also to the general justification for read-across given in chapter 5 of the CSR and attached as pdf document to section 7 of the IUCLID file.

 

a. Structural similarity and functional groups

The target substance, MDEA Esterquat C18 satd., consists of an amine backbone (MDEA = Methyldiethanol amine) esterified with the long chain fatty acid stearic acid (C18 satd.; IV (iodine value) < 1). The main reaction product is the dialkylester compound, next to that small amounts of the monoalkylester may be formed. The amine function is quaternised with two methyl groups. The counter ion is Chloride.

The source substance, MDEA Esterquat C16-18 and C18 unsatd., consists of the same amine backbone (MDEA = Methyldiethanol amine) but esterified with a mixture of the long chain fatty acids C16, C18 and C18 unsaturated (IV < 25). The main reaction product is the dialkylester compound, next to that small amounts of the monoalkylester may be formed. The amine function is quaternised with two methyl groups. The counter ion is Chloride.

The source and the target substance share structural similarities with common functional groups (quaternary amines, esters, and fatty acid chains with comparable length and degree of saturation).

b. Common breakdown products

The metabolism expected to occur is hydrolysis of the ester-bond by esterases. However, the rate of hydrolysis is assumed to be low. The fraction of metabolised molecules would result in free fatty acids and Dimethyl-DEA (DEA = Diethanolamine). The carboxylic acids are further degraded by the mitochondrial beta-oxidation process (for details see common text books on biochemistry). The fatty acids enter normal metabolic pathways and are therefore indistinguishable from fatty acids from other sources including diet. The quaternary ammonium ions are not expected to be further metabolised, but excreted unchanged via the urine. 

c. Differences

The differences in fatty acid chain length (higher percentage of C16 in the source substance MDEA Esterquat C16 -18 and C18 unsatd.) and degree of saturation (higher degree of unsaturation of the C18 fatty acid chains in the source substance substance MDEA Esterquat C16-18 and C18 unsatd.) could be relevant for local toxicity (skin and eye irritation) but arebut are not considered to be of relevance for acute toxicity.

Acute toxicity data of the target and source substance

 

Comparison of the acute toxicity data of MDEA Esterquat C18 satd. and MDEA-Esterquat C16-18 and C18 unsatd.

 

 

Source substances

Target substance

 Endpoints

MDEA-Esterquat C16-18 and C18 unsatd.

MDEA Esterquat C18 satd.

Acute oral toxicity

 

Equivalent to OECD guideline 401(acute oral toxicity study, RL 1, GLP)

                                                           5 male and 5 female WISW rats were exposed by gavage to 10000 mg/kg bw 40% w/w in oleum arachidis

 

Oral LD50 (rat, female/male) > 10000 mg/kg bw

 

According to OECD guideline 401(Irwin dose-ranging study, RL 2, GLP)

                                                     5 male CD-1 mice per dose were orally exposed to 316, 1000, 3160 and 10000 mg/kg bw

 

Oral LD50 (mouse, male) > 10000 mg/kg bw

According to OECD guideline 423(acute oral toxicity study, RL 1, GLP)

             

6 female Wistar rats were exposed by gavage to 2000 mg/kg bw 10% w/w in water

 

 Oral LD50 (rat, female) > 2000 mg/kg bw

 

Acute dermal toxicity

Equivalent to OECD guideline 402(acute dermal toxicity study, RL 1, GLP)

                                                         

3 male and 3 female New Zealand White rabbits were dermally exposed to 2000 mg/kg bw 40% w/w in oleum arachidis

 

Dermal LD50 (rabbit, male/female) > 2000 mg/kg bw

read-across from source substance

 

Bioavailability

Equivalent to OECD guideline 417 (Toxicokinetics, RL 2, GLP)

radio labelled test substance was administered to 4 male Sprague-Dawley rats by gavage at a single dose of 112 mg/kg bw

Oral adsorption48 ± 6 % over the 72-hour test period

Read-across from source substance

Equivalent to OECD guideline 427 (Skin absorption: In vivo Method, RL 2, GLP)

 

radio labelled test substance was administered to 4 male Sprague-Dawley rats by the dermal route at a single dose of 1.62 mg/cm² (62.7 mg/kg bw).

 

Dermal adsorption< 1.4% over the 72-hour test period

QSAR (RL 4)

 

 

estimation of dermal absorption using IH SkinPerm (v1.21) based on physico-chemical properties

 

 

Dermal adsorption 0% after 24 hours

Fatty Acids

<C16      <7%                                            

C16, 16‘  26-35%

C18         42-52%

C18‘        15-20%

C18‘‘,18‘‘‘ ≤ 1.5%

>C18       ≤ 2%

C16 ≤ 8%

C18 ≥ 92%

Headgroup

MDEA

MDEA

 

Conclusion acute dermal toxicity

The acute oral toxicity for MDEA-Esterquat C16-18 and C18 unsatd. and MDEA Esterquat C18 satd. is equally low for both of them with an LD50 >> 2000 mg/kg bw. Low dermal toxicity with an LD50 >> 2000 mg/kg bw is shown in vivo for the source substance, MDEA-Esterquat C16-18 and C18 unsatd.. The oral bioavailability is assumed to be around 50 times higher than dermal bioavailability (see table), therefore acute toxicity after dermal administration is not to be expected and testing in animals is not warranted.

Further support is given by retrospective data analyses undertaken by Creton et al. (2010) and Seidle et al. (2010) to ascertain the value of regulatory requirements prescribing multiroute testing for acute systemic toxicity. These analyses have examined the concordance among regulatory classifications for acute oral, dermal, and/ or inhalation toxicity for ~500 agrochemical and biocidal active substances and nearly 2000 industrial chemicals. The findings from these two independent reviews have revealed that acute dermal studies of pure substances do not add value above and beyond oral data for hazard classification of pesticides, biocides, or chemicals.

Testing of acute dermal toxicity of MDEA Esterquat C18 satd. is therefore scientifically not justified according to REACH Regulation Annex XI 1 as reliable and relevant data from a structurally related substance is used to fulfil this information requirement.

 

Acute inhalation toxicity

Inhalation is not a relevant route of exposure to MDEA Esterquat C18 satd.. This applies to both workers and the general population and is due to the physicochemical properties of the substance and the nature of the products where it is used.

MDEA Esterquat C18 satd. is a waxy solid. Generation of inhalable particles such as dust or aerosols is therefore not to be expected. Vaporization needs not to be considered due to the substance’s very low vapour pressure of < 10-7 kPa. The substance is not manufactured into any REACH relevant spray or aerosol product applications. Therefore formulation of the substance into the commercial products where it is present does not result in any likely possibility of airborne exposure. For further information please refer to the exposure scenarios in chapter 9 and 10.

Given that acute toxicity is unlikely to occur based on low acute toxicity via the oral and dermal route, as well as on low exposure levels, testing by the inhalation route is scientifically not necessary according to REACH Regulation Annex XI 1 and 3.

Based on the available information, the acute toxicity of MDEA Esterquat C18 satd. is low for all three routes of administration. 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 low acute toxicity observed in experimental animals would not be relevant for human health.

References

Seidle T. et al.: Cross-Sector Review of Drivers and Available 3Rs Approaches for Acute Systemic Toxicity Testing, TOXICOLOGICAL SCIENCES 116(2), 382–396 (2010).

Creton S. et al.: Acute toxicity testing of chemicals—Opportunities to avoid redundant testing and use alternative approaches, Critical Reviews in Toxicology, 2010; 40(1): 50–83


Justification for selection of acute toxicity – oral endpoint
OECD guideline study, no deviations, GLP

Justification for selection of acute toxicity – inhalation endpoint
Inhalation is not a relevant route of exposure and testing by the inhalation route is not required.

Justification for selection of acute toxicity – dermal endpoint
OECD guideline study, no deviations, GLP

Justification for classification or non-classification

Based on the available data, MDEA Esterquat C18 satd. does not need to be classified for acute toxicity according to regulation (EC) 1272/2008 or the former European directive on classification and labelling 67/548/EEC. Thus, no labelling is required.