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Diss Factsheets

Administrative data

Description of key information

Acute oral  toxicity data exhibited a low toxicity of the substance with an LD50 > 2000 mg/kg bw. No inhalative study is available but limited exposure is expected. Assessment of dermal acute toxicity was based on a read-across with C12 -18 -(even numbered)-alkylamines indicating also a low acute toxicity (LD50 > 2000 mg/kg body weight).

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:
26 December 2012 - 21 February 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Compliant to GLP and testing guidelines; adequate consistence between data, comments and conclusions.
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
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: breeder: Janvier, Le Genest-Saint-Isle, France
- Age at study initiation: approximately 8 weeks old on the day of treatment
- Mean body weight at study initiation: 200 g (range: 196 g to 206 g)
- Fasting period before study: yes, during the night before treatment
- Housing: the animals were housed by three from the same group in polycarbonate cages with stainless steel lids
- Diet: SSNIFF R/M-H pelleted diet (free access)
- Water: tap water filtered with a 0.22 µm filter (free access)
- Acclimation period: at least 5 days before the beginning of the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12 h/12 h.

IN-LIFE DATES: 29 January 2013 to 20 February 2013.
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL
- Maximum dose-volume applied: 10 mL/kg

DOSAGE PREPARATION:
The test item was administered as a suspension in the vehicle. The test item was ground to a fine powder, using a mortar and pestle, and then mixed progressively with the required quantity of vehicle. The dose formulations were then kept under magnetic stirring for at least 30 minutes, in a bath water at approximately 40°C.
Fresh dose formulations were prepared by the CiToxLAB France Pharmacy on the day of each administration in brown flasks prior to administration. Dose formulations were transferred to the dosing room in a tray containing hot water (starting at approximately 40°C).The temperature of the hot water was not continuously monitored.

CLASS METHOD:
- Rationale for the selection of the starting dose: the dose-levels were selected in agreement with the Sponsor following the results of a previous oral toxicity study in rats for 14 days where the NOAEL was established at 150 mg/kg/day. No death was observed in this study in rats treated with 50, 150 and 450 mg/kg/day. Clinical signs as piloerection and hunched posture were observed on the last day of treatment in 2/4 females given 450 mg/kg/day. Lower body weight, correlating with lower food consumption, was observed throughout the treatment period in both sexes given 450 mg/kg/day.
Therefore, 2000 mg/kg/day was chosen as the starting dose-level.
Doses:
2000 mg/kg.
No. of animals per sex per dose:
3 females per treatment step.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Clinical observations: frequently during the hours following treatment; then, at least once a day.
- Body weight: just before treatment on day 1; then on days 8 and 15.
- Necropsy of survivors performed: yes (macroscopic).
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No unscheduled deaths occurred during the study.
Clinical signs:
other: No clinical signs were observed in any animals.
Gross pathology:
There were no test item-related macroscopic findings.
The macroscopic observation correlated with common histological finding in control rats, and were thus was considered to be incidental.

 

Sex

 

Female

Group

CiToxLAB France Historical control data

1

2

Dose-level (mg/kg)

0

2000

2000

Body weight (mean (± SD))

 

 

 

. Day 1

208 (± 11.7)

198 (± 2.1)

202 (± 4.5)

. Day 8a

246 (± 12.7)

231 (± 3.5)

239 (± 1.0)

. Day 15

266 (± 14.0)

244 (± 5.1)

259 (± 2.5)

Body weight change (mean (± SD))

 

 

 

. Days 1-8b

+39 (± 5.1)

+33 (± 2.3)

+38 (± 3.5)

. Days 8-15c

+20 (± 6.3)

+12 (± 4.0)

+20 (± 2.6)

. Days 1-15

+58 (± 5.8)

+45 (± 3.1)

+58 (± 3.8)

a: day 9 for group 2,b: days 1-9 for group 2,c: days 9-15 for group 2.

SD: standard deviations.

Interpretation of results:
other: not classified as toxic by oral route
Remarks:
Criteria used for interpretation of results: other: CLP Regulation
Conclusions:
The oral LD50 of the test item was higher than 2000 mg/kg in rats.
Therefore, the test item is not classified as toxic by oral route according to the criteria of CLP Regulation.
Executive summary:

The objective of this study was to evaluate the potential acute toxicity of the test item following a single oral administration (gavage) to rats.

 

Methods

The test item was administered once by oral route (gavage) to two groups of three fasted female Sprague-Dawley rats under a dosage-volume of 10 mL/kg. The test item was prepared in corn oil.

Based on available test item toxicity data, the starting dose-level of 2000 mg/kg was chosen. After the first assay, as no toxicity was observed, the results were confirmed in other females.

Each animal was observed at least once a day for mortality and clinical signs for 15 days. Body weight was recorded on day 1 and then on day 8 or 9 and on day 15.

On completion of the observation period, the animals were sacrificed and then submitted for a macroscopic post-mortem examination. Macroscopic lesions were preserved in buffered formalin then destroyed at the finalization of the study report as no microscopic examination was performed.

 

Results

No unscheduled deaths occurred during the study and no clinical signs were observed in any animals.

Body weight gain was unaffected by the test item treatment, when compared to CiTox LAB historical control data.

At necropsy, there were no macroscopic findings attributed to the test item administration.

 

Conclusion

The oral LD50of the test item was higher than 2000 mg/kg in rats.

Therefore, the test item is not classified as toxic by oral route according to the criteria of CLP Regulation.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Well performed GLP study. Result supported by another study used as read-across.

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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1985
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP study similar to Guideline but only 4 animals (2 males/2females) per dose group used
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
only 4 animals per dose group used
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: CFY
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Source: Interfauna UK Limited, Huntingdon, Cambridgeshire, UK
- Age at study initiation: approx. 6 - 8 weeks
- Weight at study initiation: 200 - 245 g
Type of coverage:
occlusive
Vehicle:
water
Details on dermal exposure:
The compound was administered either unchanged at a volume of 0.63 mL/kg (= 500 mg/kg) or in water at a volume of 5 mL/kg (=2000 mg/kg).
Since the compound is described as corrosive and dermal irritative reactions were noted in the 500 mg/kg group (undiluted test material), dilution
for testing of the acute dermal toxicity at 2000 mg/kg bw is justifiable.

TEST SITE
- Area of exposure: 10% of total body surface
- % coverage: 100
- Type of wrap if used: occlusive dressing

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.63 ml/kg (undiluted, 500 mg/kg group); 5 ml/kg (40% solution, 2000 mg/kg group)
- Concentration (if solution): 40% in water (only for 2000 mg/kg dose group)

VEHICLE
- water (only for 2000 mg/kg dose group)
Duration of exposure:
24h
Doses:
500 mg/kg bw (undiluted)
2000 mg/kg bw (diluted to 40% w/v in water)
No. of animals per sex per dose:
2
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily
- Necropsy of survivors performed: yes
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No deaths occured during the study.
Clinical signs:
other: 500 mg/kg/bw: no clinical signs throughout observation period 2000 mg/kg/bw: hunched posture, abnormal gait (waddling), lethargy, and decreased respiratory rate (shortly after treatment, free of symptoms thereafter)
Gross pathology:
Terminal autopsy revealed slight bruising in the subcutaneous tissue of one male and one female rat dosed at 500 mg/kg bw and scab formation with or without ulceration was seen in all rats dosed at 2000 mg/kg bw.
An area of minimal congestion of the stomach (mucosal aspect) was seen in one female rat dosed at 2000 mg/kg bw.
Other findings:
Dermal reactions:
necrosis in all rats dosed at 500 mg/kg bw, persisting until day 12
well defined to moderate oedema in rats dosed at both levels
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute lethal dermal dose (LD 50) of Amine KK to rats was greater than 2000 mg/kg body weight
Executive summary:

In a GLP-compliant study similar to OECD TG 402, the test compound Amine KK (cocoalkylamine), a yellow liquid (purity 100%), was dermally applied under occlusion to Sprague-Dawley rats. At a dose level of 500 mg/kg body weight, the test material was applied undiluted (application volume 0.63 ml/kg bw), at a dose level of 2000 mg/kg bw the substance was diluted to a 40% solution (w/v) in distilled water (application volume 5 ml/kg). Compared to a regular OECD TG 402 study a reduced number of animals was used (4 instead of 5 animals/dose). There were no mortalities, hence, the LD50 is > 2000 mg/kg bw. No clinical signs were observed at 500 mg/kg bw. At 2000 mg/kg, hunched posture, abnormal gait, lethargy and decreased respiratory rate were noted. Signs of dermal reactions at the application site of both treatments were well defined to moderate oedema until days 4-5. Hard scabs, persisting to the end of the observation period, frequently prevented the assessment of oedema.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Read across with a GLP study.

Additional information

Oral

The toxic effects following an acute oral dose of the registered substance was determined according to the guidelines for the acute toxic class method (OECD 423) performed under GLP.

 

In step 1 three female rats were dosed by oral gavage with 2000 mg/kg body weight in corn oil. As no signs of toxicity were observed during the first 5 days in any animals, three additional female rats were dosed also with 2000 mg/kg body weight in step 2. No compound related mortality or clinical signs were again observed. According to the toxic class regime no further testing was required. The LD50 therefore was > 2000 mg/kg bw .

 

Studies for the oral route are also available for hydrogenated tallow alkylamines as well as for all other category members of primary alkylamines. For hydrogenated tallow alkylamines a LD50 of greater 5000 mg/kg body weight was established. Comparable LD50 values indicating moderate acute oral toxicity were revealed also for tallow alkylamines and octodecenylamines. This view of only moderate toxicity was also taken in the existing EU risk assessment of primary alkylamines.

 

 

Inhalation:

There is no study on inhalation toxicity available for the registered substance.

REACH stipulates that testing by the inhalation route is appropriate if exposure of humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size. REACH guidance R.7.a, chapter. 7.4 Acute toxicity, indicates that in principle no inhalation studies are needed when vp < 0.1 Pa at 20°C or particle size > 100 µm. The registered substance is a solid (scales) with no expected inhalable particles and a vapour pressure around 0.0079 Pa at 20°C (value based on read-across from oleylamine). Also the use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalation route will be unlikely to occur, and no acute inhalation test was performed. In addition, considering the apparently low systemic toxicity of the primary alkylamines, no need for further inhalative testing was seen.

 

There is no risk for aspiration as with a mp of 77°C, the registered substance is a solid upon ingestion.

 

Dermal:

There is no dermal LD 50 value for acute skin toxicity of the registered substance. Acute toxicity by oral route resulted to a LD50 cut-off value of 2500 mg/kgbw indicating relative low acute systemic toxicity for which no classification is required. Considering the apparently low systemic toxicity of the primary alkylamines, no need for further dermal testing was seen. In addition, a read-across can be made with C12 -18 -(even numbered)-alkylamines for which a dermal acute toxicity study performed in rat is available and demonstrated also a low acute toxicity (LD50 > 2000 mg/kg body weight).


Justification for classification or non-classification

No classification for acute toxicity required:

Low systemic toxicity is indicated by Oral LD50 > 2000 mg/kg bw.

Dermal systemic toxicity is expected to be similarly low based on a read across approach with primary alkylamines.

Related to low vp and no inhalable particles, there will be no exposures via inhalation.

No classification STOT-SE Cat.3 needed:

The active substance is not structurally related to any known class of neurotoxic chemicals. In addition, repeated dose studies with the substance or primary alkylamines did not show indications of specific neurotoxicity, in specific neurotoxicity measures as sensory activity, grip strength, and motor activity assessment.