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Description of key information

Acute toxicity studies with rats are available for the oral, dermal and inhalation routes of exposure. The ATE is 500 mg/kg oral and > 2,000 mg/kg bw for the dermal route. The LC50 for the inhalation route is in the range between 1.04 - 5.12 mg/L.

Oral exposure appears to lead to more significant toxicity than exposure by dermal or inhalation routes.

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:
Single dose, with 14 day observations. May 22-30, 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
Species/strain: healthy Wistar rats, Crl: WI(Han) (Full Barrier)
Source: Charles River, 97633 Sulzfeld, Germany
Sex: male and female; the female animals were non-pregnant and nulliparous.
Age at the start of the treatment period: 7-8 weeks old

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
The test item was administered at a single dose by gavage using a feeding tube.
The test item was administered at a dose volume of 10 mL/kg body weight.
Doses:
The starting dose was selected to be 300 mg/kg body weight. No compound-related
mortality was recorded for any animal of step 1.Based on these results and according to
the acute toxic class method regime, a second step was performed at a dose of 300
mg/kg body weight. No compound-related mortality was recorded for any animal of
step 2. Based on these results and according to the acute toxic class method regime, a
third step was performed at a dose of 2000 mg/kg body weight. Compound-related
mortality was recorded for all animals of step 3. Based on these results and according to
the acute toxic class method regime no further testing was required.
No. of animals per sex per dose:
Sex: female, non-pregnant, nulliparous
Number of animals: 3 per step
Control animals:
no
Sex:
female
Dose descriptor:
LD50
Effect level:
500 mg/kg bw
Based on:
test mat.
Clinical signs:
The most relevant clinical findings in the animals treated with the test item at a dose of 2000 mg/kg bw were reduced spontaneous activity, recumbency, ataxia, bradyxkinesia, kyphosis, wasp waist, piloerection, half eyelid-closure, diarrhoea.
Body weight:
Throughout the 14-day observation period, the weight gain of the surviving animals was within the normal range of variation for this strain.
Gross pathology:
Macroscopic findings of surviving animals:
At necropsy, only one of the surviving animals showed treatment-related macroscopic
findings.Necropsy of all other surviving animals did not show any treatment-related
finding.
Macroscopic findings of animals not having survived until the end of the observation
period:
Necropsy revealed bloated and bloody stomach and bloody intestine.

Results per step:

 

Step

 

Sex/ No.

 

Starting Dose

(mg/kg)

 

Number         of

Animals

 

Number of Intercurrent

Deaths

 

Step1

 

Female/ 1-3

 

300

 

3

 

0

 

Step2

 

Female/ 4-6

 

300

 

3

 

0

 

Step3

 

Female/ 7-9

 

2000

 

3

 

3

Interpretation of results:
Category 4 based on GHS criteria
Remarks:
Migrated information
Conclusions:
The median lethal dose of Formaldehyde, reaction product with ethylenediamine after a single oral administration to female rats, observed over a period of 14 days is: ATE cut-off (rat): 500 mg/ kg bw

Note that in a range-finder study, a dose of 1000 mg/kg/day was tolerated over 14 days and 800 mg/kg/day was tolerated over 28 days with limited adverse effects.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
discriminating dose
300 mg/kg bw
Quality of whole database:
The median lethal dose of Formaldehyde, reaction products with ethylenediamine after a single oral administration to female rats, observed over a period of 14 days is: ATE cut-off (rat) estimated 500 mg/ kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
June 11 - July 5, 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
inhalation
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
Air Supply: Filtered air was supplied by an air compressor (Powerex Model: SES05) to the spray atomization nozzle. Additional compressed mixing air supplied from the air compressor was introduced into the chamber to help uniformly distribute the test atmosphere by creating a vortex at the chamber inlet. Compressed airflow was measured with a Mass Flowmeter. Chamber airflow was monitored throughout the exposure period and recorded periodically
Duration of exposure:
< 4 h
Concentrations:
After establishing the desired generation procedures during pre-test trials, twenty healthy rats were selected for test and equally distributed (5 per sex/group) into two exposure levels. Exposure levels of 1.0 and 5.0 mg/L were selected for testing.
No. of animals per sex per dose:
10 Males and 10 Females. The females assigned to test were nulliparous and non-pregnant.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 1.04 - < 5.12 mg/L air
Based on:
test mat.
Exp. duration:
4 h

1.04 mg/L

The gravimetric and nominal chamber concentrations were 1.04 and 10.95 mg/L respectively. The mass median aerodynamic diameter was calculated to be 1.94 μm based on graphic analysis of the particle size distribution as measured with an ACFM Andersen Ambient Particle Sizing Sampler.

All animals survived exposure to the test atmosphere. Following exposure, all rats exhibited abnormal respiration. In addition, two males and one female showed signs of abdominal distention and/or ano-genital staining and reduced fecal volume. Ocular and nasal discharge and facial staining were also noted for this female. All five males and four female recovered from the above symptoms by Day 6. Although all rats lost body weight by Day 1 and/or through Day 3, all animals showed a weight gain over the course of the 14 day study. Apart from irregular respiration persisting through Day 14, the fifth female recovered from all other symptoms by Day 12 and showed improved health through weight gain by study termination (Day 14). No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.

5.12 mg/L

The gravimetric and nominal chamber concentrations were 5.12 and 99.61 mg/L respectively. The mass median aerodynamic diameter was calculated to be 2.36 μm based on graphic analysis of the particle size distribution as measured with an ACFM Andersen Ambient Particle Sizing Sampler.

Following exposure to the test atmosphere, all rats exhibited clinical signs including abnormal respiration, hypoactivity, nasal and ocular discharge, ano-genital staining, tremors and/or an unthrifty appearance. One female was found dead on Day 1, three males and a second female died on Day 2 and a third female died by Day 3. The fifth male showed signs of opacity in one eye, a

Interpretation of results:
Category 4 based on GHS criteria
Remarks:
Migrated information
Conclusions:
Under the conditions of this study, the single exposure acute inhalation LC50 of the test substance is between 1.04 mg/L and 5.12 mg/L in male and female rats. Based on the results of this study, Formaldehyde, reaction product with ethylenediamine is assigned EC classification of risk phrase R-20 Harmful and meets the requirements of GHS Toxicity Category 4.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Quality of whole database:
LC50 of the test substance is between 1.04 mg/L and 5.12 mg/L in male and female rats.

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:
24 hours exposure period. April 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Species/strain: healthy rats, WISTAR rats Crl: WI(Han) (full barrier)
Source: Charles River, 97633 Sulzfeld, Germany
Sex: male and female The female animals were non-pregnant and nulliparous.
Number of animals: 5 male and 5 female
Age at the beginning of the study:
males: 8 - 10 weeks old
females: 12 - 14 weeks old
Body weight on the day of administration:
males: 236 – 250 g;
females: 212 – 224 g.
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
The test item was applied at a single dose, uniformly over an area which was approximately 10% of the total body surface.
The test item was held in contact with the skin by a dressing throughout a 24-hour period. The dressing consisted of a gauze-dressing and non-irritating tape and was fixed with an additional dressing in a suitable manner.
Duration of exposure:
The test item was held in contact with the skin throughout a 24-hour period. At the end of the exposure period the residual test item was removed using aqua ad injectionem
Doses:
The test item was applied at a single dose of 2000 mg/kg body weight to each animal.
No. of animals per sex per dose:
5 male and 5 female
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Body weight:
The body weight development of all male and female animals was within the expected range
Gross pathology:
With the exception of acute injection of blood vessels in the abdominal region, which is due to the euthanasia injection, no specific gross pathological changes were recorded for any animal

Under the conditions of the present study, single dermal application of the test item Formaldehyde, reaction product with ethylenediamine to rats at a dose of 2000 mg/kg body weight was associated with neither mortality nor signs of toxicity but signs of irritation. The dermal LD50 was determined to be > 2000 mg Formaldehyde, reaction product with ethylenediamine / kg body weight.

Interpretation of results:
study cannot be used for classification
Remarks:
Migrated information
Conclusions:
The dermal LD50 was determined to be > 2000 mg Formaldehyde, reaction product with ethylenediamine / kg body weight.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

Additional information

Acute toxicity studies with rats are available for the oral, dermal and inhalation routes of exposure. The LD50 are 500 mg/kg bw and > 2,000 mg/kg bw for the oral and dermal route, respectively. The LC50 for the inhalation route is in the range between 1.04 - 5.12 mg/L.

Justification for classification or non-classification

According to the results of the acute toxicity studies, formaldehyde, reaction products with ethylendiamine are classified according to Regulation 1272/2008/EC as follows:

Acute Tox. 4, H302 + H332.