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Diss Factsheets

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
12 June 2015 to 12 October 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2015
Report date:
2015

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
yes
Remarks:
Deviations from the maximum level of daily mean relative humidity occurred. Evaluation: Laboratory historical data do not indicate an effect of the deviations. The study integrity was not adversely affected by the deviation.
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
yes
Remarks:
Deviations from the maximum level of daily mean relative humidity occurred. Evaluation: Laboratory historical data do not indicate an effect of the deviations. The study integrity was not adversely affected by the deviation.
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
Deviations from the maximum level of daily mean relative humidity occurred. Evaluation: Laboratory historical data do not indicate an effect of the deviations. The study integrity was not adversely affected by the deviation.
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes

Test material

Constituent 1
Reference substance name:
Formaldehyde, oligomeric reaction products with acetone and diphenylamine
EC Number:
500-011-5
EC Name:
Formaldehyde, oligomeric reaction products with acetone and diphenylamine
Cas Number:
9003-80-9
Molecular formula:
UVCB substance - not applicable
IUPAC Name:
N-phenylaniline; formaldehyde; propan-2-one
Test material form:
solid: flakes
Details on test material:
Identification Formaldehyde, oligomeric reaction products with acetone and diphenylamine
Appearance Dark brown flakes
Batch IC5B04P006
Purity/Composition 100% Unknown or Variable compositions, Complex reaction
products and Biological materials (UVCB)
Test substance storage At room temperature
Stable under storage conditions until 26 February 2019 (expiry date)
CAS Number: 9003-80-9
pH: (1% in water, indicative range) 7.76 – 7.37 (determined by WIL Research Europe B.V.)
Molecular structure, formular and weight: UVCB

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
Species: Rat, Wistar strain Crl:WI (Han) (outbred, SPF-Quality). Recognized by international guidelines as the recommended test system (e.g. OECD, EC)Source: Charles River Deutschland, Sulzfeld, Germany.Number of animals: 6 Females (nulliparous and non-pregnant). Each dose group consisted of 3 animals.Age and body weight: Young adult animals (approx. 10-11 weeks old) were selected. Body weight variation did not exceed +/- 20% of the sex mean.Identification: Earmark and tail markHealth inspection: At least prior to dosing. It was ensured that the animals were healthy and without any abnormality that might affect the study integrity.ConditionsEnvironmental controls for the animal room are set to maintain 18 to 24°C, a relative humidity of 40 to 70%, at least 10 air changes/hour, and a 12-hour light/12-hour dark cycle: the photoperiod is between 07:00 and 19:00 hrs daily. The light/dark cycle may be interrupted for study related activities. Any variations to these conditions will be evaluated and maintained in the raw data.Accommodation: Group housing of 3 animals per cage in labeled Makrolon cages (MIV type; height 18 cm.) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom).Acclimatization period was at least 5 days before start of treatment under laboratory conditions.Diet: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).Water: Free access to tap water.Diet, water, bedding and cage enrichment evaluation for contaminants and/or nutrients was performed according to facility standard procedures. There were no findings that could interfere with the study.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
Method: Oral gavage, using plastic feeding tubes. The test item preparations were stirred on a magnetic stirrer during dosing.Fasting: 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.Frequency: Single dosage on Day 1.Dose level (volume): 2000 mg/kg (10 mL/kg) body weight.
Doses:
Single dose adminstered by oral gavage on day 1
No. of animals per sex per dose:
6 Females (nulliparous and non-pregnant). Each dose group consisted of 3 animals each given 2000 mg/kg (10 mL/kg) body weight.
Control animals:
not specified
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 2000 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.
Statistics:
The oral LD50 value of the test substance was ranked within the following ranges: 0-5, 5-50, 50-300 or 300-2000 mg/kg b.w. or as exceeding 2000 mg/kg b.w. The LD50 cut-off value was established based on OECD guideline 423. No statistical analysis was performed (The method used is not intended to allow the calculation of a precise LD50 value).The results were evaluated according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (including all amendments) and Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures (including all amendments).

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortaility occurs
Clinical signs:
Hunched posture and/or uncoordinated movements were noted for all animals on day 1
Body weight:
The body weight gain shown by the animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.

Any other information on results incl. tables

Mortality data

TEST DAY

1

1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

HOURS AFTER TREATMENT

0

2

4

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

FEMALES 2000 MG/KG

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

FEMALES 2000 MG/KG

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Clinical signs

TEST DAY

Max grade

1

1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

HOURS AFTER TREATMENT

 

0

2

4

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

FEMALES 2000 MG/KG Animal 1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Gait / motility.

Uncoordinated movements

(3)

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Skin / fur.

Piloerection

(1)

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Animal 2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Gait / motility.

Uncoordinated movements

(3)

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Skin / fur.

Piloerection

(1)

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Animal 3

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Gait / motility.

Uncoordinated movements

(3)

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Skin / fur.

Piloerection

(1)

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Animal 4

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Posture: Hunched posture

(1)

1

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Animal 5

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Posture: Hunched posture

(1)

1

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Animal 6

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Posture: Hunched posture

(1)

1

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

 

-         Sign not observed

Body weight gain

Sex/Dose level

ANIMAL

DAY 1

DAY 8

DAY 15

FEMALES 2000 MG/KG

 

 

 

 

1

186

206

218

2

177

191

205

3

174

204

211

MEAN

179

200

211

ST.DEV.

6

8

7

N

3

3

3

1

193

212

221

2

187

209

215

3

199

216

226

MEAN

193

212

221

ST.DEV.

6

4

6

N

3

3

3

 

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The oral LD50 value of Formaldehyde, oligomeric reaction products with acetone and diphenylamine in Wistar rats was established to exceed 5000 mg/kg body weight.
Executive summary:

The aim of the test was to assess the toxicity of the test substance when administered orally in a single dose to female rats. The test was conducted in accordance to:

Organization for Economic Co-operation and Development (OECD), OECD Guidelines for Testing of Chemicals, Section 4, Health Effects. No. 423, "Acute Oral Toxicity - Acute Toxic Class Method", 2001.

Commission Regulation (EC) No 440/2008 Part B: Methods for the Determination of Toxicity and other Health Effects; B1 tris: "Acute Oral Toxicity, Acute Toxic Class Method". Official Journal of the European Union No. L142, May 2008, including the most recent amendments.

United States Environmental Protection Agency (EPA). Health Effects Test Guidelines, OPPTS 870.1100, Acute Oral Toxicity. Office of Prevention, Pesticides and Toxic Substances (7101), EPA 712-C-02-190, 2002.

Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000; including the most recent partial revisions.

In conclusion the test concluded that the oral LD50 value for Formaldehyde, oligomeric reaction products with acetone and diphenylamine was established to exceed 2000 mg/kg/bw. No mortalities occurred, however, there were clinical signs such as hunched posture, piloerection and/or uncoordinated movements were noted for all animals on Day 1. The body weight gain shown by the animals was considered to be similar to that expected for normal untreated animals of the same age and stain. No abnormalities were found at macroscopic post mortem examination of the animals.

According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.

 

Based on these results, Formaldehyde, oligomeric reaction products with acetone and diphenylamine does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2011) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments).