Registration Dossier

Administrative data

Description of key information

The oral LD50-value for the test substance Formamidopropyldimethylbetain 50 %ig in Wistar rats is higher than 2000 mg/kg.
The dermal LD50 value of FORMAMIDOPROPYLBETAINE in Wistar rats was established to exceed 2000 mg/kg body weight (corrected for purity of the test substance).

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:
06. Jun. 2005 - 22. Jun. 2005
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
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
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
Species: rat
Breed: White Wistar
Breeder: Harlan Winkelmann, Borchen, Germany
Date of receipt: 2005-05-31
Number / Sex: 12 female
Body weights: 159.9 - 180.7 g at day of application
Age: about 8 weeks at day of application
Identification: dye marks and cage numbers
Diet: Altromin International, Lage, Germany, Type 1324 - 1188,
Water: Drinking water consisted of normal tap water from municipal sources (Stadtische Werke Krefeld AG, Krefeld, Germany). The water was monthly examined for pollutants which might interfere with the study. The data are retained in the archive.
Bedding material: Lignocel BK 10/20, Rettenmaier & Sohne GmbH & Co., Batch 02101 40915
Experimental animals:
Young healthy rats acclimatized for at least 5 days to laboratory conditions were used for this test. During the acclimatization period animals were observed for their health condition to assure that they were in best condition for this investigation. Only female rats were used.
Husbandry:
Three rats were housed in one Makrolon cage type VI each. A non-barrier system with air condition was used. The air conditioning had following nominal values: Temperature: 22°C ± 3°C, Humidity: 30 - 70 %. Climate control was run automatically. The lighting was in a 12-hour light/dark-cycle. Temperature and humidity were recorded continuously using a thermohygrometer, Lambrecht GmbH, Gottingen, Germany. The data were archived. There has been a deviation from nominal humidity values. On 2005-06-17 and 2005-06-18 the humidity was slightly higher (up to 75 %). However, this deviation is not supposed to have any effect on the experimental result.
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
The starting dose of 300 mg/kg body weight was applied to six female animals as 10 % (w/w) solution in tap water. Therefore 1.5 g of the test substance were added to 13.5 g tap water and mixed on a magnetic stirrer. The density of the 10 % solution was 1.025 g/ml and of the undiluted test substance 1.22 g/ml. The density of the undiluted test sUbstance was higher than 1.05 g/ml and therefore was considered in calculation of the application volume. The dose of 2000 mg/kg body weight was applied to six female animals with the undiluted test substance.
Dose volume: 300 mg/kg group: 0.48 - 0.51 mL; 2000 mg/kg: 0.27 - 0.30 mg/kg.
Doses:
300 mg/kg, 2000 mg/kg
No. of animals per sex per dose:
6 animals per dose (female only)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical examination was performed immediately, 0.5, 1.5 and 3.5 hours after test substance administration and thereafter daily; weighing at day 0, day 7, day 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 1 000 mg/kg bw
Based on:
other: solid matter (incl. NaCl)
Sex:
female
Dose descriptor:
LD50
Effect level:
> 830 mg/kg bw
Based on:
act. ingr.
Remarks on result:
other: test substance Formamidopropyldimethylbetain 50 %ig (50 %ig based on solid matter, active matter: 41.5 %)
Mortality:
No mortality occured.
Clinical signs:
No clinical signs observed
Body weight:
The body weight development of the animals was positive and within normal ranges.
Gross pathology:
The necropsy 14 days after application showed no substance related morphological visible pathologic organ findings.

Body weights

Animal ID

Sex

Dose [mg/kg]

Day 0 [g]

Mean±SD

Day 7 [g]

Mean±SD

Day 14 [g]

Mean±SD

Average weight gain [%]

425

F

300

168.4

165.6 ±3.8

190.7

186.0 ±9.6

197.6

198.0 ±7.6

+ 19.6

425 RV

F

300

166.8

183.8

197.7

425 RH

F

300

161.6

171.0

185.7

426

F

300

169.2

183.3

201.1

426 RV

F

300

159.9

187.2

196.8

426 RH

F

300

167.4

200.0

209.3

427

F

2000

173.7

171.2 ±5.8

196.0

191.7 ±8.6

208.7

204.7 ±6.1

+ 19.6

427 RV

F

2000

165.4

180.0

197.3

427 RH

F

2000

166.4

185.3

198.0

428

F

2000

180.7

204.3

212.9

428 RV

F

2000

167.9

189.8

205

428 RH

f

2000

173.0

194.7

205.9

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
The LD50-value of the test substance Formamidopropyldimethylbetain 50 %ig is greater than 2000 mg/kg body weight.
Executive summary:

The test substance Formamidopropyldimethylbetain 50 %ig (50 %ig based on solid matter, active matter: 41.5 %) is a clear yellowish liquid. For labelling and classification purposes Formamidopropyldimethylbetain 50 %ig was tested regarding its acute toxic potential following oral application. Slight acute oral toxicity of Formamidopropyldimethylbetain 50 %ig was expected. Therefore the starting dose of 300 mg/kg body weight was chosen in the Acute-Toxic-Class-Method procedure, according to the OECD Guideline for the Testing of Chemicals No. 423 "Acute Oral Toxicity - Acute Toxic Class Method". A total of twelve female rats of the strain White Wistar were used in the study. The test substance Formamidopropyldimethylbetain 50 %ig was applied by gavage undiluted and as 10 % (w/w) solution in tap water. No toxic symptoms after administration of 300 mg/kg body weight were observed in six animals. In the next step the test substance Formamidopropyldimethylbetain 50 %ig was applied to six rats at a dose level of 2000 mg/kg body weight. No toxic symptoms were observed in this group, as well. No death occurred in all groups of the dose levels 300 mg/kg and 2000 mg/kg body weight. Body weight development of all animals was positive 7 days and 14 days post application. The necropsy 14 days after oral application showed no substance related morphological visible pathologic organ findings. Thus, the LD50-value for the test substance Formamidopropyldimethylbetain 50 %ig is higher than 2000 mg/kg. Therefore, the test substance Formamidopropyldimethylbetain 50 %ig has not to be classified according to the Globally Harmonised System. According to the guidance on classification as given in the Commission Directive 2004/73/EC the test substance Formamidopropyldimethylbetain 50 %ig has to be graded as not acute toxic by oral route.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Data from a GLP compliant guideline study with reliability 1.

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:
28. Dec. 2005 - 11. Jan. 2006
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Species : Rat, Wistar strain, Crl:WI (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 : 5 males and 5 females (females were nulliparous and nonpregnant).
Age and body weight : Young adult animals (approx. 9 weeks old) were selected. Body weight variation did not exceed +/- 20% of the sex mean.
Identification : Earmark
Health inspection : A health inspection was performed prior to commencement of treatment, to ensure that the animals were in a good state of health. Special attention was paid to the skin to be treated, which was intact and free from any abnormality.
Conditions : Animals were housed in a controlled environment, in which optimal conditions were considered to be approximately 15 air changes per hour, a temperature of 21.0 ± 3.0°C (actual range: 20.5 - 22.4°C), a relative humidity of 30-70% (actual range: 45 - 70%) and 12 hours artificial fluorescent light and 12 hours darkness per day.
Accommodation : Individually housed in labeled Macrolon cages (Mill type, height 18 cm.) containing sterilized sawdust as bedding material (Woody-Clean type 3/4; Tecnilab-BMI BV, Someren , The Netherlands) and paper as cage-enrichment (Enviro-dri, Tecnilab-BMI BV, Someren, The Netherlands ). Acclimatization period was at least 5 days before start of treatment under laboratory conditions. During the acclimatization period the animals were group housed in Macrolon cages (MIV type).
Diet : Free access to standard pelleted laboratory animal diet (from Altromin (code VRF 1), Lage, Germany).
Water : Free access to tap water.
Results of analysis for each batch of diet (nutrients) and results of quarterly analysis of diet (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.
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
Method : Dermal application.
Clipping : One day before exposure (day -1) an area of approximately 5x7 cm on the back of the animal was clipped.
Application : The test substance was applied in an area of approx. 10% of the total body surface, i.e. approx. 25 cm2 for males and 18 cm2 for
females. The test substance was held in contact with the skin with a dressing, consisting of a surgical gauze patch (Surgy 1 D)·, successively covered with aluminum foil and Coban elastic bandage*. A piece of Micropore tape* was additionally used for fixation of the bandages in females only.
*. Manufacturers: Laboratoires Stella s.a., Liege, Belgium (surgical gauze) and 3M, St. Paul, Minnesota, U.S.A. (Coban & Micropore).
Frequency : Single dosage, on day 1.
Dose level (volume) : 2000 mglkg (3.8 mllkg) body weight. Purity of the test substance was taken into account. Dose volume calculated as dose level: specific gravity.
Application period : 24 hours, after which dressings were removed and the skin cleaned of residual test substance using tap water.
Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Mortality/Viability : Twice daily.
Body weights : Days 1 (pre-administration), 8 and 15.
Clinical signs : At periodic intervals on the day of dosing (day 1) and once daily thereafter, until day 15. The time of onset, degree and duration were recorded and the symptoms graded according to fixed scales: Maximum grade 4: grading slight (1) to very severe (4), Maximum grade 3: grading slight (1) to severe (3), Maximum grade 1: presence is scored (1).
Necropsy : At the end of the observation period, all animals were sacrificed by oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
act. ingr.
Mortality:
No mortality occurred,
Clinical signs:
Chromodacryorrhoea was noted among the animals on days 1 and 2. Scales were seen in the treated skin-area of some animals between days 3 and 12.
Body weight:
The changes noted in body weight gain in males and females were within the range expected for rats used in this type of study and were therefore considered not indicative of toxicity,
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals,

BODY WEIGHTS (GRAM)

Sex/dose level

animal

Day 1

Day 8

Day 15

Males 2000 mg/kg

1

290

318

348

 

2

286

307

332

 

3

292

316

341

 

4

326

352

400

 

5

319

337

375

 

Mean

303

326

359

 

St Dev

18

18

28

 

N

5

5

5

Females 2000 mg/kg

6

211

229

243

 

7

195

206

209

 

8

206

228

244

 

9

217

233

241

 

10

220

241

251

 

Mean

210

227

238

 

St Dev

10

13

16

 

N

5

5

5

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
The dermal LD50 value of FORMAMIDOPROPYLBETAINE in Wistar rats was established to exceed 2000 mg/kg body weight (corrected for purity of the test substance).
Executive summary:

Assessment of acute dermal toxicity with FORMAMIDOPROPYLBETAINE in the rat.

The study was carried out based on the guidelines described in: OECD No 402 (1987) "Acute Dermal Toxicity" EC, Council Directive 67/548/EEC, Annex V, B.3 (1992) "Acute Toxicity (Dermal)" EPA, OPPTS 870.1200 (1998), "Acute Dermal Toxicity" JMAFF Guidelines (2000), including the most recent revisions.

FORMAMIDOPROPYLBETAINE was administered to five Wistar rats of each sex by a single dermal application at 2000 mg/kg body weight for 24 hours. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (day 15). No mortality occurred, Chromodacryorrhoea was noted among the animals on days 1 and 2, Scales were seen in the treated skin-area of some animals between days 3 and 12. The body weight gain during the observation period was within the range expected for rats used in this type of study. No abnormalities were found at macroscopic post mortem examination of the animals. The dermal LD50 value of FORMAMIDOPROPYLBETAINE in Wistar rats was established to exceed 2000 mg/kg body weight (corrected for purity of the test substance).

Based on these results FORMAMIDOPROPYLBETAINE does not have to be classified and has no obligatory labelling requirement for dermal toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (New York and Geneva, 2003) and EC criteria for classification and labelling requirements for dangerous substance and preparations (Council Directive 67/548/EEC).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Data from a GLP compliant guideline study with reliability 1.

Additional information

Assessment of acute oral toxicity with Formamidopropyldimethylbetain in the rat.

The test substance Formamidopropyldimethylbetain 50 %ig (50 %ig based on solid matter, active matter: 41.5 %) is clear yellowish liquid. For labelling and classification purposes Formamidopropyldimethylbetain 50 %ig was tested regarding its acute toxic potential following oral application. Slight acute oral toxicity of Formamidopropyldimethylbetain 50 %ig was expected. Therefore the starting dose of 300 mg/kg body weight was chosen in the Acute-Toxic-Class-Method procedure, according to the OECD Guideline for the Testing of Chemicals No. 423 "Acute Oral Toxicity - Acute Toxic Class Method". A total of twelve female rats of the strain White Wistar were used in the study. The test substance Formamidopropyldimethylbetain 50 %ig was applied by gavage undiluted and as 10 % (w/w) solution in tap water. No toxic symptoms after administration of 300 mg/kg body weight were observed in six animals. In the next step the test substance Formamidopropyldimethylbetain 50 %ig was applied to six rats at a dose level of 2000 mg/kg body weight. No toxic symptoms were observed in this group, as well. No death occurred in all groups of the dose levels 300 mg/kg and 2000 mg/kg body weight. Body weight development of all animals was positive 7 days and 14 days post application. The necropsy 14 days after oral application showed no substance related morphological visible pathologic organ findings. Thus, the LD50-value for the test substance Formamidopropyldimethylbetain 50 %ig is higher than 2000 mg/kg. Therefore, the test substance Formamidopropyldimethylbetain 50 %ig has not to be classified according to Directive 67/548 EEC as well as GHS Regulation EC No 1272/2008, and labelling is not necessary.

Assessment of acute dermal toxicity with Formamidopropyldimethylbetain in the rat.

The study was carried out based on the guidelines described in: OECD No 402 (1987) "Acute Dermal Toxicity" EC, Council Directive 67/548/EEC, Annex V, B.3 (1992) "Acute Toxicity (Dermal)" EPA, OPPTS 870.1200 (1998), "Acute Dermal Toxicity" JMAFF Guidelines (2000), including the most recent revisions.

Formamidopropyldimethylbetain was administered to five Wistar rats of each sex by a single dermal application at 2000 mg/kg body weight for 24 hours. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (day 15). No mortality occurred, Chromodacryorrhoea was noted among the animals on days 1 and 2, Scales were seen in the treated skin-area of some animals between days 3 and 12. The body weight gain during the observation period was within the range expected for rats used in this type of study. No abnormalities were found at macroscopic post mortem examination of the animals. The dermal LD50 value of Formamidopropyldimethylbetain in Wistar rats was established to exceed 2000 mg/kg body weight (corrected for purity of the test substance).

Based on these results Formamidopropyldimethylbetain does not have to be classified for dermal toxicity according to Directive 67/548 EEC as well as GHS Regulation EC No 1272/2008, and labelling is not necessary.


Justification for selection of acute toxicity – oral endpoint
Data from a GLP compliant guideline study with reliability 1.

Justification for selection of acute toxicity – dermal endpoint
Data from a GLP compliant guideline study with reliability 1.

Justification for classification or non-classification

Based on these results Formamidopropyldimethylbetain does not has to be classified and has no obligatory labelling requirement for dermal toxicity according to Directive 67/548 EEC as well as GHS Regulation EC No 1272/2008. Formamidopropyldimethylbetain 50 %ig does not have to be classified and has no obligatory labelling requirement for oral toxicity according to Directive 67/548 EEC as well as GHS Regulation EC No 1272/2008.

The maximum dose of Formamidopropyldimethylbetain (corrected for purity of the test substance) tested orally was 830 mg/kg bw. According to the expert statement on toxicokinetics, the dermal absorption for Formamidopropyldimethylbetain is expected to be even higher than the oral absorption (for details please refer to chapter 5.1: basic toxicocinetics). Based on this statement, the acute oral toxicity is expected to be even lower than the acute toxicity after dermal application. As a worst case approach for risk assessment, no assessment factor will be used for dermal-to-oral extrapolation. This is supported by a Risk Assessment performed by the German authority Bfr:

"From the physico-chemical data (water solubility (> 2160 g/l), partition coefficient log Pow of -3.3 and molecular weight (188 g/mol)) the substance can be assumed to have a probably poor oral bioavailability (This Risk assessment was conducted by BfR on 06.12.2006 on basis of data according to Annex VIIA)"

Even though the maximum dose of 2000 mg/kg bw Formamidopropyldimethylbetain has not been experimentally tested orally, in a weight of evidence approach, taking the dermal test and toxicokinetic data into account, Formamidopropyldimethylbetain does not have to be classified and has no obligatory labelling requirement for oral toxicity according to Directive 67/548 EEC as well as GHS Regulation EC No 1272/2008, a classification for Formamidopropyldimethylbetain is not required and labelling is not necessary.