Registration Dossier

Administrative data

Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
According to REACH Annex VIII column 2, 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.
The substance to be registered is a white powder with faint odour (at 20°C and 1013 hPa). The test material melts at 245.4 °C under degradation, and has also a very low vapour pressure (7.12E-08 Pa at 25°C, calculated). So, the exposure to PPSOH via inhalation of vapour can be disregarded as no vapour will be formed during handling. Further, the substance is actually not handled as a solid, but is manufactured, distributed and used as aqueous solution only, so inhalable particles do also not need to be regarded. Last but not least, sufficient precautionary measures exclude the formation of droplets of inhalable size or aerosols. In consequence, exposure of humans via inhalation is not likely.

Furthermore, testing is scientifically not necessary and would not reveal any additional information which cannot be derived from other available acute toxicity data, so that testing can be omitted due to animal welfare:
According to ECHA’s guidance, moderate log P values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. The log Pow of PPSOH was determined as < -2. Hence, this value indicates a possibly diminished potential for absorption, which is supported by a water solubility of 1280 g/l at 23°C.. Further, the available oral and dermal toxicity studies on PPSOH and the suitable read-across substance PPS indicate a very low toxicity of PPSOH. The following results were determined:

- LD50(oral) = 5000 mg/kg, Wistar rats, females, 6 dosed with 2000 mg/kg, oral: gavage, no mortality or signs of toxicity occurred (OECD 423, GLP)
- LD50(oral) > 5000 mg/kg, LD0≥5000 mg/kg, Wistar rats, m/f, oral: gavage, no mortality occurred (read-across from PPS, OECD 401, GLP)
- LD50(dermal) > 2000 mg/kg, LD0≥2000 mg/kg, Sprague-Dawley rats, m/f, 5/sex dose, 2000 mg/kg, semi-occlusive over 24h, no mortality, signs of systemic toxicity or dermal irritation occurred (read-across from PPS, OECD 402, GLP)

There is no study available and also not required for the acute inhalation toxicity of PPSOH, as the relevant information can be drawn from the acute oral LD50 values and estimation of the absorption of the test item via both routes.
According to OECD guideline 403 (Acute inhalation toxicity), the concentration of respirable particles for limit testing is 5 mg/L over 4 h. Taking into account for rats a standard respiratory volume of 0.2 l/min and average body weight of 250 g (Guidance on information and requirements and chemical safety assessment, chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012, ECHA, http://echa.europa.eu/web/guest/guidance-documents/guidance-on-information-requirements-and-chemical-safety-assessment), a total respiratory volume of 48 litre over 4 h can be assumed. This would result in a total dose of 240 mg per rat, which is equivalent to 960 mg/kg bw.
Assuming in a worst-case scenario, which is rather unrealistic, that this total dose will be absorbed to 100%, and assuming furthermore that the orally applied amount is only absorbed to 50%, this dose would correspond to an oral dose of 1920 mg/kg bw. This value is below the relevant determined LD50 and even LD0 via the oral route, i.e. ≥ 5000 mg/kg bw. Hence, it can be reasonably assumed that an additional acute toxicity test via the inhalation route would reveal an LC50inhalation >5 mg/l, most likely even a LC0inhalation ≥5 mg/l. This is supported by the reasonably assumable similar absorption via the inhalatory route compared to the oral one, which were considered equal with 100% and so the additional safety factor of 2 as indicated above does not need to be regarded.
Furthermore, PPSOH is neither a skin nor eye irritant. So it can be additionally concluded, that no local effects during inhalation toxicity testing are likely occur and need to be regarded.
In consequence, the available oral and dermal acute toxicity studies are sufficient to cover this endpoint, no acute toxicity testing via inhalation route needs to be performed and can consequently be waived due to animal welfare.
Cross-referenceopen allclose all
Reason / purpose:
data waiving: supporting information
Remarks:
Physical state
Reference
Endpoint:
appearance / physical state / colour
Type of information:
other: observation
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: acceptable company statement (specification data on manufactured product requires strict adherence to conform within range and so is reliable)
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Visual description of the colour (in daylight by an observer with normal colour vision) and the physical state (at 20°C and 1013 hPa)
- Determination of the odour at room temperature and comparison to other substances of characteristic odours
GLP compliance:
no
Physical state at 20°C and 1013 hPa:
solid
Key result
Form:
powder
Colour:
white
Odour:
faint
Substance type:
organic
Conclusions:
- physical state at 20°C and 1013 hPa: solid (form: powder)
- colour: white
- odour: faint
Executive summary:

The visual description of the colour, the physical state (at 20°C and 1013 hPa) and the determination of the odour resulted in the following: the test substance 2-hydroxy-3-pyridinium-1-ylpropane-1-sulfonate is a white powder with faint odour (at 20°C and 1013 hPa).

Reason / purpose:
data waiving: supporting information
Remarks:
vapour pressure
Reference
Endpoint:
vapour pressure
Type of information:
(Q)SAR
Adequacy of study:
supporting study
Study period:
2018-02-26
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
1. SOFTWARE
EPIWIN software by US-EPA

2. MODEL (incl. version number)
MPBPVPWIN v1.43

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
OC(C[n+]1ccccc1)CS(=O)(=O)[O-]

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- The complete test sets of experimental data for (melting point, boiling point and) vapour pressure can be downloaded via the Internet at: http://esc.syrres.com/interkow/EpiSuiteData.htm

5. APPLICABILITY DOMAIN
Estimation accuracy: The accuracy of MPBPWIN's "suggested" VP estimate was tested on a dataset of 3037 compounds with known, experimental VP values between 15 and 30 deg C (the vast majority at 25 or 20 deg C). The experimental values were taken from the PHYSPROP Database that is part of the EPI Suite. For this test, the CAS numbers were run through MPBPWIN as a standard batch-mode run (using the default VP estimation temperature of 25 deg C) and the batch estimates were compared to PHYSPROP's experimental VP. The plot clearly indicates that the estimation error increases as the vapour pressure (both experimental and estimated) decreases, especially when the vapour pressure decreases below 1x10-6 mm Hg (0.0001333 Pa).
The estimation methodology uses the normal boil point to estimate the liquid-phase vapour pressure. For solids, the melting point is required to convert the liquid-phase vapour pressure to the solid-phase vapour pressure. VP estimation error can be introduced by:
(1) poor Boiling Point estimates or values
(2) poor Melting Point estimates or values (for solids)

The 3037 compound test set contains 1642 compounds with available experimental Boiling points and Melting points. For this subset of compounds, the estimation accuracy statistics are (based on log VP):

number = 1642
r2 = 0.949
std deviation = 0.59
avg deviation = 0.32

These statistics clearly indicate that VP estimates are more accurate with experimental BP and MP data.

Estimation domain: The intended application domain is organic chemicals. Inorganic and organometallic chemicals generally are outside the domain.
Currently there is no universally accepted definition of model domain. However, users may wish to consider the possibility that property estimates are less accurate for compounds outside the Molecular Weight range of the training set compounds, and/or that have more instances of a given fragment than the maximum for all training set compounds. It is also possible that a compound may have a functional group(s) or other structural features not represented in the training set, and for which no fragment coefficient was developed. These points should be taken into consideration when interpreting model results.
The complete training sets for MPBPWIN's estimation methodology are not available. Therefore, describing a precise estimation domain for this methodology is not possible. The current applicability of the MPBPWIN methodology is best described by its accuracy in predicting vapour pressure as described above in the accuracy section.

6. ADEQUACY OF THE RESULT
The result calculated for the organic substance 2-hydroxy-3-pyridinium-1-ylpropane-1-sulfonate (PPSOH) seems reasonable. The beginning of melting (245.4°C) under decomposition has been used in addition to the estimated melting point to estimate the vapour pressure of the substance at 20 and 25°C. Further, due to the magnitude of the result it is considered as adequate.
Guideline:
other: REACH guidance on QSARs Chapter R.6
Version / remarks:
May 2008
Principles of method if other than guideline:
Vapour Pressure is estimated by three methods; all three methods use the boiling point. The first is the Antoine method (see Chapter 14 of W.J. Lyman's book "Handbook of Chemical Property Estimation Methods", Washington, DC: American Chemical Society, 1990). The second is the modified Grain method (see page 31 of Neely and Blau's Environmental Exposure from Chemicals, Volume I, CRC Press, 1985). The third is the Mackay method (see page 31-2 of Neely and Blau's Environmental Exposure from Chemicals, Volume I, CRC Press, 1985).
GLP compliance:
no
Remarks:
not applicable
Type of method:
other: QSAR estimation
Key result
Temp.:
25 °C
Vapour pressure:
0 Pa
Remarks on result:
other: Modified Grain Method (MPBPWIN v1.43) - most relevant for solids
Remarks:
based on experimentally determined melting point of 245.4°C
Temp.:
25 °C
Vapour pressure:
0 Pa
Remarks on result:
other: Antoine Method (MPBPWIN v1.43)
Remarks:
based on experimentally determined melting point of 245.4°C
Temp.:
25 °C
Vapour pressure:
0 Pa
Remarks on result:
other: Mackay Method (MPBPWIN v1.43)
Remarks:
based on experimentally determined melting point of 245.4°C
Temp.:
25 °C
Vapour pressure:
0 Pa
Remarks on result:
other: Modified Grain Method (MPBPWIN v1.43) - most relevant for solids
Remarks:
based on estimated Melting Point
Temp.:
25 °C
Vapour pressure:
0 Pa
Remarks on result:
other: Antoine Method (MPBPWIN v1.43)
Remarks:
based on estimated Melting Point
Temp.:
25 °C
Vapour pressure:
0 Pa
Remarks on result:
other: Mackay Method (MPBPWIN v1.43)
Remarks:
based on estimated Melting Point
Temp.:
20 °C
Vapour pressure:
0 Pa
Remarks on result:
other: Modified Grain Method (MPBPWIN v1.43) - most relevant for solids
Remarks:
based on experimentally determined melting point of 245.4°C
Temp.:
20 °C
Vapour pressure:
0
Remarks on result:
other: Modified Grain Method (MPBPWIN v1.43) - most relevant for solids
Remarks:
based on estimated Melting Point
Conclusions:
The study report describes a scientifically accepted calculation method for the vapour pressure using the US-EPA software MPBPWIN v1.43.No GLP criteria are applicable for the usage of this tool and the QSAR estimation is easily repeatable. The result is adequate for the regulatory purpose.
The calculation resulted in a value of 7.12E-08 Pa at 25 °C (Modified Grain Method).
Executive summary:

The vapour pressure of the substance 2-hydroxy-3-pyridinium-1-ylpropane-1-sulfonate (PPSOH) was determined by the computer program MPBPWIN v1.43 (EPIWIN software) by US-EPA (2012). The program calculates the vapour pressure according to three different methods: Antoine, Modified Grain and Mackay. The Modified Grain method is preferentially adopted and therefore the most important one [Lyman, W.J., 1985. In: Environmental Exposure From Chemicals. Volume I., Neely, W.B. and Blau, G.E. (eds), Boca Raton, FL: CRC Press, Inc., Chapter 2]. The beginning of melting (245.4°C) under decomposition has been used in addition to the estimated melting point to estimate the vapour pressure of the substance at 20 and 25°C. According to the Modified Grain Method the substance has a vapour pressure of 7.12E-08 Pa at 25°C (most relevant for solids) using a melting point of 245.4°C. The estimation error increases as the vapour pressure decreases, especially when the vapour pressure is below 0.000133Pa, but the calculated value can anyway viewed as indicative of a very low vapour pressure, which is sufficient considering the magnitude of the result.

Reason / purpose:
data waiving: supporting information
Remarks:
water solubility
Reference
Endpoint:
water solubility
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
non-GLP
Qualifier:
according to
Guideline:
OECD Guideline 105 (Water Solubility)
Version / remarks:
(27.07.95)
Deviations:
no
GLP compliance:
no
Type of method:
flask method
Key result
Water solubility:
1 280 g/L
Incubation duration:
3 h
Temp.:
23 °C
Remarks on result:
other: pH not available
Details on results:
Determination of the water solubility on the basis of observation of the solution (solid, solution with many crystals, solution).
Conclusions:
Water solubility = 1280 g/L (soluble).
The study was performed according to OECD TG105 with deviations (no determination of pH, lacking information of individual results of the three flasks, no analytical method) and therefore reliability of Klimisch 2 has been assigned.
Executive summary:

The water solubility of the test material was determined experimentally using the flask method in a non-GLP test according to OECD guideline 105. The water solubility of the test material is 1280 g/L at 23 °C, the substance is soluble in water.

Reason / purpose:
data waiving: supporting information
Remarks:
logPow
Reference
Endpoint:
partition coefficient
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2018-05-23 - 2018-05-25 (experimental phase)
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
under GLP
Qualifier:
according to
Guideline:
OECD Guideline 107 (Partition Coefficient (n-octanol / water), Shake Flask Method)
Version / remarks:
OECD Guideline 107 „Partition Coefficient (n-octanol/water): Shake Flask Method“ of 27. July 1995
Deviations:
no
Qualifier:
according to
Guideline:
EU Method A.8 (Partition Coefficient - Shake Flask Method)
Version / remarks:
Council Regulation (EC) No. 440/2008 of 30. May 2008, published on 31. May 2008: Method A.8 Partition coefficient
Deviations:
no
GLP compliance:
yes (incl. certificate)
Type of method:
flask method
Partition coefficient type:
octanol-water
Specific details on test material used for the study:
The test item was stored in a closed vessel at room temperature (20 ± 5°C).
Analytical method:
high-performance liquid chromatography
Key result
Type:
log Pow
Partition coefficient:
< -2
Temp.:
24 °C
pH:
>= 7.16 - <= 7.34
Remarks on result:
other: logPow = < -2 ± 0.006 (log POW ± stand. dev.)
Remarks:
The test was performed at 23.8 - 24 °C, column temperature was 25°C.
Conclusions:
The study was performed according to the OECD TG107 and EU Method A.8 (GLP) without deviations and therefore considered to be of the highest quality (reliability Klimisch 1).The validity criteria are fulfilled. The log POW of the test item 1-(2-hydroxy-3-sulphonatopropyl)pyridinium, inner salt (PPSOH) was calculated as (log POW ± stand. dev.): < -2 ± 0.006. The outcome of the study is considered reasonable.
Executive summary:

The partition coefficient of 1-(2-hydroxy-3-sulphonatopropyl)pyridinium, inner salt (PPSOH) was determined in a GLP study according to OECD 107 resp. EU Method A.8, shake-flask method. Partition coefficient was determined using n-octanol and double-distilled water.

Three volume ratios of n-octanol: water (1:2, 1:4, 1:1) were tested in duplicate.

The separated phases were analysed using HPLC.

The measurements of the phases gave the following log POW of the test item at the respective ratio:

 

Table Results

Ratio n-octanol: water

Mean log POW

1 : 2

< -2

1 : 4

< -2

1 : 1

< -2

 

Overall log POW (Mean ± standard deviation): < -2 ± 0.006

Range of pH values in the aqueous phases: 7.21 – 7.34
Reason / purpose:
data waiving: supporting information
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-guideline-study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
OECD n° 423 (24 April 2002)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
Test method B.1tris directive 2004/73/EC
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source : Elevage JANVIER (53940 Le Genest St Isle –France)
- Age at study initiation : 8 weeks
- Weight at study initiation : 186g - 206g
- Fasting period before study : no
- Housing : Three rats were kept in solid-bottomed clear polycarbonate cages with a stainless steel mesh lid. Each cage contains sawdust bedding which was changed at least 2 times a week.
- Diet (e.g. ad libitum): M20-rat/mouse maintenance diet , ad libitum (Food was removed at D-1 and then redistributed 4 hours after the test item administration.)
- Water (e.g. ad libitum) : Drinking water, ad libitum (tap-water from public distribution system)
- Acclimation period : at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature : 20°C - 23°C
- Humidity : 32% - 60%
- Air changes (per hr) : not stated
- Photoperiod (hrs dark / hrs light) : 12/12
Route of administration:
oral: gavage
Vehicle:
other: distilled water
Details on oral exposure:
The animals of treated group, received an effective dose of 2000 mg/kg body weight of the test item, diluted in distilled water and administered by gavage under a volume of 10 mL/kg body weight using a suitable syringe graduated fitted with an oesophageal metal canula.
Doses:
2000 mg/kg
No. of animals per sex per dose:
6
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing : on day D0 (just before administering the test item) then on D2, D7, and D14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, macroscopical examination
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
5 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred during the study.
Clinical signs:
No clinical signs related to the administration of the test item were observed.
Body weight:
The body weight evolution of the animals remained normal throughout the study.
Gross pathology:
The macroscopical examination of the animals at the end of the study did not reveal treatment-related changes.
Interpretation of results:
GHS criteria not met
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The study was performed according to the OECD guideline No. 423 dated 17 December 2001 concerning acute oral toxicity and the test method B.1 tris of the Directive No. 2004/73/EC with no deviations and according to the good laboratory practice principles. It is considered to be of the highest quality (reliability Klimisch 1). The test item 1-(2-Hydroxy-3-sulfopropyl)-pyridinium-betain was administered by oral route to a group of 6 female Sprague Dawley rats at the single dose of 2000 mg/kg body weight.
The LD50 of the test item 1-(2-Hydroxy-3-sulfopropyl)-pyridinium-betain is higher than 5000 mg/kg body weight by oral route in the rat, in accordance with Annex 2d of the OECD guideline 423.
Executive summary:

The test item 1-(2-Hydroxy-3-sulfopropyl)-pyridinium-betain was administered by oral route to a group of 6 female Sprague Dawley rats at the single dose of 2000 mg/kg body weight. The experimental protocol was established on the basis of the official method as defined in the O.E.C.D. guideline N° 423 dated December 17th, 2001 and the test method B.1tris of the Directive N° 2004/73/EC.

No mortality occurred during the study. No clinical signs related to the administration of the test item were observed. The body weight evolution of the animals remained normal throughout the study. The macroscopical examination of the animals at the end of the study did not reveal treatment-related changes.

In conclusion, the LD50 of the test item 1-(2-Hydroxy-3-sulfopropyl)-pyridinium-betain is higher than 5000 mg/kg body weight by oral route in the rat, in accordance with Annex 2d of the OECD guideline n°423.

According to the criteria for classification, packaging and labelling of dangerous substances and preparations in accordance with the E.E.C. Directives 67/548, 2001/59 and 99/45, the test item 1-(2- Hydroxy-3-sulfopropyl)-pyridinium-betain must not be classified. No symbol and risk phrase are required.

In accordance with the Globally Harmonized System (COM(2007)355 final), the test item must not be classified in category 4. No signal work and hazard statement are required.

Reason / purpose:
data waiving: supporting information
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1982-11-30 - 1983-12-17
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
see target record
Reason / purpose:
read-across source
Remarks:
link to target
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: rats outbred with Wistarstock KFM:WIST (SPF HAN.)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Kleintierfarm Madoerin AG/ 4414 Fuellingsdorf, Switzerland
- Age at study initiation: 7 weeks (males), 9 weeks (females)
- Weight at study initiation: 160 - 224 g (males) and 156 - 200 g (females)
- Fasting period before study: fasting overnight
- Housing: the animals were caged in groups of five in macrolon cages with wire mesh tops (Dipl. Ing. W. Ehret GmbH, 7330 Emmendingen, Germany) and standardized granulated soft wood bedding (Lignocel/Schill AG / 4132 Muttenz, Switzerland).
- Diet (e.g. ad libitum): pelleted standard KLIBA 343/BATCH 69/82 rat maintenance diet (Klingentalmuehle AG/ 4303 Kaiseraugust/Switzerland). Defined for acceptable contaminant level, ad libitum.
- Water (e.g. ad libitum): tap water ad libitum (water quality according to the requirements oft he "schweiz. Lebensmittelbuch".
- Acclimation period: 1 week under test conditions

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2°C
- Humidity (%): 55 +/- 10%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 hours light, 12 hours dark

IDENTIFICATION: by cage number and individual colour spots
RANDOMIZATION: in order to set up a fully randomized experiment/animals were assigned to the different groups by means of a random algorithm.
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 2 % solution of CMC (Carboxymethylcellulose Natriumsalt purum/ Vise./ 100 CPS/ Fluka AG/ Buchs/Switzerland) in distilled water
- Amount of vehicle (if gavage): 10 mL at 1000 mg/kg and 20 mL at 5000 mg/kg

MAXIMUM DOSE VOLUME APPLIED: 20 mL at 5000 mg/kg

DOSAGE PREPARATION: A dilution (w/w) of the test compound was prepared using a homogenizer (Ultra-Turrax/Janke and Kunkel/Staufen/ West-Germany) and kept homogenous during treatment using a magnetic stirrer (Auer-Bittmann/Switzerland).
Doses:
1000 mg/kg bw and 5000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
- single oral intubation via gavage to animals fasted overnight
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Bodyweights were recorded at the day of administration and days 7 and 14 after the administration / Symptoms were assessed five times at day 1 and then daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
The LD50 was calculated without use of a statistical model by estimation.
Sex:
male/female
Dose descriptor:
LD0
Effect level:
>= 5 000 mg/kg bw
Based on:
test mat.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
In both groups no mortalities occurred.
Clinical signs:
In both groups the animals showed ruffled fur (slight) within 1 to 5 hours after dosing. All rats had recovered within 2 observation days.
Body weight:
In both groups no body weight changes were observed.
Gross pathology:
Three male rats of the 5000 mg/kg group showed mottled lungs. Apart from this unspecific finding, no macroscopical organ changes were observed.
Other findings:
No other findings were reported.
Interpretation of results:
GHS criteria not met
Remarks:
Criteria used for interpretation of results: other: EU-GHS
Conclusions:
The study was performed according to the OECD TG401 without deviations and therefore considered to be of the highest quality (reliability Klimisch 1). The validity criteria of the test system are fulfilled. The test material did not induce mortality or treatment-related clinical signs. The test material was considered to be non-toxic under the conditions of the test, and does not need to be classified as acutely toxic via the oral route.
Executive summary:

The acute oral toxicity of the test material was investigated in rats (Ullmann et al,1993). The test was conducted according to OECD TG401. As doses 1000 and 5000 mg/kg bw of the test substance were administered via gavage to the rats. Observations were made for a period of 14 days. No mortalities or signs of systemic toxicity, beside slightly ruffled fur during the first 5 hours following administration were observed. No treatment-related body weight changes were reported. In 3 male animals pathological abnormalities were found: mottled lungs (dose group 5000 mg/kg bw). This findings are not to be considered to be specific, but unspecific. The acute oral medina lethal dose (LD50) of the test material in rats of both sexes observed over a period of 14 days was estimated to be greater than 5000 mg/kg bw.

Reason / purpose:
data waiving: supporting information
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2001-08-22 - 2001-10-05
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline Study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
see target record
Reason / purpose:
read-across source
Remarks:
link to target
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS: Sprague-Dawley CD (Crl: CD® (SD) IGS BR) strain rats
- On receipt the animals were randomly allocated to cages. The females were nulliparous and non-pregnant.
- Source: Charles River (UK) Ltd, Margate, Kent, UK.
- Animal selection: at random and given a unique number within the study by indelible ink-marking on the tail and a number written on a cage card.
- Age at study initiation: approximately eight weeks
- Weight at study initiation: at least 200 g
- Housing: housed in suspended polypropylene cages furnished with wood flakes, individually during the 24-hour exposure period and in groups of five, by sex, for the remainder of the study
- Diet (e.g. ad libitum): ad libitum (Rat and Mouse SQC Expanded Diet No. 1, Special Diets Services Limited, Witham, Essex, UK)
- Water (e.g. ad libitum): ad libitum drinking water
The diet, drinking water and bedding were routinely analysed and were considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study.
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25°C (Any occasional deviations from these targets were considered not to have affected purpose or integrity of the study)
- Humidity (%): 30 to 70% (Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study)
- Air changes (per hr): at least fifteen per hours
- Photoperiod (hrs dark / hrs light): twelve hours continuous light (06:00 to 18:00) and twelve hours darkness

The animals were provided with environmental enrichment items: wooden chew blocks (B&K Universal Ltd, Hull, UK) and cardboard fun tunnels (Datesand Ltd, Cheshire, UK) or suitable alternatives. These items were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.
Type of coverage:
semiocclusive
Vehicle:
other: distilled water
Details on dermal exposure:
TEST SITE
- Preparation: on the day before treatment the back and flanks of each animal were clipped free of hair.
- Area of exposure: approximately 10% of the total body surface area
- Type of wrap if used: A piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): after the 24-hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with distilled water to remove any residual test material.

- Other: the absorption of the test material was not determined.
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observed for deaths or overt signs of toxicity 0.5, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days, Individual bodyweights were recorded prior to application of the test material on Day 0 and on Days 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

All animals were subjected to gross necropsy.
Statistics:
Using the mortality data obtained, an estimate of the acute dermal median lethal dose (LD50) of the test material was made.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects
Sex:
male/female
Dose descriptor:
LD0
Effect level:
>= 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects
Mortality:
No mortality occurred.
Clinical signs:
No signs of systemic toxicity occurred.
No signs of dermal irritation occurred.
Body weight:
One female animal showed a slight loss in bodyweight during the second week of the study. All other animals showed expected gains in bodyweight during the study.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
No other findings were reported.
Interpretation of results:
GHS criteria not met
Remarks:
Criteria used for interpretation of results: EU-GHS
Conclusions:
The study was performed according to the OECD TG 402 without deviations and therefore considered to be of the highest quality (reliability Klimisch 1).The validity criteria of the test system was fulfilled. The test material did not induce any signs of acute dermal toxicity. The test material was considered to be not toxic via the dermal exposure route under the conditions of the test.
Executive summary:

The acute dermal toxicity of the test material was investigated in rats. The test was conducted according to OECD TG 402 and EU Method B. 3. 2000 mg/kg bw of the test substance was applied semiocclusive to the shaved skin of rats. After 24 h the animals were unwrapped and observations were made for a period of 14 days. No mortalities, signs of systemic toxicity, signs of dermal irritation, treatment-related body weight changes or pathological abnormalities were reported. The acute dermal median lethal dose (LD50) of the test material, in the Sprague-Dawley CD strain rat was found to be greater than 2000 mg/kg bodyweight.

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion