Registration Dossier

Administrative data

Description of key information

Acute oral toxicity: LD50 value: 300 < LD50 ≤ 2000 mg/ kg bw

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:
2017-11-30 to 2017-12-28
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)
Version / remarks:
2001-12-17
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
signed 2015-06-05
Test type:
acute toxic class method
Limit test:
no
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: dry, < 30°C
Species:
rat
Strain:
Wistar
Remarks:
Crl:WI (Han)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 8-10 weeks

- Weight at study initiation: 158 - 177 g
- Fasting period before study: Prior to the administration food was withheld from the test animals for 16 to 19 hours (access to water was permitted).
- Housing: animals were kept in groups of three animals in IVC cages, type III H, polysulphone cages; bedding material: Altromin saw fibre bedding
- Diet (ad libitum, for exception refer to "fasting period before study" above): Altromin 1324 maintenance diet for rats and mice (Altromin Spezialfutter GmbH & Co. KG, Im Seelenkamp 20, 32791 Lage, Germany)
- Water (ad libitum): tap water, sulphur acidified to a pH value of approximately 2.8 (drinking water, municipal residue control, microbiological controls at regular intervals)
- Acclimation period: at least 5 days under laboratory conditions

ENVIRONMENTAL CONDITIONS
- Temperature: 22 °C ± 3 °C
- Humidity: 55 ± 10%
- Air changes: 10x/hour
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Source: Sigma-Aldrich Chemie GmbH, Riedstrasse 2, 89555 Steinheim, Germany
- Justification for choice of vehicle: this vehicle was chosen due to its non-toxic characteristics.
- Lot no.: MKCC0462
- Expiry date: 2018-01-31
Doses:
Starting dose (step 1): 300 mg/kg bw
Step 2: 2000 mg/kg bw
Step 3: 300 mg/kg bw
No. of animals per sex per dose:
9 female rats (3 animals/step)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: A clinical examination was made several times on the day of dosing (at least once during the first 30 minutes and with special attention given during the first 4 hours post-dose). Thereafter, the animals were observed for clinical signs once daily until the end of the observation period. The animals were weighed on day 1 (prior to the administration) and on days 8 and 15.
- Necropsy of survivors performed: yes, all animals were subjected to gross necropsy and examined macroscopically for gross pathological changes. The animals which had to be sacrificed for ethical reasons or died spontaneously during the observation period were necropsied as soon as they were killed.
Statistics:
No statistical analysis could be performed (the method used is not intended to allow a calculation of a precise LD50 value).
Preliminary study:
not applicable
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Based on:
test mat.
Mortality:
300 mg /kg bw: no animals died
2000 mg/kg bw: all animals died prematurely
Clinical signs:
300 mg/kg bw
after 0-30 min: slightly reduced spontaneous activity, prone position, slight ataxia, moderate piloerection, moving the bedding
after 30-60 min: prone position, moderate ataxia, moderate piloerection, moving the bedding, hunched posture, moderately reduced spontaneous activity, sunken flanks, slow movements
after 60-120 min: slightly reduced spontaneous activity, hunched posture, moderate piloerection, half eyelid-closure, slow movements, prone position, moderate ataxia, moderately reduced spontaneous activity, severely reduced spontaneous activity, sunken flanks
after 120-180 min: slight ataxia, moderate piloerection, moderately reduced spontaneous activity, half eyelid-closure, slightly reduced spontaneous activity, hunched posture
after 240 min-2d: slight ataxia, slight piloerection, slightly reduced spontaneous activity

2000 mg/kg bw
after 0-30 min: slightly reduced spontaneous activity, slight piloerection, hunched posture, prone position
after 30-60 min: severely reduced spontaneous activity, prone position, moderate ataxia, moderate piloerection, hunched posture, sunken flanks, half eyelid-closure
after 60-120 min: moderately reduced spontaneous activity, moderate ataxia, moderate piloerection, hunched posture
after 120-240 min: slightly reduced spontaneous activity, hunched posture, moderate piloerection, slight diarrhoea, slight ataxia
after 120-180 min: moderately reduced spontaneous activity, slight, moderate piloerection, hunched posture, moderate diarrhoea, moving the bedding, slight ataxia, prone position
after 240 min-2d: slightly reduced spontaneous activity, moderate ataxia, slight/moderate piloerection, slight/moderate diarrhoea, hunched posture, slow movements

Body weight:
All animals gained the expected body weight.
Gross pathology:
No specific gross pathological changes were recorded for any animal.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
LD50 value: 300 < LD50 ≤ 2000 mg/ kg bw
According to the Regulation (EC) NO 1272/2008 and subsequent adaptations, the substance is classified as acute toxic via the oral route (Cat.4; H302).
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Quality of whole database:
one key study available

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Barium 4-dodecylphenolate

 

One acute toxicity study in rats (key study) via the oral route with barium 4-dodecylphenolate is available, resulting in a LD50 in the range of 300 to 2000 mg/kg bw.

Barium 4-dodecylphenolate was administered in three steps at doses of 300 and 2000 mg/kg bw to female Wistar Crl:WI (Han) rats. All animals were observed daily for a period of 14 days. Individual body weights were recorded before administration and thereafter in weekly intervals. At the end of the study all animals were sacrificed, dissected and inspected macroscopically. At 300 mg/kg bw no mortality and changes in body weight or pathological changes were observed. At 2000 mg/kg bw all animals died prematurely. The LD50 results in a classification of the barium 4-dodecylphenolate for acute toxicity via the oral route Category 4 and is in line with the legally binding harmonised classification of barium salts ((EC) No 1272/2008; Index No. 056-002-00-7). The read-across to data of the barium chloride dossier (assessment entity barium cations), which was itself classified as acute toxic via the oral route Category 3 thus represents an overly conservative approach for read-across.

The acute oral toxicity study was conducted as a bridging study for systemic effects displaying the applicability to read-across to the assessment entities barium cations and m-toluic acid anions (for a detailed description of the read-across approach please refer to the separate report attached to section 13).

Therefore, in the assessment of the systemic toxicity of barium 4-dodecylphenolate, a read-across to data for dodecylphenolate and soluble barium substances is applied since only the ions of barium and dodecylphenolate are systemically available and determine the toxicological potential of barium 4-dodecylphenolate.

 

Signs of acute dermal toxicity are not expected for barium 4-dodecylphenolate, since the two moieties barium and dodecylphenolate have not shown signs of acute dermal toxicity in experimental testing (LD50 > 2000mg/kg). Under the assumption that the moieties of barium 4-dodecylphenolate show their toxicological profile individually upon dissolution, the acute dermal toxicity of barium 4-dodecylphenolate can be calculated using the equation given in regulation (EC) 1272/2008, Annex I, Section 3.1.3.6.1.

A study for acute toxicity via inhalation was not conducted with barium m-toluate, since it is produced and placed on the market in a form in which no inhalation hazard is anticipated, thus acute toxic effects are not likely to occur during manufacture and handling of that substance. For further information on the toxicity of the assessment entities, please refer to the relevant sections in the IUCLID and CSR.

 

Barium

Acute oral toxicity

There are three reliable studies for acute oral toxicity testing (Müller, 1983, Borzelleca, 1988 and Tardiff, 1980). All studies were used in a weight of evidence approach. The study performed by Müller, 1983 results in an LD50of 645 mg BaCl2/kg bw (male/female), the study performed by Borzelleca in 1988 leads to an LD50>100 and <300 mg/kg bw. whereas the study conducted by Tardiff 1980 results in an LD50of 300 mg/kg bw.

 

Acute dermal toxicity

According to the SIAR 27 prepared for barium dichloride, an acute dermal toxicity study on barium dichloride was conducted according to OECD 402, in compliance with GLP. In this study, the dermal LD50 was greater than 2000 mg BaCl2/kg bw in rats. Nevertheless, primary data could not be made available by the registrant.

Dodecylphenolate

 

Acute oral toxicity

In accordance with the SIDS Initial Assessment Profile (SIAP), “intestinal absorption and distribution in the body is anticipated, due to the high lipophilicity and the effects in rat repeated-dose toxicity studies. Tetrapropenyl phenol is not acutely toxic, with LD50s of around 2000 and 15000 mg/kg by the oral and dermal routes of exposure, respectively. The acute oral toxicity of four different commercial samples of tetrapropenyl phenol has been evaluated in tests in rats conducted in accordance with OECD Test Guideline 401 or testing guidelines that were applicable at the time the studies were conducted. The key study for tetrapropenyl phenol for acute mammalian oral toxicity (Randall and Robinson 1990) indicates that the LD50 is 2100 mg/kg in rats. Groups of five animals that included animals of each sex were treated with dose levels of 1260, 1580, 2000, 2510, 3160, and 3980 mg/kg. The incidence of death in each group was 1/5, 2/5, 2/5, 4/5, 4/5 and 4/5. Signs of toxicity included weight loss on Days 2-6 in animals that survived, increasing weakness, diarrhea, and collapse. The summary report did not indicate at which dose levels signs of toxicity were observed. In a study reported by Mürmann (1984a), a similar acute oral LD50 of 2200 mg/kg in rats was observed. Groups of 10 animals that included animals of each sex were dosed with 1580, 1990 and 2510 mg/kg. The incidence of death in each group was 0/10 at the low dose, 2/10 at the mid dose, and 3/10 at the high dose. Signs of toxicity at all dose levels included ruffled fur, a crouched posture, diarrhea, diuresis, bloodstained nose, deep red eyes, retarded motion, slight to medium sedation and ataxia. Animals in the high dose were observed in the prone position. In two other studies (Cavalli et al. 1968 and Unpublished 1982) conducted at a limit dose of 5000 mg/kg, 100% mortality was observed in both studies. In one study (Cavalli et al. 1968), animals appeared depressed and had soft gelatinous stools prior to death. There was no mortality in animals dosed with 500 mg/kg in this study, and one animal at this dose level showed bloody urine that cleared up by 48 hours after dosing. In the other study (Costello and Gilman 1982), animals had ruffled oily coats and mild to severe diarrhea, which persisted until death.” (SIAP, 2006)   References: SIAP (2006): SIDS Initial Assessment Profile for Phenol, (tetrapropenyl) derivates; Tetrapropenyl phenol and Phenol, dodecyl-, branched; SIAM 22, 18-21 April 2006)

 

Acute dermal toxicity

In accordance with the SIDS Initial Assessment Profile (SIAP), “intestinal absorption and distribution in the body is anticipated, due to the high lipophilicity and the effects in rat repeated-dose toxicity studies. Tetrapropenyl phenol is not acutely toxic, with LD50s of around 2000 and 15000 mg/kg by the oral and dermal routes of exposure, respectively. The acute dermal toxicity of two different commercial samples of tetrapropenyl phenol has been evaluated in tests in rabbits conducted in two non-guideline studies. Both studies are considered to be reliable with restrictions (Klimisch Code = 2). The key study for tetrapropenyl phenol for acute mammalian dermal toxicity (Cavalli et al. 1968) indicates that the LD50 is approximately 15,000 mg/kg. At this dose level, 3/6 animals died within 7 days of treatment, and death was preceded by depression, anorexia, and terminal clonic convulsions. None of the six animals treated with 5,000 mg/kg died, and there were no signs of systemic toxicity reported in this group. In a more recent study (Randall and Robinson 1990), dermal treatment of pairs of rabbits with dose levels of 1260, 2000, 3160, 5010, and 7940 mg/kg yielded an estimated LD50 greater than 2000 mg/kg. Deaths occurred at dose levels above 3160 mg/kg, and signs of toxicity included increasing weakness and collapse prior to death. Minor weight loss was observed in animals that survived from Days 2-4.” (SIAP, 2006)  References: SIAP (2006): SIDS Initial Assessment Profile for Phenol, (tetrapropenyl) derivates; Tetrapropenyl phenol and Phenol, dodecyl-, branched; SIAM 22, 18-21 April 2006)

Justification for classification or non-classification

The LD50 for barium 4-dodecylphenolate is 300 < LD50 ≤ 2000 mg/ kg bw, hence the substance is classified as acute toxic via the oral route Category 4 according to the Regulation (EC) 1272/2008 and subsequent adaptations (Cat.4; H302).

 

The calculated dermal LD50 for barium 4-dodecylphenolate is > 2000mg/kg, hence the substance is not to be classified according to regulation (EC) 1272/2008 for acute dermal toxicity.