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Diss Factsheets

Administrative data

Description of key information

Acute Toxicity via Oral Route

Key value determined in a GLP accredited laboratory study using the Acute Toxic Class Method, performed in accordance with OECD Guideline 423, EU Method B.1 tris and US EPA Procedure OPPTS 870.1100.

The oral LD50 value of Lowinox® 22IB46 in Wistar rats was established to be within the range of 300-2000 mg/kg body weight. 

According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 500 mg/kg body weight.

Acute Toxicity via Dermal Route

Key value determined in a GLP accredited laboratory study using the standard acute method in rats, performed in accordance with OECD Guideline 402, EU Method B.3 and US EPA Procedure OPPTS 870.1200.

The dermal LD50 value of Lowinox® 22IB46 in Wistar rats was established to exceed 2000 mg/kg body weight.

 

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:
05 April 2016 to 28 April 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods
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
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes
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: 9 Females (nulliparous and non-pregnant). Each dose group consisted of 3 animals.
Age and body weight: Young adult animals (approx. 8-9 weeks old) were selected. Body weight variation did not exceed +/- 20% of the sex mean.
Identification: Earmark and tail mark
Health inspection: At least prior to dosing. It was ensured that the animals were healthy and without any abnormality that might have affected the study integrity.
Animal Husbandry Conditions: Environmental controls for the animal room were 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 was between 07:00 and 19:00 hrs daily. Any variations to these conditions were maintained in the raw data and had no effect on the outcome of the study.
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 be considered to interfere with the study.
Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
Test Item Preparation
Vehicle: Propylene glycol (Merck, Darmstadt, Germany) (specific gravity 1.036)
Rationale: The vehicle was selected based on trial preparations performed at WIL Research Europe and on test item data supplied by the Sponsor.
Preparation: The preparations (w/w) were kept at room and were dosed within 4 hours after adding the vehicle to the test item. Homogeneity was assessed by visual inspection of the solutions and the formulations were stirred during dosing, which ensures homogeneity sufficient for these kinds of studies. Adjustment was made for specific gravity of the vehicle. No correction was made for purity of the test item. The concentration of the test item in vehicle was varied to allow constant dosage volume in terms of mL/kg body weight.The toxicity of the test item 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.
Doses:
2000 mg/kg (10 mL/kg) body weight.300 mg/kg (10 mL/kg) body weight.
No. of animals per sex per dose:
The toxicity of the test item was assessed by stepwise treatment of groups of 3 females.
Control animals:
not specified
Details on study design:
The toxicity of the test item 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.
Treatment 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 item. Water was available ad libitum.
Frequency: Single dosage on Day 1.
Dose level: (volume) 2000 mg/kg (10 mL/kg) body weight. 300 mg/kg (10 mL/kg) body weight.

Observations
Mortality/Viability: Twice daily. Animals showing pain, distress or discomfort, which was considered not transient in nature or was likely to become more severe, were sacrificed for humane reasons based on OECD guidance document on humane endpoints (ENV/JM/MONO/ 2000/7).
Body weights: Days 1 (pre-administration), 8 and 15 and at death (if found dead or sacrificed after Day 1).
Clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15. The signs were graded according to fixed scales and the time of onset, degree and duration were recorded: 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: The moribund animals and animals surviving to the end of the observation period were sacrificed by oxygen/carbon dioxide procedure. All animals assigned to the study were subjected to necropsy and descriptions of all internal macroscopic abnormalities recorded.

Evaluation: The oral LD50 value of the test item 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 items and mixtures (including all amendments).
Statistics:
No statistical analysis was performed.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
500 mg/kg bw
Based on:
test mat.
Mortality:
At 2000 mg/kg, all animals were sacrificed for humane reasons on Day 2. At 300 mg/kg, no mortality occurred.
Clinical signs:
At 2000 mg/kg, lethargy, tremor, hunched posture, uncoordinated movements, slow breathing, shallow respiration, piloerection, watery discharge from eyes, lean appearance and/or hypersensitivity to touch were noted for the animals on Days 1 and/or 2.
At 300 mg/kg, lethargy, tremor, hunched posture, uncoordinated movements, rales and/or piloerection were noted for the animals between Days 1 and 5.
Body weight:
At 2000 mg/kg, the animals showed body weight loss during the first two days of the study.
At 300 mg/kg, the body weight gain 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.
Other findings:
No other findings were specified.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The oral LD50 value of Lowinox® 22IB46 in Wistar rats was established to be within the range of 300-2000 mg/kg body weight.
Executive summary:

The objective of this study was to assess the toxicity of the test item when administered in a single dose to female rats at one or more defined dosages. Furthermore, the results of the study allowed the test item to be ranked according to most classification systems, currently in use.

This study should provide a rational basis for risk assessment in man. The oral route was selected as it is a possible route of human exposure during manufacture, handling or use of the test item. The study complied with the following guidelines:

- 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 Items (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.

 

Female rats administered with 2000 mg/kg were all sacrificed for humane reasons on Day 2. Clinical signs included:lethargy, tremor, hunched posture, uncoordinated movements, slow breathing, shallow respiration, piloerection, watery discharge from eyes, lean appearance and/or hypersensitivity to touch were noted for the animals on Days 1 and/or 2. At 2000 mg/kg, the animals showed body weight loss during the first two days of the study.

No mortality occurred in any of the female rats that were received a single dose of 300 mg/kg. There were however clinical signs including lethargy, tremor, hunched posture, uncoordinated movements, rales and/or piloerection which was noted for the animals between Days 1 and 5. The body weight of the rats administered 300mg/kg were comparable to animals of the same age and strain.

No abnormalities were found at macroscopic post mortem examination of the animals. 

The oral LD50 value of Lowinox® 22IB46 in Wistar rats was established to be within the range of 300-2000 mg/kg body weight. According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 500 mg/kg body weight. Based on these results:

-according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2015) (including all amendments), Lowinox® 22IB46 should be classified as: harmful if swallowed (Category 4) for acute toxicity by the oral route;

-according to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments), Lowinox® should be classified as Category 4 and should be labelled as H302: Harmful if swallowed.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
500 mg/kg bw
Quality of whole database:
K1 - Study performed in GLP accredited laboratory to recognised OECD, EU & EPA standards.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

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:
4 April 2016 to 15 April 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
(1987)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: JMAFF Guidelines (2000), including the most recent revisions.
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
Chemical name (IUPAC), synonym or trade name2,2’-(2-methylpropylidene)bis[4,6-xylenol]CAS Number33145-10-7pH (1% in water, indicative range)8.0 – 7.2 (determined by WIL Research Europe)
Species:
rat
Strain:
Wistar
Remarks:
Crl:WI (Han) (outbred, SPF-Quality).
Sex:
male/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: 5 males and 5 females (females were nulliparous and non-pregnant).
Age and body weight: Young adult animals (approx. 10 weeks old) were selected. Body weight variation did not exceed +/- 20% of the sex mean.
Identification: Tail mark with indelible ink.
Health inspection: At least prior to dosing. It was ensured that the animals were healthy and that the skin to be treated was intact and free from any abnormality.
Animal Husbandry
Conditions: Environmental controls for the animal room were 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 was between 07:00 and 19:00 hrs daily. Any variations to these conditions were maintained in the raw data and had no effect on the outcome of the study.
Accommodation: Individually housed in labeled Makrolon cages (MIII 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. During the acclimatization period the animals were group housed in Makroloncages (MIV type, height 18 cm).
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.
Type of coverage:
occlusive
Vehicle:
propylene glycol
Details on dermal exposure:
Method: Dermal application.
The test item (preparation) was stirred on a magnetic stirrer during application.
Clipping: One day before exposure (Day -1) an area of approximately 5x7 cm on the back of the animal was clipped with a clipper (Moser Genio plus, standard blade (0.7 mm).
Application: The preparation was applied on an area of approx. 10% of the total body surface, i.e. approx. 25 cm² for males and 18 cm² for females. The preparation was held in contact with the skin with a dressing, consisting of a surgical gauze patch (Surgy 1D)*, 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 mg/kg (10 mL/kg) body weight.
Application period: 24 hours, after which dressings were removed and the skin cleaned of residual test item by gentle washing using tap water.
Duration of exposure:
24 hours
Doses:
2000 mg/kg (10 mL/kg) body weight.
No. of animals per sex per dose:
5 females and 5 males (10 animals total) administered a single dose of 2000 mg/kg (10 mL/kg) body weight on day 1.
Control animals:
not specified
Details on study design:
Test Item Preparation
Vehicle: Propylene glycol (Merck, Darmstadt, Germany) (specific gravity 1.036) Rationale: The vehicle was selected based on trial preparation performed at WIL Research Europe and on test item data supplied by the Sponsor. There was no information available regarding the solubility or stability in vehicle.
Preparation: The preparation (w/w) were kept at room temperature and dosed within 4 hours after adding the vehicle to the test item. Homogeneity was assessed by visual inspection of the solutions and the formulations were stirred during dosing, which ensures homogeneity sufficient for these kinds of studies. Adjustment was made for specific gravity of the vehicle. No correction was made for purity of the test item.

Observations
Mortality/Viability: Twice daily.
Body weights: Days 1 (pre-administration), 8 and 15 and at death (if found dead or sacrificed after Day 1).
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: The moribund animal and those surviving to the end of the observation period were sacrificed by an oxygen/carbon dioxide (40% / 60%) inhalation procedure. All animals assigned to the study were subjected to necropsy and descriptions of all internal macroscopic abnormalities recorded.

Evaluation: A dermal LD50 value was derived. The results were evaluated according to: -Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2015) (including all amendments);-Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of items and mixtures (including all amendments)..
Statistics:
Statistical analysis was not conducted.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
One female animal was sacrificed for humane reasons on Day 3. No further mortality occurred.
Clinical signs:
Lethargy, tremors, flat- and hunched posture, lateral recumbency, rales, uncoordinated movements, shallow respiration, piloerection, chromodacryorrhoea (snout), hypersensitivity to touch and/or ptosis were noted for the animals of both sexes.
The male animals had recovered from the symptoms by Day 4 and the females by Day 6. Additionally, one female animal showed lean appearance between Days 5 and 10.
General erythema, erythema maculate and/or scabs were seen in the skin-area of the animals during the observation period. These local effects were considered not to have affected the conclusion of the study.
Body weight:
The changes noted in body weight gain in males were within the range expected for rats used in this type of study and were therefore considered not indicative of toxicity.
The female animals showed body weight loss or reduced body weight gain between Days 1 and 8. At Day 15 the body weight of the animals were within the expected rage again.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.
Other findings:
No other findings were specified.

Mortality Data

Test day

1

1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

Hours after treatment

0

2

4

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Males 2000 MG/KG

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Females 2000 MG/KG

-

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

 

Clinical signs

Test day

 

1

1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

Hours after treatment

Max grade

0

2

4

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Males 2000 MG/KG

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANIMAL 1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Behaviour

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Lethargy

(3)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

Spasms

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tremor (General)

(3)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

Posture

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Flat posture

(1)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

Hunched posture

(1)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Breathing

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Shallow Respiration

(3)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

Skin/fur

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

General erythema (Treated skin)

(4)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Piloerection

(1)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

Secretion/excretion

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chromodacryorrhoea (Snout)

(3)

-

-

1

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Various

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Hypersensitivity to touch

(1)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

Ptosis

(3)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

ANIMAL 2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Spams

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tremor (General)

(3)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

Posture

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Hunched posture

(1)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Gait/motility

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoordinated movements

(3)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Breathing

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Shallow respiration

(3)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

Skin/fur

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Erythema maculate (treated skin)

(4)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Piloerection

(1)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Secrretion/excretion

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chromodacryorrhoea (snout)

(3)

-

1

1

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Various

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Hypersensitivity to touch

(1)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

Ptosis

(3)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

ANIMAL 3

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Spams

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tremor (General)

(3)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

Posture

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Hunched posture

(1)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Gait/motility

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoordinated movements

(3)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Breathing

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Shallow respiration

(3)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

Skin/fur

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

General Erythema (Treated skin)

(4)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Piloerection

(1)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Scabs (shoulder right)

(3)

-

-

-

-

-

-

-

1

1

1

1

1

1

1

1

1

1

Secretion/excretion

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chromodacryorrhoea (Snout)

(3)

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Various

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Hypersensitivity to touch

(1)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

Ptosis

(3)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

ANIMAL 4

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Spasms

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tremor (General)

(3)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

Posture

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Hunched posture

(1)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Gait/motility

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoordinated movements

(3)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Breathing

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Shallow respiration

(3)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

Skin/fur

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

General erythema (Treated skin)

(4)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Piloerection

(1)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Secretion/excretion

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chromodacryorrhoea (Snout)

(3)

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Various

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Hypersensitivity to touch

(1)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

ANIMAL 5

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Behaviour

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Lethargy

(3)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Spasms

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tremor (General)

(3)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

Posture

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Hunched posture

(1)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Gait/motility

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoordinated movements

(3)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Breathing

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Quick breathing

(1)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

Skin/fur

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

General erythema (Treated skin)

(4)

-

-

-

1

1

1

1

-

-

-

-

-

-

-

-

-

-

Piloerection

(1)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Secretion/excretion

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chromodacryorrhoea (snout)

(3)

-

1

1

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Various

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Hypersensitivity to touch

(1)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

Ptosis

(3)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

FEMALES 2000 MG/KG

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANIMAL 6

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Behaviour

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Lethargy

(3)

-

-

-

1

2

2

1

-

-

-

-

-

-

-

-

-

-

Spasms

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tremor (General)

(3)

-

-

-

1

1

1

1

-

-

-

-

-

-

-

-

-

-

Posture

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Flat posture

(1)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Gait/motility

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoordinated movements

(3)

-

-

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

Breathing

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Shallow respiration

(3)

-

-

-

1

1

1

-

-

-

-

-

-

-

-

-

-

-

Skin/fur

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

General erythema (Treated skin)

(4)

-

-

-

1

1

1

-

-

-

-

-

-

-

-

-

-

-

Piloerection

(1)

-

-

1

1

1

1

1

-

-

-

-

-

-

-

-

-

-

Secretion/excretion

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chromodacryorrhoea (snout)

(3)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Various

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Lean

(1)

-

-

-

-

-

-

1

1

1

1

1

1

-

-

-

-

-

Hypersensitivity to touch

(1)

-

-

-

1

1

1

-

-

-

-

-

-

-

-

-

-

-

Ptosis

(3)

-

-

1

1

2

-

-

-

-

-

-

-

-

-

-

-

-

Hypothermia

(1)

-

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

ANIMAL 7

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Behaviour

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Lethargy

(3)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Spasms

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tremor (General)

(3)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Posture

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Flat posture

(1)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

Gait/motility

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoordinated movements

(3)

-

-

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

Breathing

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Shallow respiration

(3)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

Skin/fur

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

General erythema (Treated skin)

(4)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Piloerection

(1)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Various

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Hypersensitivity to touch

(1)

-

-

-

1

1

1

-

-

-

-

-

-

-

-

-

-

-

Ptosis

(3)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

ANIMAL 8

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Behaviour

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Lethargy

(3)

-

-

-

2

3

 

 

 

 

 

 

 

 

 

 

 

 

Spasms

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tremor (General)

(3)

-

-

-

1

1

 

 

 

 

 

 

 

 

 

 

 

 

Posture

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Flat posture

(1)

-

-

-

1

-

 

 

 

 

 

 

 

 

 

 

 

 

Lateral recumbency

(1)

-

-

-

-

1

 

 

 

 

 

 

 

 

 

 

 

 

Hunched posture

(1)

-

-

-

1

-

 

 

 

 

 

 

 

 

 

 

 

 

Breathing

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Rales

(3)

-

-

-

1

2

 

 

 

 

 

 

 

 

 

 

 

 

Shallow respiration

(3)

-

-

-

1

2

 

 

 

 

 

 

 

 

 

 

 

 

Skin/fur

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

General erythema (treated skin)

(4)

-

-

-

1

2

 

 

 

 

 

 

 

 

 

 

 

 

Piloerection

(1)

-

-

-

1

1

 

 

 

 

 

 

 

 

 

 

 

 

Secretion/excretion

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chromodacryorrhoea (snout)

(3)

-

1

1

1

1

 

 

 

 

 

 

 

 

 

 

 

 

Various

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Hypersensitivity to touch

(1)

-

-

-

1

1

 

 

 

 

 

 

 

 

 

 

 

 

Ptosis

(3)

-

-

-

1

2

 

 

 

 

 

 

 

 

 

 

 

 

Hypothermia

(1)

-

-

-

-

1

 

 

 

 

 

 

 

 

 

 

 

 

ANIMAL 9

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Behaviour

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Lethargy

(3)

-

-

-

2

1

-

-

-

-

-

-

-

-

-

-

-

-

Spasms

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tremor (general)

(3)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Posture

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Flat posture

(1)

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

-

Hunched posture

(1)

-

-

-

1

1

1

1

-

-

-

-

-

-

-

-

-

-

Gait/motility

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoordinated movements

(3)

-

-

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

Breathing

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Shallow respiration

(3)

-

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Skin/fur

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

General erythema (Treated skin)

(4)

-

-

-

1

1

1

-

-

-

-

-

-

-

-

-

-

-

Piloerection

(1)

-

-

1

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Secretion/excretion

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chromodacryorrhoea (Snout)

(3)

-

1

1

1

1

-

-

-

-

-

-

-

-

-

-

-

-

Various

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Hypersensitivity to touch

(1)

-

-

-

1

1

1

-

-

-

-

-

-

-

-

-

-

-

Ptosis

(3)

-

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

ANIMAL 10

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Behaviour

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Lethargy

(3)

-

-

1

1

 

 

 

 

 

 

 

 

 

 

 

 

 

Spasms

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tremor (general)

(3)

-

-

-

1

 

 

 

 

 

 

 

 

 

 

 

 

 

Posture

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Hunched posture

(1)

-

-

1

1

1

 

 

 

 

 

 

 

 

 

 

 

 

Gait/motility

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoordinated movements

(3)

-

-

-

1

1

1

 

 

 

 

 

 

 

 

 

 

 

Breathing

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Shallow respiration

(3)

-

-

-

1

1

 

 

 

 

 

 

 

 

 

 

 

 

Skin/fur

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

General erythema (Treated skin)

(4)

-

-

-

1

1

1

 

 

 

 

 

 

 

 

 

 

 

Piloerection

(1)

-

-

1

1

1

 

 

 

 

 

 

 

 

 

 

 

 

Secretion/excretion

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chromodacryorrhoea (Snout)

(3)

-

1

2

2

1

 

 

 

 

 

 

 

 

 

 

 

 

Various

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Hypersensitivity to touch

(1)

-

-

-

1

 

 

 

 

 

 

 

 

 

 

 

 

 

Ptosis

(3)

-

-

1

1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

‘-‘ = Sign not observed


 

Body weights (gram)

SEX/DOSE LEVEL

ANIMAL

DAY 1

DAY 8

DAY 15

MALES 2000 MG/KG

 

 

 

 

 

1

282

292

317

 

2

286

303

340

 

3

276

285

313

 

4

276

287

316

 

5

273

292

316

 

MEAN

279

292

320

 

ST. DEV.

5

7

11

 

N

5

5

5

FEMALES 2000 MG/KG

 

 

 

 

 

6

186

180

194

 

7

189

188

193

 

8

185*

---

--

 

9

188

191

211

 

10

191

193

200

 

MEAN

188

188

200

 

ST. DEV.

2

6

8

 

N

5

4

4

* Animal sacrificed for humane reasons on Day 3. Body weight: 161 gram.

 

MACROSCOPIC FINDINGS

ANIMAL

ORGAN

FINDING

DAY OF DEATH

MALES 2000 MG/KG

 

 

 

1

 

No findings noted

Scheduled necropsy Day 15 after treatment

2

 

No findings noted

Scheduled necropsy Day 15 after treatment

3

 

No findings noted

Scheduled necropsy Day 15 after treatment

4

 

No findings noted

Scheduled necropsy Day 15 after treatment

5

 

No findings noted

Scheduled necropsy Day 15 after treatment

FEMALES 2000 MG/KG

 

 

 

6

 

No findings noted

Scheduled necropsy Day 15 after treatment

7

 

No findings noted

Scheduled necropsy Day 15 after treatment

8

 

No findings noted

Killed in extremis Day 3 after treatment.

9

 

No findings noted

Scheduled necropsy Day 15 after treatment

10

 

No findings noted

Scheduled necropsy Day 15 after treatment

Interpretation of results:
other: EU classification criteria not met
Conclusions:
The dermal LD50 value of Lowinox® 22IB46 in Wistar rats was established to exceed 2000 mg/kg body weight.
Executive summary:

The objective of the study was to assess the systemic toxicity of the test item when administered to rats as a single dermal application. The results of the study allows for the test item to be ranked according to most classification systems. This study should provide a rational basis for risk assessment in man. The dermal route was selected, as it is a possible route of human exposure during manufacture, handling or use of the test item. The study complied to the following guidelines:

-Organization for Economic Co-operation and Development (OECD), OECD Guidelinesfor Testing of Chemicals, Section 4, Health Effects, No. 402, "Acute Dermal Toxicity",Paris, 1987.

 

-Commission Regulation (EC) No 440/2008 Part B: Methods for the Determination ofToxicity and other Health Effects; B.3: "Acute Toxicity (Dermal)". Official Journal of theEuropean Union No. L142, May 2008, including most recent amendments.

 

-United States Environmental Protection Agency (EPA). Health Effects Test Guidelines,OPPTS 870.1200, Acute Dermal Toxicity. Office of Prevention, Pesticides and ToxicItems (7101), EPA 712-C-98-192, August 1998.

 

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

 

One female animal was sacrificed for humane reasons on Day 3. No further mortality occurred.

Lethargy, tremors, flat- and hunched posture, lateral recumbency, rales, uncoordinated movements, shallow respiration, piloerection, chromodacryorrhoea (snout), hypersensitivity to touch and/or ptosis were noted for the animals of both sexes. The male animals had recovered from the symptoms by Day 4 and the females by Day 6. Additionally, one female animal showed lean appearance between Days 5 and 10. General erythema, erythema maculate and/or scabs were seen in the skin-area of the animals during the observation period. These local effects were considered not to have affected the conclusion of the study.

 

The changes noted in body weight gain in males were within the range expected for rats used in this type of study and were therefore considered not indicative of toxicity. The female animals showed body weight loss or reduced body weight gain between Days 1 and 8. At Day 15 the body weight of the animals were within the expected rage again.

No abnormalities were found at macroscopic post mortem examination of the animals.

The dermal LD50 value of Lowinox® 22IB46 in Wistar rats was established to exceed 2000 mg/kg body weight. Based on these results the following can be concluded:

 

-According to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2015) (including all amendments), Lowinox® 22IB46 should be classified as: may be harmful in contact with skin (Category 5) for acute toxicity by the dermal route;

-According to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures, Lowinox® 22IB46 does not have to be classified and has no obligatory labelling requirement for dermal toxicity.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
K1 - Study performed in GLP accredited laboratory to recognised OECD, EU & EPA standards.

Additional information

Justification for classification or non-classification

Acute Toxicity via Oral Route

According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 500 mg/kg body weight. Based on these results:

-according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2015) (including all amendments), Lowinox®22IB46 should be classified as: harmful if swallowed (Category 4) for acute toxicity by the oral route;

-according to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments), Lowinox® should be classified as Category 4 and should be labelled as H302: Harmful if swallowed.

Acute Toxicity via Dermal Route

The dermal LD50 value of Lowinox® 22IB46 in Wistar rats was established to exceed 2000 mg/kg body weight.

Based on these results:

-According to the Globally Harmonized System of Classification and Labelling ofChemicals (GHS) of the United Nations (2015) (including all amendments), Lowinox®22IB46 should be classified as: may be harmful in contact with skin (Category 5) for acute toxicity by the dermal route;

-According to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures, Lowinox® 22IB46 does not have to be classified and has no obligatory labelling requirement for dermal toxicity.