Registration Dossier

Administrative data

Description of key information

A read-across approach was conducted on source substance isobutyl 4-hydroxybenzoate:

Acute toxicity after single oral application was tested in female rats, which received 2000 mg/kg bw (two groups of three females). All animals survived until the end of the study.The most relevant clinical findings in the animals treated with the test item at a dose of 2000 mg/kg bw were reduced spontaneous activity, prone position, moving the bedding, ataxia, hunched posture, piloerection and half eyelid closure. All symptoms recovered within 1 day post-dose.

Throughout the 14-day observation period, the weight gain of the animals was within the normal range of variation for this strain.

At necropsy, no macroscopic findings were observed in any animal of any step.

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
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)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 10 -11 weeks
- Weight at study initiation:
Step 1: 173 -192 g
Step 2: 176 - 194 g
- Fasting period before study: 16 -19 h
- Housing: in groups in IVC cages, type III H, polysulphone cages on Altromin sae fibre bedding
- Diet (e.g. ad libitum): Altromin 1324 maintenance diet fro rats and mice, ad libitum
- Water (e.g. ad libitum): Tap water, ad libitum
- Acclimation period:
Step 1: 19 days
Step 2: 22 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 °C
- Humidity (%): 55 +/- 10%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES:
From: 1. March To: 6. April 2018
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle:
Step 1: 2.079 g/10 mL
Step 2: 2.032 g/ 10 mL
- Amount of vehicle (if gavage): 10 mL/kg bw
- Justification for choice of vehicle: due to solubility and non-toxic characteristics
- Lot/batch no. (if required): MCC0462

Doses:
2000 mg/kg bw
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
clincal examination: at least once during the first 4 h post-dose, several times on th day of dosing, thereafter once daily
Weight assessment: days 1 (prio to administration), 8 and 15
- Necropsy of survivors performed: yes
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
no mortaliy observed
Clinical signs:
reduced spontaneous activity, prone position, moving the bedding, ataxia, hunched posture, piloerection and half eyelid closure. All symptoms recovered within 1 day post-dose.
Body weight:
weight gain was within the normal range
Gross pathology:
no macroscopic findings reported
Interpretation of results:
GHS criteria not met
Conclusions:
The median lethal dose of Isobutyl 4-hydroxybenzoate after a single oral administration to female rats, observed over a period of 14 days is:
LD50 (rat): > 2000 mg/kg bw
According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg bw.
Executive summary:

Two groups, each of three female WISTAR Crl: WI(Han) rats, were treated with the test item by oral gavage administration at a dosage of 2000 mg/kg body weight. The test item was suspended with the vehicle corn oil at a concentration of 0.2 g/mL and administered at a dose volume of 10 mL/kg.

All animals used in the study after their entrance at BSL were allowed to acclimatise to the laboratory conditions for at least 5 days. The animals were observed on delivery, on inclusion in the study and before administration for mortality/morbidity and other clinical signs. All animals were examined for clinical signs several times on the day of dosing and once daily until the end of the observation period. Their body weights were recorded on day 1 (prior to the administration) and on days 8 and 15.All animals were necropsied and examined macroscopically.

All animals survived until the end of the study showing signs of toxicity.

The most relevant clinical findings in the animals treated with the test item at a dose of 2000 mg/kg bw were reduced spontaneous activity, prone position, moving the bedding, ataxia, hunched posture, piloerection and half eyelid closure. All symptoms recovered within 1 day post-dose.

Throughout the 14-day observation period, the weight gain of the animals was within the normal range of variation for this strain.

At necropsy, no macroscopic findings were observed in any animal of any step.

LD50:                                     > 2000 mg/kg bw

LD50cut-off (rat):                   > 5000mg/kg bw (according to OECD 423 test guideline)

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
reliable with restriction due to read across purposes

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Read-across justification

There is no study on the acute oral toxicity of target substance butyl 4 -hydroxybenzoate available. The assessment of the acute oral toxicity was based on a study conducted with source substance isobutyl 4 -hydroxybenzoate as part of a read across approach, which is in accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.5. For each specific endpoint the source substance structurally closest to the target substance is chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).

Based on the results of the oral toxicity study performed with isobutyl 4 -hydrxybenzoate the LD50value for acute oral was considered to be greater than 2,000 mg/kg bw.

Justification for classification or non-classification

Due to the findings described in the acute oral toxicity toxicity study performed with isobutyl 4 -hydroxybenzoate (LD50oral in rats greater than 2,000 mg/kg bw) and based on the read-across approach the test substance does not have to be classified as acute orally toxic. Therefore, the test item does not have to be classified as acute toxic.