Esterification product of castor oil and tetrahydromethyl-1,3-isobenzofuranedione

Endpoint summary

Description of key information

REACH_LD50 > 2000 mg/kg | rat (female) | OECD 423 |  #key study#

REACH_LD50 > 2000 mg/kg | rat (male/female) | similar to OECD 402 |  #key study#

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:

May - June 2008

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

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:

- Husbandry
Animals were housed in a controlled environment, in which optimal conditions were considered to be approximately 15 air changes per hour, a temperature of 21.0 +/- 3.0°C (actual range: 19.3 - 21.3°C), a relative humidity of 30-70% (actual range: 31 - 80%) and 12 hours artificial ftuorescent light and 12 hours darkness per day.
Cleaning procedures in the room might have caused the temporary ftuctuations above the optimal maximum level of 70% for relative humidity. Based on laboratory historical data, these
fluctuations were considered not to have affected the study integrity.
- Accommodation
Group housing of 3 animals per cage in labeled Macrolon cages (MIV type; height 18 cm,) containing sterilized sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and
paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham MiIIltd), Surrey, United Kingdom).
Acclimatization peried was at least 5 days belere start 01 treatment under laboratory conditions.
- Diet
Free access to pelleted rodent diet (SM R/M-Z lrom SSNIFF® Spezialdiaten GmbH, Soest, Germany).
- Water
Free access to tap water.

Results of analysis for each batch of diet (nutrients and contaminants), sawdust, paper and water were assessed and did not reveal any findings that were considered to have affected the study integrity. All certificales and results of analysis are retained in the NOTOX archives.

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Details on oral exposure:

The formulations were prepared within 4 hours prior to dosing. Homogeneity was accomplished to a visually acceptable level. Adjustment was made for specific gravity of the vehicle and the density of the test substance. The test substance could technically not be dosed undiluted as delivered by the sponsor. In order to obtain homogeneity, the test substance formulations were heated in a water bath with a maximum temperature of 65 °C for a maximum of 25 minutes.

- Method: Oral gavage, using plastie feeding tubes
- Fasting: Food was withheld overnight (for a maximum of 20 hours) prior to dosing until 3-4 hours after administration of the test substance.
- Frequency: Single dosage, on Day 1
- Dose level (volume): 2000 mg/kg (10 mL/kg) body weight

Doses:

2000 mg/kg body weight

No. of animals per sex per dose:

3 per step

Control animals:

no

Details on study design:

The toxicity of the test substance 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 lor determination of the time interval between the dose groups.

Statistics:

No statistical analysis was performed. The method used is not intended to allow the calculation of a precise LD50 value.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

act. ingr.

Mortality:

No mortality occurred.

Clinical signs:

No clinical signs were observed in the first group of three females. The second group showed hunched posture on Days 1 and 2 and uncoordinated movements on Day 1. There is no indication in the raw data that could explain the difference in clinical signs observed between both groups.

Body weight:

The mean body weight gain shown by the animals over the study period was considered to be normal.

Gross pathology:

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

Interpretation of results:

GHS criteria not met

Conclusions:

The oral LD50 value of the substance in Wistar rats was established to exceed 2000 mg/kg body weight.
According to the OECD 423 test guideline the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.
Based on these results the substance does not have to be classified and has no obligatory labeling requirement for oral toxicity according to the Globally Harmonized System of Classification and Labeling of Chemicals (GHS) of the United Nations (2007) and EC criteria for classification and labeling requirements for dangerous substances and preparations (Council Directive 67/548/EEC).

Executive summary:

The study was carried out based on the guidelines described in: OECD No.423 (2001) "Acute Oral Toxicity, Acute Toxic Class Method" EC, Council Directive 67/548/EEC, Annex V, B.1 tris (2004) "Acute Toxic Class Method" EPA, OPPTS 870.1100 (2002), "Acute Oral Toxicity" JMAFF guidelines (2000) including the most recent partial revisions.

The substance was administered by oral gavage to two subsequent groups of three female Wistar rats at 2000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15). No mortality occurred. No clinical signs were observed in the first group of three females. The second group showed hunched posture on Days 1 and 2 and uncoordinated movements on Day 1. There is no indication in the raw data that could explain the difference in clinical signs observed between both groups. The mean body weight gain shown by the animals over the study period was considered to be normal. No abnormalities were found at macroscopic post mortem examination of the animals.

The oral LD50 value of the Substance in Wistar rats was established to exceed 2000 mg/kg body weight.

According to the OECD 423 test guideline the LD50 cut-off value was considered to exceed 5000 mg/kg body weight. Based on these results the substance does not have to be classified and has no obligatory labeling requirement for oral toxicity according to the Globally Harmonized System of Classification and Labeling of Chemicals (GHS) of the United Nations (2007) and EC criteria for classification and labeling requirements for dangerous substances and preparations (Council Directive 67/548/EEC).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study technically not feasible

Justification for data waiving:

the study does not need to be conducted because exposure of humans via inhalation is not 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

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Remarks:

The test was performed for registration purpose outside EU

Type of information:

experimental study

Adequacy of study:

key study

Study period:

January-February 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

According to the Guidelines for the testing of chemicals “Acute Dermal Toxicity” (402) published by the Ministry of Environmental Protection of People’s Republic of China in the year of 2013.

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Specific details on test material used for the study:

Test item code in the facility: 2017CO 16

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Animals
- Number of animals: 10 rats (5 females, 5 males). The females were nulliparous and non-pregnant.
- Age: 10-11 weeks at the commencement of each animal’s dosing.
- Range of body weights (dosing): Males: 295~300 g, Females: 247~272 g
- Physical check-up and acclimation: Physical check-up and acclimation were made to all animals imported. Healthy young adult animals were acclimatized to the laboratory conditions and housed two per cage for at least 5 days prior to the test. Clinical observations were performed daily during acclimation.
All animals were marked by the special animal markers on the hair and numbers written on cage cards. At the end of the necropsy, animals were also marked on the tails.

Husbandry
Animals were housed in Room A120-1 of the facility. Animals were raised in suspended, stainless steel cages on cage racks. There were 10 cages per layer, and 4 layers per rack.
Animals were housed individually during the test.
Temperature and humidity were controlled automatically and daily recorded. The values in the animal room were 20-25°C for temperature, and 40%-70% for humidity. A controlled light cycle was 12 hour light, 12 hour dark.
Food and water: Animals were provided sterilized diet with complete nutrition supplied by Beijing Keaoxieli Feed Co., LTD. (Product License No: SCXK (jing) 2014-0010, Batch No.17113221). Analysis reports of diet were supplied by the supplier. All the nutrition components and contaminants were within the permitted limits described in the national standard (GB 14924.3-2010 and GB 14924.2-2001). Water was purified by HT-R01000 purity system. Water analysis was conducted routinely analyzed (annually), and all parameters were within the permitted limits described in the national drinking water standard (8B5749-2006). The diet and water were considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study. Diet and water were available to the animals ad libitum during test.

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

Approximately 24 hours before the test, fur was removed from the dorsal area of the trunk of the test animals by shaving. Care was taken to avoid abrading the skin, which could alter its permeability. Clear area was about 40 cm2.
Dosing frequency: Dosing once for each animal.
The test item was applied evenly to the treatment area. The gauze (6×6.5 cm2) on no-irritating adhesive tape was placed over the treatment area and wrapped with a piece of medical self-adhesive bandage to hold the test substance in contact with the skin. The dressing was semi-occlusive. Shortly after dosing the dressing was examined to ensure that the animals cannot ingest the test item.
At the end of the exposure period for approximated 24 hours, residual test item was removed with cotton ball soaked with water.

Duration of exposure:

24 hours

Doses:

2000 mg/kg/bw

No. of animals per sex per dose:

5 male and 5 female

Control animals:

no

Details on study design:

A limit test at dose level of 2000mg/kg body weight was carried out in one group of 10 animals (5 males and 5 females). Clinical observations were made during the first 30 minutes, at 1, 2 and 4 hours after dosing and then once each day for up to 14 days. Individual weights of animals were determined. At the end of the test, a gross necropsy was performed on all animals under test.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths or moribund during the test.

Clinical signs:

There were no abnormal findings in all animals after dosing from the first day until the end of the test.

Body weight:

The body weight gain of the animals was within the range commonly recorded for this strain and age.

Gross pathology:

No abnormalities were found at necropsy.

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the results, the acute dermal LD50 in rats for Cyclohexene-1,2-dicarboxylic acid, methyl-, castor-oil alkyl esters was as follows: Male/female rats: > 2000 mg/kg bw.
According to the GHS’s classification criteria of acute dermal toxicity, no classification is warranted.

Executive summary:

The study was performed to assess the acute dermal toxicity of Cyclohexene-1,2-dicarboxylic acid, methyl-, castor-oil alkyl esters in Sprague Dawley rats. The method was designed to meet the Guidelines for the testing of chemicals “Acute Dermal Toxicity” (402) published by the Ministry of Environmental Protection of People’s Republic of China in the year of 2013.

A limit test at dose level of 2000mg/kg body weight was carried out in one group of 10 animals (5 males and 5 females).Clinical observations were made during the first 30 minutes, and at 1, 2 and 4 hours after dosing and then once each day for up to 14 days. Individual weights of animals were determined. At the end of the test, a gross necropsy was performed on all animalsunder test.

Results

- Mortality: There were no deaths or moribund during the test.

- Clinical observations: There were no abnormal findings in all animals after dosing from the first day until the end of the test.

- Body Weights: The body weight gain of the animals was within the range commonly recorded for this strain and age. 

- Necropsy: No abnormalities were found at necropsy.

Conclusion

Based on the results, the acute dermal LD50 in rats for Cyclohexene-1,2-dicarboxylic acid, methyl-, castor-oil alkyl esters was as follows: Male/female rats: >2000 mg/kg/bw. According to the GHS’s classification criteria of acute dermal toxicity, no classifiaction is warranted.

 

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Justification for classification or non-classification

Based on the acute oral LD₅₀in rats (>2000 mg/kg) and the dermal LD₅₀in rats (>2000 mg/kg) the substance does not need to be classified for acute toxicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.