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Description of key information

LD50 of 2000 mg/kg/bw  was established in the available studies for the related substances of C7-C9-alkyl 3-(3,5-di-tert-butyl-4 hydroxyphenyl)propionate, indicating low acute toxicity potential by both oral and dermal routes of exposure. 

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The study is a GLP compliant and has Klimish score 2 (due to read-across).

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The study is a GLP compliant and has Klimish score 2 (due to read-across).

Additional information

To assess acute toxicity potential of Reaction mass of isomers of: C7 -C9 -alkyl 3 -(3,5 -di-tert-butyl-4hydroxyphenyl) propionate the following acute studies on the related substances were used:

Acute Toxic Class Determination (Oral) conducted with Butyl 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoate (CAS No. 52449 -44 -2)

The objective of the study was the determination of the potential for oral toxicity using the Acute Toxic Class Determination (Cerven, 2005, Report No. 05 -13628.01). This study is designed to comply with the standards set forth in OECD Guidelines for the Testing of Chemicals, Guideline 423 adopted December 17, 2001. Guideline 423 is referred to in OPPTS 870.1 000 (December 2002) as an acceptable method to assess lethality within a dose range. Three healthy male and three healthy female Wistar albino rats were dosed orally with the test material at 2000 mg/kg bw. The rats were observed at 0.5,1, 2, 3 and 4 hours postdose and once daily for 14 days for mortality, toxicity and pharmacological effects. Body weights were recorded immediately pretest, weekly and at termination. All animals were examined for gross pathology. The test article was assigned to a toxic category based on the mortality response noted. All animals survived the 2000 mg/kg oral dose in good health. There were no abnormal physical signs noted during the observation period. Body weight changes were normal in 5/6 animals. One female lost weight during the second week of the observation period. Necropsy results were normal. The test material was considered to be Acute Toxic Category 5, as the LD50 was greater than 2000 mg/kg bw.

Acute Oral Toxicity/LD50 in Rats conducted with Butyl 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoate (CAS No. 52449 -44 -2)

The objective of the study was the determination of the potential for toxicity of the test article when administered orally (Graver, 2000, Report No. MB 00 -8187 -01). This study was designed to comply with the standards set forth in EPA Health Effects Test Guidelines, OPPTS 870.1 100, final guideline, August 1998. Five male and five female Wistar albino rats were dosed orally with the test article at 500 mg/kg of body weight. The rats were observed at 1, 2 and 4 hours postdose and once daily for 14 days for toxicity and pharmacological effects. The animals were observed twice daily for mortality. Body weights were recorded immediately pretest, weekly and at termination of the study. All animals were examined for gross pathology. All animals survived the 500 mg/kg oral dose. Diarrhea was noted in one animal at one hour postdose. At all other observation periods, all animals appeared normal. Body weight changes were normal. Necropsy results were normal in all animals. The oral LD50 of test material was greater than 500 mg/kg.

Acute Oral Toxicity Study in the Rat - Acute Toxic Class Method conducted with Butyl 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoate (CAS No. 52449 -44 -2)

A study was performed to assess the acute oral toxicity of the test material following a single oral administration to Sprague-Dawley CD strain rats (Driscoll, 2000, Report No. 525/202). The method followed that in the OECD guideline 423 and EU Method B1 tris.

Using all available information, as a starting dose 2000 mg/kg bodyweight was selected. A group of three fasted females was treated with the starting dose. Based on the results from this dose level further groups of fasted animals were treated at a dose level of 200 mg/kg bodyweight. Dosing was performed sequentially. The test material was administered orally as a solution in arachis oil BP. The animals were observed at 1/2, 1, 2 and 4 hours after dosing and then once daily for up to fourteen days. Bodyweights were recorded on day 0 (day of dosing) and on days 7 and 14, or at death. At the end of the observation period the surviving animals were killed by cervical dislocation and all animals were subjected to gross necropsy.

Two animals treated with 2000 mg/kg were found dead 2 days after dosing. There were no deaths noted at a dose level of 200 mg/kg. Clinical signs of toxicity noted at a dose level of 2000 mg/kg were ataxia, hunched posture, lethargy, pilo-erection, decreased respiratory rate, laboured respiration, splayed gait and staining around the eyes and mouth. The surviving animal treated with 2000 mg/kg appeared normal three days after dosing. No signs of toxicity were noted at a dose level of 200 mg/kg. The surviving animals showed expected gains in bodyweight over the study period. Abnormalities noted at necropsy of animals that died during the study were haemorrhagic lungs, dark liver, dark kidneys, haemorrhage of the gastric mucosa and haemorrhage of the small intestines. No abnormalities were noted at necropsy of animals that were killed at the end of the study.

The acute oral median lethal dose (LD50) of the test material, in the Sprague-Dawley CD strain rat, was estimated as being in the range of 500 - 1000 mg/kg bodyweight. Mortalities were noted at a dose level of 2000 mg/kg bodyweight. No mortalities were noted in animals treated with 200 mg/kg bodyweight. The test material met criteria for classification as harmful (the symbol "Xn" and risk phrase R 22 "Harmful if swallowed").

Acute Oral Toxicity in the Rat - Fixed Dose Method conducted with (Benzenepropanoic acid, 3,5 -bis(1,1 -dimethylethyl)-4 -hydroxy-,2 -ethylhexylester (CAS No. 144429 -84 -5)

The GLP study was performed to assess the acute oral toxicity of the test material in the Sprague-Dawley CD strain rat (Sanders, 2007, Report No. 0525/0752). The method was designed to meet the requirements of the OECD guideline 420 and EU method B1 bis. Following a sighting test in which no mortality at a dose level of 2000 mg/kg was noted, an additional four fasted female animals were given a single oral dose of undiluted test material at a dose level of 2000 mg/kg. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy. There were no deaths or signs of systemic toxicity. All animals showed expected gains in bodyweight. No abnormalities were noted at necropsy. The acute oral median lethal dose (LD50) of the test material in the female Sprague-Dawley CD strain rat was estimated to be greater than 2000 mg/kg bodyweight (Globally Harmonised Classification System Category - Unclassified).

Acute Dermal Toxicity (Limit Test) in the Rat conducted with Butyl 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoate (CAS No. 52449 -44 -2)

A GLP study was performed to assess the acute dermal toxicity of the test material in the Sprague-Dawley CD strain rat (Driscoll, 2000, Report No.525/203). The method used followed that described in the OECD guideline 402 and EU Method B3. A group of ten animals (five males and five females) was given a single 24-hour, semioccluded dermal application to intact skin at a dose level of 2000 mg/kg bodyweight. The animals were observed for fourteen days after the day of treatment and were then killed for gross pathological examination. There were no deaths. No signs of toxicity or dermal irritation were noted during the study. All animals showed expected gain in body weight during the study. No abnormalities were noted at necropsy. 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. No symbol and risk phrases were required according to the EU Regulations valid at the time point of study conduction.

Acute Dermal Toxicity (Limit Test) in the Rat conducted with (Benzenepropanoic acid, 3,5 -bis(1,1 -dimethylethyl)-4 -hydroxy-,2 -ethylhexylester (CAS No. 144429 -84 -5)

The GLP study was performed to assess the acute dermal toxicity of the test material in the Sprague-Dawley CD strain rat (Sanders, 2007, Report No. 0525/0753). The method was designed to meet the requirements of the OECD guideline 402 and EU Method B3. A group of ten animals (five males and five females) was given a single, 24-hour, semi-occluded dermal application of the undiluted test material to intact skin at a dose level of 2000 mg/kg bodyweight. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy. There were no deaths. There were no signs of systemic toxicity or signs of dermal irritation. All animals showed expected gains in bodyweight over the study period. No abnormalities were noted at necropsy. 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.

Prediction by the TOXTREE modelling tool (v2.1.0.)

The chemical structure of the C9 -representative of the reaction mass of isomers (nonyl-3(3,5 -ditert-butyl-4 -hydroxyphenyl)propanoate)

was assessed by Toxtree (v.2.1.0) modelling tool for its toxicity class according to the rules of Cramer (with extensions). Nonyl 3-(3,5-ditert-butyl-4-hydroxyphenyl)propanoate is of intermediate level of toxicity because it is not a normal constituent of the body and contains an aromatic ring with substituents. The software identified aromatic structures with one aromatic ring and substituents like hydroxyl group and aliphatic tert-butyl branches as chemicals which may act as toxicants. However, the target substance does not contain functional groups associated with enhanced toxicity (no aliphatic secondary amines or salts thereof, cyano, N-nitroso, diazo or quarternary nitrogen etc). The structure is not heterocyclic or terpene or hydrolyzed terpene and does not contain Cl or alkoxy groups.

Conclusion on acute toxicity

In the oral studies conducted with Butyl 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoate (CAS No. 52449 -44 -2) in Wistar rats no animals had died (Cerven, 2005, Report No. 05 -13628.01; Graver, 2000, Report No. MB 00 -8187 -01). There were no signs of systemic toxicity at the 2000 mg/kg bw (Cerven, 2005). The animals appeared normal at all observation time points and showed expected gains in bodyweight. No abnormalities were noted at necropsy. Two other oral studies conducted in Sprague Dawley rats provide contradictory results. In an older study, two animals treated with the same substance (CAS No. 52449-44-2) and at the same dose level (2000 mg/kg bw) were found dead but third animal appeared normal three days after dosing (Driscoll, 2000; Report No. 525/202). However, in the second, more recent study performed with Benzenepropanoic acid, 3,5 -bis(1,1 -dimethylethyl)-4 -hydroxy-,2 -ethylhexylester (CAS No. 144429 -84 -5), another related substance, there were neither mortalities nor clinical signs of toxicity (Sanders, 2007; Report No. 0525/0752). All animals survived the 2000 mg/kg bw oral dose in good health.

After thorough evaluations, the test performed according to the acute toxic class method (Cerven, 2005) was regarded as the key study for the following reasons: (i) it was conducted using a bigger sample size at a higher dose level (3 animals/sex, 2000 mg/kg fixed dose), whereas the other two studies were performed using less animals (Driscoll, 2000: 3 females only at 2000 mg/kg), or a lower dose (Graver, 2000: 500 mg/kg); (ii) subacute oral study (Jones et al., 2000, OECD 407, dose level up to 500 mg/kg/d; please refer to repeated dose toxicity section of this report) and subchronic dietary study (Dunster et al., 2009, OECD 408 and Marr, 2010, OECD 415, dose level up to 2500 ppm) did not cause mortalities in the test animals (rats), suggesting this substance was not acutely toxic. Acute toxicity was evaluated on another analogous substances (CAS No. 144429 -84 -5) by Sanders (2007) and LD50 were greater than 2000 mg/kg, further supported test result of Cerven (2005).

In two acute dermal studies performed with two related substances in Sprague Dawley rats there were no deaths, no signs of toxicity or dermal irritation. No influence of test material administration on bodyweight was noted. Necropsy findings were normal. The LD50 in these studies was calculated to be greater than 2000 mg/kg bw.

Although the C9 -representative of reaction mass of isomers is assigned into the class II according to the rules of Cramer, the weight of experimentally obtained values prevails an assignment by a modelling software. Therefore, based on overall weight of evidence it can be concluded that the substance reaction mass of isomers of: C7 -C9 -alkyl 3 -(3,5 -di-tert-butyl-4hydroxyphenyl) propionate does not possess acute toxicity potential by oral and dermal exposure route in test animals at dose level of 2000 mg/kg bw.

 


Justification for selection of acute toxicity – oral endpoint
The study was conducted using a bigger sample size at a higher dose level. Moreover, subacute and sub-chronic studies did not cause mortalities in the test animals (rats), supporting the study result.

Justification for selection of acute toxicity – dermal endpoint
The most recent study available.

Justification for classification or non-classification

Acute toxicity: oral

In accordance with EU CLP Regulation (EC) No. 1272/2008, classification and labelling of Reaction mass of isomers of: C7 -C9 -alkyl 3 -(3,5 -di-tert-butyl-4hydroxyphenyl) propionate is not required for acute oral toxicity.

Acute toxicity:dermal

In accordance with EU CLP Regulation (EC) No. 1272/2008, the classification and labelling of Reaction mass of isomers of: C7 -C9 -alkyl 3 -(3,5 -di-tert-butyl-4hydroxyphenyl) propionate is not required for acute dermal toxicity.

Acute toxicity:inhalation

Integrated testing strategies for acute toxicity state that determination of the most likely route of exposure needs to take into account not only how the substance is manufactured and handled, including engineering controls and risk management measures, but also the physicochemical properties of the substance. The test material has a very low volatility. The vapour pressure has been determined to be 2.0 x 10E-5 Pa at 25oC, thus there is minimal potential for any inhalation of gases or vapours. ECHA guidance states that for the inhalation route no testing is required if the vapour pressure is very low (< 0.1 Pa at 20oC) (see ECHA Guidance R.7 as well as OECD GD 39). Therefore, inhalative acute toxicity is of no relevance.

 

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