Reactionmass of octan-2-yl prop-2-enoate and octan-3-yl prop-2-enoate and octan-4-yl prop-2-enoate

Endpoint summary

Description of key information

The acute toxicity of MTDID 44428 was evaluated in rats via oral gavage. Acute dermal toxicity data was read-across to MTDID 44428 from structural analog isooctyl acrylate (IOA). The results of the studies were:

The rat acute oral LD50 of MTDID 44428 is greater than 2,000 mg/kg when tested according to OECD 425.

The rabbit acute dermal LD50 of the source substance was greater than 2,000 mg/kg when tested according to EPA OPP 81 -2. Reading this data across to the target substance, the rabbit acute dermal LD50 of MTDID 44428 is greater than 2,000 mg/kg.

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:

2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Version / remarks:

2001

Deviations:

no

Remarks:

No deviations ocurred that impacted the integrity of the study.

GLP compliance:

yes (incl. QA statement)

Test type:

up-and-down procedure

Limit test:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source (i.e. manufacturer or supplier) and lot/batch number of test material: 3M Company, Lot 11
- Purity, including information on contaminants, isomers, etc.: 99.7%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Kept in a room with controls set to maintain 18°C to 24°C

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing (e.g. warming, grinding): None, dosed neat.

FORM AS APPLIED IN THE TEST (if different from that of starting material) : The test article was dosed neat.

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc.
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: 10-11 weeks
- Weight at study initiation: 205-244 g
- Fasting period before study: Overnight
- Housing: Animals were individually housed in stainless steel wire mesh cages equipped with an automatic watering valve.
- Diet (e.g. ad libitum): PMI Nutrition International, LLC Certified Rodent LabDiet 5002 meal was provided ad libitum
- Water (e.g. ad libitum): Municipal tap water after treatment by reverse osmosis and ultraviolet irradiation was freely available to each animal via an automatic watering system
- Acclimation period: At least five days.
- Microbiological status when known : No data.
- Method of randomisation in assigning animals to test and control groups : Randomized via a computerized randomization program.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-26
- Humidity (%): 30-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 18 June 2019 To: 05 July 2019

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

VEHICLE: None, dosed neat.

MAXIMUM DOSE VOLUME APPLIED: 2.308 mL/kg body weight.

DOSAGE PREPARATION (if unusual): Neat

Doses:

2,000 mg/kg body weight.

No. of animals per sex per dose:

5 females were utilized in the study.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The rats were observed at the time of dosing and approximately 15 ± 5 minutes and 1, 2, and 4 hours postdosing on Day 1 and once daily thereafter for 14 days. Body weights were obtained and recorded on Days 1 (initiation), 8, and 15 (termination).
- Necropsy of survivors performed: yes
- Clinical signs including body weight: The rats were observed at the time of dosing and approximately 15 ± 5 minutes and 1, 2, and 4 hours postdosing on Day 1 and once daily thereafter for 14 days. Body weights were obtained and recorded on Days 1 (initiation), 8, and 15 (termination).
- Other examinations performed: clinical signs, body weight,gross necropsy

Statistics:

At the termination of the project, all data will be collected and the acute oral median lethal dose (LD50) will be determined using the EPA-provided statistical program AOT425StatPgm.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

All animals survived to the scheduled necropsy.

Clinical signs:

other: There were no abnormal clinical signs observed during the study.

Gross pathology:

No test article-related observations were noted at necropsy.

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the results of the study, the acute oral LD50 of MTDID 44428 is greater than 2,000 mg/kg body weight.

Executive summary:

The acute oral lethality of MTDID 44428 was evaluated in female Sprague Dawley rats. The study was conducted according to OECD 423 in compliance with OECD GLP. Female rats (5) were dosed neat (no vehicle) via oral gavage with 2,000 mg/kg bw MTDID 44428. The rats were observed at the time of dosing and approximately 15 ± 5 minutes and 1, 2, and 4 hours postdosing on Day 1 and once daily thereafter for 14 days. Body weights were obtained and recorded on Days 1 (initiation), 8, and 15 (termination). All rats survived with no clinical signs of toxicity and no abnormal body weight changes. No treatment-related findings were observed upon gross necropsy. Based on the results of the study, the acute oral LD50 of MTDID 44428 is greater than 2,000 mg/kg body weight.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The target chemical (MTDID 44428, CASRN 87015-11-0) and the source chemical (isooctyl acrylate (IOA) CAS 29590-42-9) are isomers that contain the same functional acrylate moiety attached to primarily C8 alkyl hydrocarbon chains (C7-C9, C8 rich for the source chemical) with variable branching. The source chemical differs from the target chemical in both the degree and position of branching of the alkyl ester group with the source chemical being branched at the terminal end of the alkyl chain while the target chemical is branched near the acrylate functional group. The acrylate group is expected to be metabolized in the same manner in both substances and the remaining alkyl chain will be metabolized and excreted via the same pathway. The source chemical and target chemical have the same molecular weight and very similar log Kow values (Target: 4.7-4.8, Source: 4.5-4.7). Similar ADME profiles are expected between the two substances as the metabolic pathway of acrylate esters has been well characterized. Acrylate and methacrylate functionalities are electrophilic and both may participate in Michael addition reactions. Metabolism is expected to occur through the same pathways, hydrolysis by carboxylesterases into two metabolites, an alcohol and an acrylic acid moiety with minor conjugation to gluthathione. Hydrolysis is similar across the acrylate family and enhances the elimination of the chemical upon exposure (McCarthy & Witz, 1997). Studies with n-butyl acrylate and 2-ethylhexyl acrylate confirm that the acrylic acid metabolite enters aerobic oxidation and in completely metabolized to CO2 with only a minor proportion be conjugated to glutathione and excreted in the urine as a N-acetyl cysteine conjugate (Sanders, JM et. al, 1988; Gut, I, et al. 1988). The previously mentioned studies have also demonstrated that enzymatic hydrolysis kinetic constants for methacrylate and acrylate esters are similar.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Target Chemical
The target molecule, MTDID 44428 (CASRN 87015-11-0), is a multi-constituent substance defined as the reaction mass of octan-2-yl acrylate, octan-3-yl acrylate and octan-4-yl acrylate as represented by the following structures.
(see attached read-across justification document).
Molecular weight of the target chemical is 184.3
Source Chemical:
The source chemical, isooctyl acrylate (IOA) CAS 29590-42-9, is defined as a UVCB and is represented by the following structure (see attached read-across justification document).
The average molecular weight of the source substance is ca. 184.0. The source chemical differs from the target chemical in the degree and position of branching of the alkyl ester group with the source chemical having variable methyl branching along the alkyl chain while the target chemical is branched immediately adjacent to the acrylate functional group.

Purity and Impurities :
MTDID 44428 is a multi-constituent substance and the three acrylate constituents contribute >99% of the content. There are very low levels of residual reactants and reaction side products.
Isooctyl acrylate is a UVCB substance, based on the mixed-isomer nature of the material. As a UVCB substance, all components are considered part of the substance and the concept of impurities has little meaning. Acrylate ester content of IOA is >99 %, with very low levels of residual reactants and reaction side products. These non-acrylate components are substantially similar and do not impact the read-across of test results from IOA.
3. ANALOGUE APPROACH JUSTIFICATION
Analogue Approach Justification

The target chemical and source chemical are closely related alkyl acrylate compounds. They differ slightly in the structure of the alkyl ester portion of the molecule. MTDID 44428 contains a methyl, ethyl or propyl branch at the 1-carbon of the alkyl chain portion of the molecule, which is always C8 in total. IOA may have methyl or ethyl branches at one or more positions along the alkyl ester group. The carbon chain is predominantly C8 in total with lesser contributions of C7 and C9 (C8 on average).
The environmental toxicity of low molecular weight acrylate esters (aquatic mortality and immobilization) is by protein adduct formation via a Michael-type addition mechanism. In the environment, toxicity increases on a molar concentration basis with molecular weight (and concomitantly, hydrophobicity) due to increased ability of the molecule to reach its active site. The excess toxicity is mitigated in high molecular weight acrylate esters with log P > 5.

The mammalian toxicity of IOA and MTDID 44428 is also based on protein adduct formation via a Michael-type addition with the acrylate groups. Both the target and source chemical are weak dermal sensitizers (section 5) indicating that an equivalent mechanism of toxicity is at work for both substances based on identical functional groups and molecular weights and very similar log Kow values and water solubilities.

The number of hydrophobic carbons of IOA relative to MTDID 44428 is predicted to be similar resulting in very similar octanol water partition coefficient values. This was confirmed experimentally and the log Kow for IOA is 4.5-4.7 while the log Kow for MTDID 44428 is 4.7-4.8. Additionally, IOA and MTDID 44428 have very similar water solubility at 12.44 and 14.6 mg/L, respectively. IOA is expected to be metabolized via the same hydrolytic and enzymatic pathways as MTDID 44428, forming acrylic acid and isooctanol.

Similar mammalian metabolic pathways are expected for IOA and MTDID 44428 based on Sanders, et. al and Gut, et al. The source chemical and target chemical have the same molecular weight and very similar log Kow values. Similar ADME profiles are expected between the two substances as the metabolic pathway of acrylate esters has been well characterized. Acrylate and methacrylate functionalities are electrophilic and both may participate in Michael addition reactions. Metabolism is expected to occur through the same pathways, hydrolysis by carboxylesterases into two metabolites, an alcohol and an acrylic acid moiety with minor conjugation to gluthathione. Hydrolysis is similar across the acrylate family and enhances the elimination of the chemical upon exposure (McCarthy & Witz, 1997). Studies with n-butyl acrylate and 2-ethylhexyl acrylate confirm that the acrylic acid metabolite enters aerobic oxidation and in completely metabolized to CO2 with only a minor proportion be conjugated to glutathione and excreted in the urine as a N-acetyl cysteine conjugate (Sanders, JM et. al, 1988; Gut, I, et al. 1988). The previously mentioned studies have also demonstrated that enzymatic hydrolysis kinetic constants for methacrylate and acrylate esters are similar.

As can be seen in the table in section 5, the source and target substances have very similar environmental and mammalian hazard profiles for endpoints where each substance has experimental data. This further supports the hypothesis that the target and source substances are expected to behave similarly in mammalian and environmental systems with the same mechanism of action and that read-across of the data for higher-tier endpoints is appropriate in an effort to reduce unnecessary animal testing.

4. DATA MATRIX
See 'Other Information Including Tables' or attached justification.

Supporting References
Gut, I, Vodička, Cikrt, M, Sapota, A, and Kavan, I (1988) Distribution and elimination of (14C)-2-ehtylheyxyl acrylate radioactivity in rats. Archives of Toxicology 62:346-350.
McCarty, TJ and Witz, G (1997) Structure-activity relationships in the hydrolysis of acrylate and methacrylate esters by carboxylesterase in vitro. Toxicology 116: 153-158.

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: All animals survived the 2.0 g/kg dose level.

Read-Across Data Matrix

	Target substance	Source substance
CHEMICAL NAME	Reaction mass of octan-2-yl acrylate, octan-3-yl acrylate and octan-4-yl acrylate	Isooctyl acrylate
CAS#	44914-03-6	29590-42-9
Molecular formula	C11H20O2	C11H20O2 (on average)
Molecular Weight	184.3	184.3 (on average)
Melting Point	Experimental: <-35 °C	Experimental: < -90 °C at 1004 hPa
Boiling Point	Experimental: 217.6 °C (normalized)	Experimental: 196.8 °C at 1016 hPa
Density	Experimental: 0.8665 at 23 °C	Experimental: 0.885 g/cm3 at 20.0 °C
Vapour Pressure	Experimental: .06 hPa at 18 °C	Experimental: 1 hPa at 20 °C
Partition Coefficient (log KOW)	Experimental: 4.7-4.8	Experimental: 4.5 - 4.7
Water Solubility	Experimental: Individual isomers had solubilites of 4-5 mg/L, total was 14.6 mg/L	Experimental: 12.44 mg/L at 23.1 °C
Stability in Water	Experimental: t1/2at 25 °C, pH 9, 37.7-116 days t1/2at 25 °C, pH 7, 137 days - not determinable t1/2at 25 °C, pH 4, 154 days - not determinable. Hydrolysis product could be detected at pH 9 but not pH 7 and 4. Half-life increased from 2-octyl < 3-octyl < 4-octyl isomers.	Adaptation, readily biodegradable
Aerobic Biodegradation	Experimental: 54.7% after 28 days, biodegradation essentially stopped at day 11 (OECD 301F)   67% after 28 days. No residual material could be detected in test chambers on day 28. In abiotic control, residual test material was 4.8% of initial result (OECD 302C)	Experimental: 93-95% after 28 days (OECD 301D)
Bioconcentration		Not bioaccumulative (Extensive metabolism)
Transport and Distribution	Experimental: Koc 630 (OECD121)	Experimental: Koc 650-3900 (OECD121)
Henry's Law constant	NDA	Experimental: 1780 Pa*m3/mol at 23.1 °C
Acute Toxicity to Fish  (P. promelasunless noted)	NDA	Experimental: 96-hour LC50 0.67 mg/L (OECD 202)
Chronic Toxicity to Fish	NDA	Waived
Acute Toxicity to Aquatic Invertebrates (D. magna)	NDA	Experimental: 48-hour EC50 0.4 mg/L (OECD 202)
Long-Term Toxicity to Aquatic Invertebrates (D. magna)	NDA	Experimental: 28-day NOEC 0.065 mg/L (OECD 202 rev 1984)
Toxicity to Algae and Aquatic Plants (P. subcapitata)	NDA	QSAR result not read across
Toxicity to Microorganisms (activated sludge respiration)	Experimental: 3-hour EC50 >1000 mg/L (OECD 209)	Experimental: 3-hour EC50 >1000 mg/L (OECD 209)
Acute Oral Toxicity	Experimental: Rat oral LD50 > 2,000 mg/kg	Experimental: Rat oral LD50 > 5,000 mg/kg
Acute Dermal Toxicity	Read-across from source: Rabbit dermal LD50 > 2,000 mg/kg	Experimental: Rabbit dermal LD50 > 2,000 mg/kg
Acute Inhalation Toxicity	Read-across from source: NDA	Experimental: NDA
Skin Irritation	Experimental: Irritating (GHS Cat. 2)	Experimental: Not irritating
Eye Irritation	Experimental: Not Irritating	Experimental: Not irritating
Skin Sensitization	Experimental: Weak sensitizer (GHS Category 1B)	Experimental: Weak sensitizer (GHS Category 1B)
Ames Assay	Experimental: Non-mutagenic	Experimental: Non-mutagenic
in vitroChromosome Aberration	Read-across from source: Clastogenic at cytotoxic concentrations	Experimental: Clastogenic at cytotoxic concentrations
in vitroMouse Lymphoma Assay	Read-across from source: Non-mutagenic	Experimental: Non-mutagenic
28 Day Oral Toxicity	Read-across from source: NOAEL = 1,000 mg/kg/day	Experimental: NOAEL = 1,000 mg/kg/day
90 Day Oral Toxicity	Read-across from source: NOAEL = 600 mg/kg/day	Experimental: NOAEL = 600 mg/kg/day
Reproductive/Developmental Screening Study (Dermal)	Read-across from source: NOAEL = 20% Dermal Exposure	Experimental: NOAEL = 20% Dermal Exposure
Prenatal Developmental Study (Oral)	Read-across from source: NOAEL = 1,000 mg/kg/day	Experimental: NOAEL = 1,000 mg/kg/day
Carcinogenicity (Dermal)	Read-Across from source: Not Carcinogenic	Experimental: Not Carcinogenic (5% Dermal Exposure)

Interpretation of results:

GHS criteria not met

Executive summary:

The similarities between the structural, physical & chemical, toxicity, and predicted metabolic properties of the source and target substances presented above support the read-across hypothesis for acute dermal toxicity. The data are adequate and reliable scientific information to support the hypothesis. Therefore, based upon the data and considerations presented in the above sections, it can be concluded that the results of the acute dermal toxicity study with source substance will accurately predict the results for the target substance and are considered as adequate to fulfil the information requirement of Annex VIII, of the REACH Regulation for the target substance.

Justification for classification or non-classification

Based on the results of the studies, MTDID 44428 is not classified for acute oral or dermal toxicity.