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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

A reproductive/developmental screening study and teratogenicity study were conducted on a close structural analog (IOA, source substance) and were read-across to the target substance (MTDID 44428). The results of the study were:

Repro/Dev Screening Study: NOAEL = 20% dermal exposure

Developmental Toxicity: NOAEL = 1000 mg/kg/day

Link to relevant study records

Reference

Reference 1

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study by an experienced laboratory

Qualifier:

according to guideline

Guideline:

other: Internal laboratory guideline according to GLP

Deviations:

no

GLP compliance:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River
Laboratories, Inc. (Kingston, New York)

- Age at study initiation: 12 weeks

- Weight at study initiation:

The males for Groups 1 through 4 weighed between 211.9 and 249.2 g; the femalesweighed between 140.3 and 165.6g. The animals for Groups 5 and 6 weighed between 246.5 and 271.6 g (males)and 144.6 and 169.6 g (females).


- Fasting period before study: NA

- Housing: Individual housing

- Use of restrainers for preventing ingestion (if dermal): Yes

- Diet (e.g. ad libitum): ad libitum

- Water (e.g. ad libitum): ad libitum

- Acclimation period:
Forty-six males and 44 females were received and acclimated for Phase I; 23 males and 23 females were received and acclimated for Phase II. One female from Phase I died before the randomization. The remaining animals in Phase I and animals in Phase II were examined on April 16, 1992, and May 28, l992, respectively, by the
laboratory animal veterinarian and found to be suitable for study consideration. Animals were randomized for assignment to groups (10/sex/group). Animals not selected for the study were sacrificed and discarded.

ENVIRONMENTAL CONDITIONS

- Temperature (°C): 19 to 25 deg C.

- Humidity (%): 50 +/- 20%

- Air changes (per hr): NA

- Photoperiod (hrs dark / hrs light): 12hours/12hours

Route of administration:

dermal

Vehicle:

acetone

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

VEHICLE
Acetone, test compound is not soluble or stable in water

- Concentration in vehicle: 0%, 1%, 7.5%, 5%, 15% 25%
- Amount of vehicle (if gavage): 100ul/day for 2 weeks prior to mating.

- Lot/batch no. (if required): NA
- Purity: high grade solvent


TEST SITE
- Area of exposure: dorsal intrascapular area of trunk

- % coverage: test material was applied uniformly

REMOVAL OF TEST SUBSTANCE

- Washing (if done):

- Time after start of exposure:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100 ul
- Concentration (if solution): 0 to 25%
- Constant volume or concentration used: constant volume

VEHICLE
- Justification for use and choice of vehicle (if other than water): Solubility and stability in acetone better than water

- Amount(s) applied (volume or weight with unit): 100 ul
- Concentration (if solution): 0 to 25% of test compound
- Lot/batch no. (if required): NA
- Purity:
USE OF RESTRAINERS FOR PREVENTING INGESTION: Yes

Details on mating procedure:

Each female was paired with one male from the same group for a maximum of 14 days. Vaginal examinations were done daily during cohabitation and the presence of sperm in the vaginal smear or a copulatory plug was considered evidence of positive mating. The day when such evidence was found was considered Day 0 of gestation, and the female was then housed individually. When mating was confirmed, the males and females were separated. Females that showed no evidence of mating were placed in nesting boxes after completion of the mating period.

- M/F ratio per cage:
- Length of cohabitation: UP to 14 days
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: Vaianal smear or copulatory plug

- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: [no / yes (explain)]
- After successful mating each pregnant female was caged (how):
- Any other deviations from standard protocol:

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Homogenecity was determined for the 1%, 15%, and 25% concentrations. Samples taken from the top, middle, and bottom of the dose preparations were analyzed for test material content.

Duration of treatment / exposure:

Each animal was exposed to the test materialor carrier for at least 6 hours/day at a dose volume of 100 uL/day for 2 weeks before mating and throughout mating until sacrifice.

Frequency of treatment:

Daily

Details on study schedule:

Each female was paired with one male from the same group for a maximum of 14 days. Vaginal examinations were done daily during cohabitation, and the presence of sperm in the vaginal smear or a copulatory plug was considered evidence of positive mating. The day when such evidence was found was considered Day 0 of gestation, and the female was then housed individually. When mating was confirmed, the males and females were separated. Females that showed no evidence of mating were placed in nesting boxes after completion of the mating period.

Remarks:

Doses / Concentrations:
0%, 1%, 7.5%, 5%, 15% , 20/25%
Basis:
nominal conc.

No. of animals per sex per dose:

10

Control animals:

yes

Details on study design:

- Dose selection rationale: Toxicity screens

Positive control:

None

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule:Daily
DETAILED CLINICAL OBSERVATIONS: Yes / No / No data

The animals were observed twice daily (a.m. and p.m.) for mortality,moribundity,and signs of poor health or abnormal behavior. Females were observedfor signs of abortion,excessive bleeding, premature delivery,or difficult and prolonged parturition. Each animal was removed from its cage and examined when body weights were recorded.

BODY WEIGHT: Yes
There were no significant differences in body weight changes during pre- and postmating for males or during premating for females. Body weight gains were significantly higher for females at 20%/25% IOA during Day 0 to 20 of gestation and Days 0 to 4 of lactation; however, these differences are not considered to be toxicologically important.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
Individual food consumption data were recorded weekly during the premating phase. Food consumption was measured for mated females for presumed Gestation Days 0-7, 7-14, and 14-20, and for femalesthat deliveredlittersfor Lactation Days 0 through 4.

- Time schedule for examinations:

Hematology and clinical chemistry parameters were evaluatedf or all adult males before scheduled sacrifice. The animals were fasted overnight, then anesthetized with ketamine and blood was collected from the retro-orbital plexus. After the pup necropsies were completed,the parental animals were anesthesized with sodium pentobarbital, weighed, exsanguinated, and necropsied. The necropsy included a macroscopic examination of the external surface of the body; all orifices;the cranial cavity; the external and cut surfacesof the brain and spinal cord; and the cervical, thoracic,and abdominal viscera.:

Oestrous cyclicity (parental animals):

NA

Sperm parameters (parental animals):

NA

Litter observations:

STANDARDISATION OF LITTERS

Birth (Day 0 of Lactation). As soon as possibleafter birth, the sex of each pup was determined,and the litter size (totalnumber of pups born live or found dead) was recorded. Each live pup was examined for external abnormalities and weighed.

- Performed on day 4 postpartum: Yes

Day 4. The sex of each pup was determined,and the litter size {numberof live pups) was recorded. The pups were examined for external abnormalities and weighed individually before sacrifice. Pups were sacrificed using B euthanasia®-D euthanasia solution;examined for cervical,thoracic,or abdominal visceral
abnormalities;then discarded. Abnormal tissues were preserved in
10% phosphate-buffered formalin [exceptf or kidney lesions for pups from three litters.

PARAMETERS EXAMINED

As soon as possible after birth, the sexa of each pup was determined, and the litter size (total number of pups born live or found dead) was recorded. Each live pup was examined for external abnormalities and weighed.


The following parameters were examined in [F1 / F2 / F3] offspring:
[number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, other:]

GROSS EXAMINATION OF DEAD PUPS:
Whenever possible,dead pups were examined macroscopically for cervical,thoracic, and abdominal visceral abnormalities and congenital abnormalities and then discarded.

Whenever possible, dead pups were examined macroscopically for cervical, thoracic, and abdominal visceral abnormalities and congenital abnormalities and then discarded.

Postmortem examinations (parental animals):

SACRIFICE

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at [#?] days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:
GROSS NECROPSY
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]
HISTOPATHOLOGY / ORGAN WEIGTHS
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.

Statistics:

One-way ANOVA was used to analyze continuous data such as body weights, body weight changes, food consumption, clinical chemistry and hematology values {except red blood cell morphology}, litter data, and length of gestation. Reproduction
indices {number inseminated,numberpregnant,female fertility,and gestation index} were analyzed by the Cochran-Armitage test (Thakur, et. al., 1985} for trend and departure and by a Fisher-Irwin exact test (Thakur, et. al., 1985). One-way analysis of covariance [ANCOVA (Winer,1971b)] was used to analyze the pup body weights (male and female), with the number of pups in the litter as the covariate.

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

not specified

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)

There were no significant differences in food consumption during premating for males or during premating or gestation for females. Food consumption was significantly higher for females treated with 20% IOA during lactation (16% higher than those of controls); however, this is not considered to be toxicologically important.
Week I body weights were significantlylower for females at 20%/25% IOA. However, no significant differences were noted at Week 2 and there were no other significant differences in body weights during premating,gestation,or lactation. Therefore,the significant difference at Week 1 was not consideredt o be toxicologically important. There were no significant differences for males pre- or postmating.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS): na

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS): Female Data. There were no test material-related significant differences observed for mating or female fertility indices, mean days to mate, or length of gestation.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)

Male Data. There were no test material-related differences for male fertility based on the percent of pregnant females.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)

No effects reported

There were no test material-related changes for terminal body weights,absolute organ weights, organ-to-body weight percentages or macroscopic or microscopic findings
OTHER FINDINGS (PARENTAL ANIMALS): Significant dermal irritation at 25% concentration

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 20 other: %

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

mortality

dermal irritation

body weight and weight gain

haematology

clinical biochemistry

organ weights and organ / body weight ratios

gross pathology

histopathology: non-neoplastic

histopathology: neoplastic

reproductive function (sperm measures)

reproductive performance

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

VIABILITY (OFFSPRING): Normal
CLINICAL SIGNS (OFFSPRING) Normal
GROSS PATHOLOGY (OFFSPRING): Normal

Key result

Dose descriptor:

NOEL

Generation:

F1

Effect level:

ca. 20 other: %

Sex:

female

Basis for effect level:

other: overall effects including clinical signs; mortality; body weight; food consumption and compound intake; food efficiency; water consumption and compound intake; gross pathology; organ weights; histopathology;

Key result

Reproductive effects observed:

no

Interpretation of results: negative

Criteria used for interpretation of results: expert judgment

Conclusions:

When IOA was administered dermally to rats in concentrations of 1%, 7.5%, 15%, and 20%, the no-observable-effect level for effects on reproductive performance and growth and development of offspring was 20%. There was no overt material toxicity
at the highest dose level tested (20/,IOA). Minimal increases in aspartate aminotransferase and alanine aminotransferase were noted in animals given 20% IOA. Severe dermal irritation precluded dosing at higher dose levels (i.e., 25% IOA).

Executive summary:

The purpose of this study was to provide information concerning toxic effects and effects of 2-PropenoicAcid, Isooctyl Ester (IOA), on reproductive performance following repeated dosing in the rat.

Animals were assigned at random to six groups (10/sex/group) that received 0%,1.0%, 7.5%, 15%, and 20%/25% IOA applied to the intact dorsal dermal surface at a dose volume of 100 uL/day. Due to a notable irritation at 25% after 1 week of dosing, the dose was lowered to 20% for the remainder of the study. Animals in the control groups received acetone at a dose volume equal to that applied to the test animals. Antemortem data (i.e.,clinical observations,dermal observations,body weights, and food consumption, reproduction data, and litter data were recorded. Clinical chemistry and hematology parameters were evaluated for all adult males. All adults were examined macroscopically,and selected tissues were weighed and preserved in 10% phosphate-buffered formalin. Tissues from the control and high-dose groupswere sectioned,stained,and examined microscopically. There were no test material-related clinical observations or adverse effects on body weights, body weight changes, food consumption,or reproductive performance.

Dermal irritation was noted at 20% and included slight to moderate erythema and slight desquamation for males and slight erythema, slight to moderate desquamation, and slight fissuring for females. Minimally higher aspartate aminotransferase and alanine aminotransferase was present at 20% IOA. There were no test material-related changes for terminal body weights, absolute organ weights, organ-to-body weight percentages or macroscopic or microscopic findings. The no-observable-effect level for effects on reproductive performance and growth and development of offspring was 20% IOA. There was no overt material toxicity at the highest dose level tested (20% IOA). Minimal increases in aspartate aminotransferase and alanine aminotransferase were noted in animals given 20% IOA. Severe dermal irritation precluded dosing at higher dose levels (i.e., 25% IOA).

Reference 2

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

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

Adequacy of study:

key 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

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
There were no test material-related changes for terminal body weights, absolute organ weights, organ-to-body weight percentages or macroscopic or microscopic findings.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
There were no significant differences in food consumption during premating for males or during premating or gestation for females. Food consumption was significantly higher for females treated with 20% IOA during lactation (16% higher than those of controls); however, this is not considered to be toxicologically important.
Week I body weights were significantly lower for females at 20%/25% IOA. However, no significant differences were noted at Week 2 and there were no other significant differences in body weights during premating, gestation, or lactation. Therefore, the significant difference at Week 1 was not considered to be toxicologically important. There were no significant differences for males pre- or post-mating.
REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS): Female Data. There were no test material-related significant differences observed for mating or female fertility indices, mean days to mate, or length of gestation.
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
Male Data. There were no test material-related differences for male fertility based on the percent of pregnant females.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
No effects reported
OTHER FINDINGS (PARENTAL ANIMALS):
Significant dermal irritation at 25% concentration

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 20 other: %

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

mortality

dermal irritation

body weight and weight gain

haematology

clinical biochemistry

organ weights and organ / body weight ratios

gross pathology

histopathology: non-neoplastic

histopathology: neoplastic

reproductive function (sperm measures)

reproductive performance

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

VIABILITY (OFFSPRING): No treatement-related changes were noted in viability.
CLINICAL SIGNS (OFFSPRING) No treatement-related changes were noted in clinical signs.
GROSS PATHOLOGY (OFFSPRING): No treatement-related changes were noted upon necropsy.

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

ca. 20 other: %

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Other:

Key result

Reproductive effects observed:

no

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)

Conclusions:

Reading-across the results from the source substance (IOA), the reproductive and developmental No Observed Adverse Effect Level (NOAEL) is 20% MTDID 44428 applied dermally.

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 genetic 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 reproductive/developmental 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.

Effects on developmental toxicity

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: data reliablity constrained by design as a limit test

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

no

Limit test:

yes

Species:

rat

Strain:

Crj: CD(SD)

Details on test animals or test system and environmental conditions:

Sex: Female
TEST ANIMALS
- Source: Charles river Breeding Laboratories, Inc. Kingston, MY
- Age at study initiation:
5 weeks at receipt
9 weeks for acclimitization and to reach sexual maturity

- Diet (e.g. ad libitum): adlibitum,
Purina Rodent Laboratory Chow
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 9 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 deg
- Humidity (%): 57%
- Air changes (per hr): Not available
- Photoperiod (hrs dark / hrs light):12/12

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Test material was diluted to the appropriate dosing volume in corn oil vehicle by magnetic stirring. The prepared dilutions were well shaked before use and the animals were dosed while solutions werer mixed on a magnetic stirrer.

Fresh solutuions were prepared weekly.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 1000 mg/kg
- Concentration (if solution): NA
- Constant volume or concentration used: Yes and Yes


VEHICLE
- Justification for use and choice of vehicle (if other than water):

Corn oil was used as the test compound is not soluble in water

Details on mating procedure:

- Impregnation procedure: [artificial insemination / purchased timed pregnant / cohoused]: co-housed

- If cohoused:
Animals were placed in breeding cages for a maximum of three weeks. Females were rotated after the tenth day of mating.

- M/F ratio per cage: One male per two females

- Length of cohabitation: 3 weeks maximum

-Females were rotated after the 10th day of mating.

- Further matings after two unsuccessful attempts: [no / yes (explain)] N.A.


- Verification of same strain and source of both sexes: [yes / no (explain)] Yes

- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy

Mating was confirmed by presence of a vaginal plug or daily examination of vaginal smears for the presence of sperm.

Duration of treatment / exposure:

The test compound (C-236) was administered to a group of 22 pregnant rats at a single dose level (1000 mg/kg) from days 6 to 15 of gestation. A separate groups served as a vehicle (corn oil) control.

Frequency of treatment:

Daily

Duration of test:

Days 6 to 15 of gestation

Details on study schedule : Age at mating of the mated animals in the study: ca 9] weeks

Remarks:

Doses / Concentrations:
1000 mg/kg
Basis:
analytical conc.

No. of animals per sex per dose:

22

Details on study design:

- Limit test at 1000 mg/kg

Maternal examinations:

All animals were obseved once daily and records made of martalizty, moribundity, and clinical signs

- Cage side observations checked in table were included. Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were taken on days 0, 6, 9, 12, 15,and 20 of gestation.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes Food and water consumption were recorded for Days 6-8, 9-11, 12-14, 15-17 and 18-20 of gestation.

Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes

Food and water consumption were recorded for Days 6-8, 9-11, 12-14, 15-17 and 18-20 of gestation.

- Time schedule for examinations:

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #20
On day 20 of gestations, females were sacrificed by carbon dioxide asphyziation and the fetuses were taken by cesarean section. Following gross examination of each dam, the number of corpora lutea per ovary and the number and placement of implantation sites, early and late resorptions, and live and dead fetuses in each uterine horn were recorded. Fetuses were removed from the placenta, individually identified, examinied externally, weighed and sexed and measured. Gravid and nongravid uterine weights (with ovaries attached) were recorded at cesarean section.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes / No / No data
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes: 2/3rds
- Soft tissue examinations: Yes 2/3rds
- Skeletal examinations: Yes: 2/3rds
- Head examinations: Yes: [all per litter / half per litter / #? per litter ] / No / No data

Statistics:

Box's test, ANOVA Dunnett's T-Test, Chi-square test, Fishers "Exact" test

Historical control data:

Not applicable

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Maternal toxicity was noted.
Symptoms consisted on effect of body weight, clinical signs and gross pathology. Apparent effects on food and water water consumption were also noted.

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 1 000 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Any visceral or sketelat effects noted were correlated with the maternal toxicity.

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reduction in number of live offspring

changes in sex ratio

fetal/pup body weight changes

changes in litter size and weights

external malformations

skeletal malformations

visceral malformations

Developmental effects observed:

yes

Lowest effective dose / conc.:

1 000 mg/kg bw/day

Treatment related:

yes

Relation to maternal toxicity:

developmental effects as a secondary non-specific consequence of maternal toxicity effects

Dose response relationship:

no

Relevant for humans:

no

Conclusions:

The test materials toxicity at 1000 mg/kg/day from days 6 to days 15 of gestation were largely attributed to maternal toxicity. As this was a limit study, no definitive dose-response relationship was established.

Executive summary:

Pregnant female rats were exposed to IOA (C-236) at 1000 mg/kg from days 6 to days 15 gestation in a limit test. Clear signs of maternal toxicity were noted as evidenced by effects of body weight, clinical signs and gross pathology. Apparent effects on food and water consumption were also noted. No definitive indication of teratogenic effects were noted in the fetuses. Any effects observed in the developing fetuses were believed attributable to the maternal toxicity. The developmental No Observed Adverse Effect Level (NOAEL) for IOA was 1000 mg/kg/day.

Reference 2

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

key 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: supporting information

Clinical signs:

effects observed, treatment-related

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Details on results:

Maternal toxicity was noted. Symptoms consisted on effect of body weight, clinical signs and gross pathology. Apparent effects on food and water water consumption were also noted.

An increase incidence of visceral and/or skeletal variants were observed and were correlated with maternal toxicity and considered to be related to those effects on the dam. While these findings are considered to be serious developmental variations, the significance of these findings in relationship to the test compound is unclear since dose relationships have not been established. No definitive incidence of teratogenic effects were noted in this study.

A higher than control number of fetuses exhibited skeletal variants was noted. Most of these findings consisted of lagging ossification. These types of variations were reported to be suggestive of maternal toxicity rather than a specific compound effect on the fetus.

Details on maternal toxic effects:

There was an increased incidence of skeletal variants and delayed ossification in the fetuses. The types of skeletal anomalies noted were believed to be due to maternal toxicity, which consisted of effects on body weight gain, clinical signs, and gross pathology.

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: Other: Overall maternal toxicity.

Key result

Abnormalities:

effects observed, treatment-related

Localisation:

other: Maternal systemic toxicity.

Description (incidence and severity):

There was an increased incidence of skeletal variants and delayed ossification in the fetuses. The types of skeletal anomalies noted were believed to be due to maternal toxicity, which consisted of effects on body weight gain, clinical signs, and gross pathology.

Fetal body weight changes:

no effects observed

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

External malformations:

no effects observed

Skeletal malformations:

effects observed, treatment-related

Description (incidence and severity):

There was an increased incidence of skeletal variants and delayed ossification in the fetuses. The types of skeletal anomalies noted were believed to be due to maternal toxicity.

Visceral malformations:

no effects observed

Details on embryotoxic / teratogenic effects:

Any visceral or skeletal effects noted were correlated with the maternal toxicity.

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reduction in number of live offspring

changes in sex ratio

fetal/pup body weight changes

changes in litter size and weights

external malformations

skeletal malformations

visceral malformations

Key result

Abnormalities:

effects observed, treatment-related

Localisation:

other: There was an increased incidence of skeletal variants and delayed ossification in the fetuses. The types of skeletal anomalies noted were due to maternal toxicity, which consisted of effects on body weight gain, clinical signs, and gross pathology.

Key result

Developmental effects observed:

yes

Lowest effective dose / conc.:

1 000 mg/kg bw/day (nominal)

Treatment related:

yes

Relation to maternal toxicity:

developmental effects as a secondary non-specific consequence of maternal toxicity effects

Dose response relationship:

no

Relevant for humans:

no

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)

Conclusions:

Reading-across the results from the source substance (IOA), MTDID 44428 has a developmental No Observed Adverse Effect Level (NOAEL) of 1000 mg/kg/day.

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 genetic 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 developmental 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 conducted on the structural analog IOA, MTDID 44428 does not meet the classification criteria for reproductive or developmental toxicity.