Isooctyl acrylate

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP Study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2010

Report date:

2010

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

1. Temporary deviations from the maximum humidity occurred in teh animal room. Lab data do not indicate an effect of the dviations. 2. In the second wek of treatment, test substance used for formulations was inadverrently stored at room temperature in

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

MTDID 7819

IUPAC Name:

MTDID 7819

Details on test material:

- Name of test material (as cited in study report: mtdid 7819
- Molecular formula (if other than submission substance): CnH(2n+1)-O-CO=CH2
- Physical state: Clear colorless liquid
- Analytical purity: 99% with a C8 acrylate content of 92%
- Lot/batch no.: 4/2009
- Expiration date of the lot/batch: 01 April 2011
- Radiochemical purity (if radiolabelling):

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: 6 weeks
- Housing:Animals were group housed in macrolon cages with setrilized houseing as bedding and paper as cage enrichment.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: At least 5 days prior to the start of treatment
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.2-22.0 C
- Humidity (%): 41-78%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light 12 hours light/ 12 hours dark with temporary fluctuations (1 hour max) dues to pupullary rflex tesets and/or ophthalmoscopic exam.):
IN-LIFE DATES: From: 21 August 2009 To: 18 September 2009

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Justification for use and choice of vehicle (if other than water): Test article solubility in vehicle
- Concentration in vehicle: 10-333 mg/ml resulting in doses of 0 (control), 30,300 and 1000

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Dosing samples were prepared within 6 hours of dosing. Samplese were analyzed on a single occasion during the in-life phase for homgeneity and accuracy of prparation (all concentrations). Accuracy was acceptable is the mean measured concentrations were 90-110% of the target concentration.

Duration of treatment / exposure:

28 Days

Frequency of treatment:

Daily

Doses / concentrations

Remarks:

Doses / Concentrations:

Basis:
actual ingested

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Bsed on results of a 5 day range finding study. Animals in main study were doses at 0 (control), 30, 300 and 1000 mg/kg/day
- Rationale for animal assignment (if not random): random

Positive control:

corn oil

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice Daily
- Cage side observations checked in table [No.?] were included. Yes
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once Daily
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- 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
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 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 / No / No data
- Time schedule for examinations:
OPHTHALMOSCOPIC EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Collected from all surving animals prior to post mortem exam
- Anaesthetic used for blood collection: Yes iso-flurane
- Animals fasted: Yes
- How many animals: All surviving
- Parameters checked in table [No.1] were examined. Yes
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Same as haematology
- Animals fasted: Yes
- How many animals: all surviving
- Parameters checked in table [No.2] were examined.
URINALYSIS: No
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: During week 4 of treatment
- Dose groups that were examined: all animals
- Battery of functions tested: grip strength: other: hearing ability, pupillary reflex, static righting reflex,
OTHER:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes see Table 3 All tissue samples in groups 1 and 4 (control and hight dose) were examined by the pathologist. In addition, the thyroid, kidneys, stomach and liver in groups 2 and 3 males and females (stomach and liver only for females) were also examined by the pathologist.
HISTOPATHOLOGY: Yes see Table 4

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
BODY WEIGHT AND WEIGHT GAIN
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
FOOD EFFICIENCY
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
OPHTHALMOSCOPIC EXAMINATION
HAEMATOLOGY
CLINICAL CHEMISTRY:
Higher bilirubin in males at 1000 mg/kg
Higher cholesterol levels in females at 300 1000 mg/kg
Lower cholesterol in males at 1000 mg/kg
Higher postssium levels in males and females at 1000 mg/kg
Higher inforganix phosphate in males at 1000 mg/kg
URINALYSIS
NEUROBEHAVIOUR
ORGAN WEIGHTS
Higher liver weight and liver to body weight ration in males at 300(not statistically significant for liver weight) and males and females at 1000 mg/kg
Higher thyroid and thyroid to body weight ratio in males and females at 1000 mg/kg
Higher kidney weight and kidney to body weight ratio in one male (no 17) at 1000 mg/kg
GROSS PATHOLOGY
Kidneys in one male at 300 mg/kg and two males at 1000 mg/kg had pale discoloration of the kidneys. One male at 1000 mg/kg (no 17) had grey-white/dark red, part firm/part soft nodules on teh left kidney which was enlarged in size.
HISTOPATHOLOGY: NON-NEOPLASTIC
HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Stomach: Hyperplasia of teh squamous epithelium of the forestomach was recorded in 2/5 females at 300 mg/kg(minimal) and in 2/5 males (minimal) and 3/5 females (minmal-slight) at 1000 mg/kg.
Liver: Hypertrophy of the hepatoxytes of teh centrilobular are(minimal-slight) was recorded in 4/5 males at 1000 mg/kg
Kidneys: Cortical hyaline droplets in teh kidneys were recorded in 4/5 males at 300 mg/kg (minimal-slight) and 5/5 males at 1000 mg/kg (slight-moderate). This was the microscopic correlate to teh pale kiscoloration recroded at necropsy. The occurrence of cortical hyaline droplets was accompanied by an increased incidence and severity of corticomedullary tubular basophilia in males at 1000 mg/kg (4/5 animals minimal-slight)
Thyroid: A slightly increased incidence and severity of hypertrophy /hyperplasia of teh follicular epithelium as recorded in males at 1000 mg/kg (4/5 animals, moderate-slight)
HISTORICAL CONTROL DATA (if applicable)

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

behaviour (functional findings)

body weight and weight gain

clinical biochemistry

clinical signs

gross pathology

haematology

histopathology: non-neoplastic

mortality

organ weights and organ / body weight ratios

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

NOAEL of 30 mg/kg established in the study but the effects are rodent specific and of no relevance to human risk assessment. Based on the results of the study, the human-relevant No Observed Adverse Effect Level is 1000 mg/kg-day.

Executive summary:

The repeated-dose oral toxicity potential of MTDID 7819 (clear colorless liquid, lot 4/2009) was evaluated in male and female Wistar rats. METHODS: This study was performed in compliance with OECD GLP (1997). The study design was based on the following guidelines: EC No. 440/2008 B.7 (2008), OECD 407 (2008) and OPPTS 870.3050 EPA 712-C-00-366 (2000). MTDID 7819 was prepared in corn oil (vehicle) within 6 hours prior to dosing. Rats (5/sex/group) received 0 (vehicle), 30, 300 or 1000 mg/kg-day MTDID 7819 via oral gavage for 28 days. Parameters evaluated: clinical observations (daily), functional observations (week 4), body weight (weekly), food consumption (weekly), clinical pathology (termination), macroscopic examination (termination), organ weights and microscopic examination of specific tissues. RESULTS: No toxicologically-relevant changes were noted for clinical observations, functional observations, body weights, food consumption or hematology. Adaptive liver changes included increased liver weights (300 mg/kg-day males and 1000 mg/kg-day males and females); centrilobular hepatocellular hypertrophy (1000 mg/kg-day males); total bilirubin, cholesterol, potassium, and/or inorganic phosphate concentrations (1000 mg/kg-day males and females); and cholesterol changes in 300 mg/kg-day females. Although these changes were adaptive, the report authors considered the magnitude of the liver weight increase in the 1000 mg/kg-day-treated animals (i.e. >20%) to be adverse. Adaptive thyroid changes included increased thyroid weights (1000 mg/kg-day males and females); and increased incidence and severity of thyroid follicular epithelium hypertrophy/hyperplasia (1000 mg/kg-day males). Hyperplasia was noted in the forestomach of 300 mg/kg-day-treated females and males and females at 1000 mg/kg-day. The hyperplasia was considered an adaptive response to local irritation in the forestomach and is a common adaptive phenomenon in rat studies. Hyaline droplet formation was noted in the kidneys of the 300 and 1000 mg/kg-day-treated male rats. This result is attributed to the male rat-specific alpha-2u-globulin protein and is not considered relevant for female rats or higher species, including humans. Nephroblastoma correlated with nodules and higher kidney weight in one 1000 mg/kg-day-treated male rat which was considered spontaneous and not related to the test article. CONCLUSION: Based on the results of this study, the authors proposed a rat NOAEL of 30 mg/kg-day. The findings at 300 mg/kg-day were considered rat-specific and of no relevance to humans. Based on the results of the study, the human-relevant No Observed Adverse Effect Level is 1000 mg/kg-day.