Exo-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl methacrylate

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2008

Report date:

2008

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: OECD 421

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Exo-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl methacrylate

EC Number:

231-403-1

EC Name:

Exo-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl methacrylate

Cas Number:

7534-94-3

Molecular formula:

C14H22O2

IUPAC Name:

1,7,7-trimethylbicyclo[2.2.1]hept-2-yl methacrylate

Test material form:

liquid

Specific details on test material used for the study:

Supplier : Rhodia Inc. (Cranbury, NJ USA)
Name : Isobornyl Methacrylate (IBOMA)
CAS Registry No. : 7534-94-3
Molecular weight : 222 g/mol

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories France, L’Arbresle, France
- Age at study initiation: males 8 weeks; females 10 weeks
- Weight at study initiation: mean body weight of 308 g; males (range: 277 to 338 g) and 229 g for the females (range: 214 to 246 g)
- Fasting period before study: no data
- Housing: individually (except during mating) in suspended wire-mesh cages (43.0 x 21.5 x 18.0 cm). A metal tray, containing autoclaved sawdust
SICSA, Alfortville, France) with wood shaving as nesting material, was placed under each cage. Shortly before parturition, the females were moved
to polycarbonate cages (43.0 x 21.5 x 20.0 cm) with wood shavings as nesting material.
- Diet: ad libitum, SSNIFF R/M-H pelleted maintenance diet, batch No. 6704545 (SSNIFF Spezialdiäten GmbH, Soest, Germany)
- Water: tap water, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12h/12h

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

males:
- 15 days before mating, during the mating and post-mating periods until sacrifice (at least 4 weeks in total)
females:
- 15 days before mating,
- during the mating period,
- during pregnancy and lactation, until day 5 post-partum inclusive (or until sacrifice, for unmated females).

Frequency of treatment:

7 days a week

Doses / concentrations

Remarks:

Doses / Concentrations:
0 (vehicle), 25, 100, 500 mg/kg/day
Basis:
nominal in diet

No. of animals per sex per dose:

10 male and 10 female animals per dose group with appropriate randomization.

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale:
The dose-levels were selected following the results of a previously conducted study CIT/Study No. 28200 TSR, in which male and female rats were
dosed with 0, 100, 300 or 1000 mg IBOMA/kg/day for 10 consecutive days. In this study, weight loss and significantly increased liver and kidney
weights were observed at the 1000 mg/kg/day dose. Liver weight was also increased at 300 mg/kg/day. The high dose-level of 500 mg/kg/day was
selected because it was expected to elicit effects on body weight and food consumption during the in-life phase of the study and also to result in
increased liver weights in both males and females. As the dosing period was significantly longer than the 10 days used in the above mentioned study, higher dose-levels than 500 mg/kg/day were considered likely to produce marked effects on body weight as well as increased liver weights, and,
therefore, would endanger the survival of the animals.

Examinations

Observations and examinations performed and frequency:

PARENT ANIMALS:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Each animal was checked at least twice a day for mortality and signs of morbidity

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once a day; Animals were also observed in the afternoon on week days as part of the mortality check and any clinical signs were
recorded

BODY WEIGHT: Yes
- Time schedule for examinations: each male was recorded on the first day of treatment (day 1), then once a week until sacrifice; each female was
recorded on the first day of treatment (day 1), then once a week until mated (or until sacrifice) and on days 0, 7, 14 and 20 post-coitum and
days 1 and 5 post-partum

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

The quantity of food consumed by each animal was recorded once a week, over a 7-day period, from the first day of treatment through gestation
(days 0-7, 7-10, 10-14, 14-17 and 17-20 post-coitum intervals) and lactation (days 1-5 post-partum interval). During the mating period, the food
consumption was noted for neither males nor females.

Food intake per animal and per day was calculated by noting the difference between the food given and that remaining in the food hopper at the end
of the specified interval.

Sacrifice and pathology:

HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

No characteristic or consistent treatment-related clinical signs were noted in any of the test rats; general appearance and behavior were comparable between control and test animals throughout the study.

Mortality:

no mortality observed

Description (incidence):

No characteristic or consistent treatment-related clinical signs were noted in any of the test rats; general appearance and behavior were comparable between control and test animals throughout the study.

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Clinical biochemistry findings:

no effects observed

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

acidophilic globules related to micro-2µ-globulin

Details on results:

Hypersalivation was observed in a dose-related manner in males and females given 100 or 500 mg/kg/day during the pre-mating period (from
week 2) and then in females during gestation and lactation. This clinical sign was not considered to be adverse as it likely represents a reaction
to the dosing procedure and not a direct effect of IBOMA toxicity. There were no clinical signs in the 25 mg/kg/day group.
During the first week of the pre-mating period, males given 500 mg/kg/day gained less weight than controls. Neither food consumption nor body
weight was affected during the gestation period. There were no other treatment-related effects on body weight, weight gain or food consumption
during the study for males or females.
There was no effect of treatment on mating at any dose-level. The male and female fertility indices were unaffected by treatment; all pregnant females had live pups. The duration of gestation was similar in the control and IBOMA treated groups. There was no effect of treatment on the mean
number of liveborn pups or on pup death after birth. There were no gross external pup abnormalities in the control or IBOMA treated groups.

No differences of toxicological importance were noted in the male and female pup body weight gain. No relevant findings were observed in the pups
sacrificed on day 6 post-partum. There was a statistically significant increase in liver weight (both sexes) and kidney (males only) at 500 mg/kg
bw/day.
No treatment-related findings were found in the reproductive organs examined (testes, epididymides and ovaries).
Microscopic findings in the liver included biliary proliferation/hypertrophy associated with fibrosis and macrophages infiltration (500 mg/kgbw/day males and females), disorganization of the hepatic cords (500 mg/kg bw/day males and females), and necrosis in the parenchyma (500 mg/kg bw/day males).
In the 100 mg/kg dose group, 1 of 10 male test animals showed minimal hepatocellular degeneration necrosis in the liver. 3 males showed minimal bilary proliferation/hypertrophy.
No treatment-related microscopic findings were observed at 25 mg/kg/day. In the kidneys, acidophilic globules were
observed in the cortical tubular epithelium with a higher severity in males given 100 or 500 mg/kg bw/day relative to controls.
The latter finding is considered to be related to micro-2µ-globulin which is rat specific and therefore not relevant to human hazard assessment.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

25 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: parental toxicity. Based on liver and kidney findings.

2

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: reproductive toxicity

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Based on the experimental conditions of the reproductive/developmental toxicity screening study according to OECD 421 a NOAEL for parental
toxcitity of 25 mg/kg bw/day (based on liver and kidney findings) and a reproductive NOAEL of 500 mg/kg bw/day was found.
However, the minimal hepatocellular degeneration in 1/10 males and the minimal bilary proliferation/hypertrophy in3/10 animals observed in the 100 mg/kg dose group are not considered as clear signs of toxicity. The increase in acidophilic globules in the 100 and 500 mg/kg male dose groups is considered to be related to micro-2µ-globulin which is rat specific and therefore not relevant to human hazard assessment.

Executive summary:

In a reproduction/developmental toxicity screening study according to OECD 421 Sprague-Dawley rats (10 male and 10 females per dose group) received Isobornyl Methacrylate (IBOMA; purity: 99.66%), by daily oral (gavage) administration for 15 days before mating, through mating, gestation and the beginning of the lactation period (until day 5 post-partum, p.p.). The dose-levels were 25, 100 and 500 mg/kg/day. Another group of 10 males and 10 females received the vehicle, corn oil, alone, under the same experimental conditions and acted as a control group. The dosing volume was 5 mL/kg.

Based on the experimental conditions of the reproductive/developmental toxicity screening study the NOAEL for parental toxcitity was 25 mg/kg bw/day (based on liver and kidney findings) and the reproductive NOAEL was 500 mg/kg bw/day.

The minimal hepatocellular degeneration in 1/10 males and the minimal bilary proliferation/hypertrophy in 3/10 animals observed in the 100 mg/kg dose group are not considered as clear signs of toxicity. The increase in acidophilic globules in the 100 and 500 mg/kg male dose groups is considered to be related to micro-2µ-globulin which is rat specific and therefore not relevant to human hazard assessment.