5-vinylnorborn-2-ene

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEC (maternal toxicity): 123mg/m3
NOAEC (developmental toxicity): 492mg/m3

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

GLP test according to guideline. The test report from the Japanese Ministry of Health & Welfare is not available, but all the data were validated by the Japanese authorities within the OECD SIDS program Information in this record is from therefore from the SIDS dossier, a reliable secondary source, and used as supportive information. Reliability assessment based on that given in SIDS dossier.

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: CrjCD(SD)IGS

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 9 week old for both sexes
- Weight at study initiation: 320-356 g for males , 203-237 g for females
- Housing: polycarbonate cages spread with Beta chip bedding, individually, in pairs during mating or in litters during lactation period.
- Use of restrainers for preventing ingestion (if dermal): yes/no
- Diet (e.g. ad libitum): Rat chow pellets available ad libitum.
- Water (e.g. ad libitum): filtered tap water available ad libitum.
- Acclimation period: Animals were quarantined and acclimated for 6 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22±20°C
- Humidity: at  and 55±15% 
- Air changes: 12 air changes per hour
- Photoperiod: 12 hr light-dark cycle

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
- Test material was prepared in corn oil, stored under refrigeration protected from light and used for dosing within 8 days of preparation.  Stability and concentrations of dosing solutions were verified prior to dosing (Analytical method not specified).
- Dosing schedules and pre and post dosing observations periods for P, F1 and F2, if appropriate: Male rats were dosed orally by gavage for 45 days, from 14 days prior to mating, during mating and up to the day before necropsy.  Females were dosed from 14 days prior to mating, through gestation to day 3 of lactation.  

Details on mating procedure:

After 14 days dosing
- M/F ratio per cage: 1:1
- Length of cohabitation: 5 days
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Premating exposure period (males): 14 days
Premating exposure period (females): 14 days
Duration of test: maximum 45 consecutive days

Frequency of treatment:

once daily, in the morning

Dose / conc.:

4 mg/kg bw/day (actual dose received)

Dose / conc.:

20 mg/kg bw/day (actual dose received)

Dose / conc.:

100 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

12

Control animals:

other: yes, corn oil

Parental animals: Observations and examinations:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: P and F1 Clinical observations performed and frequency: Observations for mortality, external appearance and behavior were made every day before and after dosing.

BODY WEIGHT: Yes
- Time schedule for examinations: Males and females were weighed on the day dosing started, on days 3, 7, 14, and weekly thereafter.  Mated females were weighed on days 0, 7, 14, and 20 of gestation, and on days 0 and 4 of lactation. In females, body weight gain during premating, gestation and lactation was calculated from body weight at initiation of dosing, day 0 of gestation, and day 0 of lactation, respectively. 

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption was measured on the day animals were weighed, except during mating.

Oestrous cyclicity (parental animals):

Yes, details not specified.

Sperm parameters (parental animals):

Not performed.

Litter observations:

STANDARDISATION OF LITTERS
- Not applicable.

PARAMETERS EXAMINED
Neonates were examined at parturition to determine number of offspring born (live-births and stillborn), sex, and external anomalies, and observed daily until day 4 of lactation for general condition and mortality. Surviving offspring were weighed individually on days 0 and 4 of lactation, body wt gain was calculated from day 0 body wt.  

Postmortem examinations (parental animals):

SACRIFICE
- Maternal animals: Parameters calculated were gestational period, delivery (#females with live births÷# females which conceived), implantation (#implantation sites÷corpora lutea) and gestation (total # offspring÷#implantation sites) indices.  

GROSS NECROPSY
- Gross necropsy consisted of: Ovaries and uterus of maternal rats were removed at necropsy on day 4 of lactation; and the number of corpora lutea and implantation sites counted.  

Postmortem examinations (offspring):

GROSS NECROPSY
- Offspring were killed on lactation day 4 and necropsied.
- F1 and F2: After the final day of dosing, all surviving rats of both sexes were killed and necropsied.  Livers of males and females, testes and epididymides were weighed and relative organ/body wt at necropsy calculated.  Seminal vesicles and prostate, ovaries, uterus and vagina, and mammary glands from maternal animals in which all neonates died, and sites of macroscopic anomalies were also fixed and retained.  Slides from livers (both sexes), testes and epididymides from control and high dose groups, sites of any anomalies, and ovaries from non-pregnant females, were prepared, stained with hematoxylin-eosin and examined microscopically. Livers from males at the 2 lower dose groups and additional lipid (Oil-Red-O) stained sections from selected high dose males were also examined.

Statistics:

Bartlett's test for homogeneity of variance, ANOVA if variance homogenous or Kruskal Wallis if variance heterogeneous or data non-parametric. Dunnett's or Dunnett's multiple comparison test. Histopathology analyzed by Chi square, then Armitage. Other counted data anlayzed by Fisher's exact probability. maternal animal is specimen unit for neonate data.

Reproductive indices:

Parameters recorded were number of days required for successful mating, number of estrus cycles missed until successful mating, mating index and fertility index. Only 10/12 mated females in the 20 mg/kg group and 11/12 females in the 100 mg/kg were pregnant but fertility indices were not statistically different from controls.

Offspring viability indices:

Live birth index and neonatal viability index on day 4 of lactation were calculated. The live birth index was 100% and lactation behavior was normal in all groups. All pups from one 20mg/kg dam died on day 2 of lactation.  This event did not appear treatment related since no other instances of 100% mortality occurred in other treated groups.  The number of surviving offspring on day 4 of lactation in the high dose group (6.8 pups) was significantly lower than controls (14.2 pups) (p<0.01) but the neonatal viability index on day 4 of lactation (# live pups on day 4 ÷ # live pups on day 0) was not statistically significantly different for any treated group compared to controls.   There were no changes in sex ratio, offspring body wt, appearance of offspring or necropsy findings attributable to test substance.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

Two males in the high dose group died 25 days and 36 days after start of dosing. Examination of the 2 dead high dose male rats revealed pulmonary and hepatic congestion in both animals and milky appearance and petechiae in the thymus of 1 rat, with histopathologic findings of diffuse thymic hemorrage in that rat, and pulmonary congestion and edema in both rats. Pulmonary congestion and edema is suggestive of misdosing as a cause of death and therefore is not treatment related.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body wt gain was suppressed and food consumption decreased in both sexes in 100 mg/kg group from 7 days after dose initiation to necropsy, but, though a consistent trend, these effects were not always statistically significant. Absolute body wt. in high dose males and females were statistically significantly lower than controls at necropsy (p<0.01).

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Histopathologic examination of livers from high dose males revealed hypertrophy and vacuolization of hepatocytes; liver sections from males at the 2 lower doses were comparable to controls.

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

The number of estrus cycles missed until mating were comparable for treated animals and controls.

Reproductive performance:

effects observed, treatment-related

Description (incidence and severity):

All animals mated within 5 days. Mating index and days required for successful mating were comparable for treated animals and controls. Only 10/12 mated females in the 20 mg/kg group and 11/12 females in the 100 mg/kg were pregnant but fertility indices were not statistically different from controls. Parturition was normal and corpora lutea counts were comparable for all groups. In the 100 mg/kg group, the implantation index (72.8%), total number of offspring born (7.1 pups) and the delivery index (53.1%) were significantly lower than controls (p<0.01), (94.5%, 14.3 pups, and 93.1 %, respectively). The live birth index was 100%

Dose descriptor:

NOAEL

Effect level:

20 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

organ weights and organ / body weight ratios

reproductive performance

Critical effects observed:

yes

Lowest effective dose / conc.:

100 mg/kg bw/day (actual dose received)

System:

hepatobiliary

Organ:

liver

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Critical effects observed:

yes

Lowest effective dose / conc.:

100 mg/kg bw/day (actual dose received)

System:

male reproductive system

Organ:

testes

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Clinical signs:

no effects observed

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

All pups from one 20mg/kg dam died on day 2 of lactation. This event did not appear treatment related since no other instances of 100% mortality occurred in other treated groups.
The number of surviving offspring on day 4 of lactation in the high dose group (6.8 pups) was significantly lower than controls (14.2 pups) (p<0.01) but the neonatal viability index on day 4 of lactation (# live pups on day 4 ÷ # live pups on day 0) was not statistically significantly different for any treated group compared to controls.

Body weight and weight changes:

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

Other effects:

no effects observed

Description (incidence and severity):

Lactation behavior was normal in all groups. There were no changes in sex ratio.

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

20 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

mortality

Critical effects observed:

no

Reproductive effects observed:

not specified

NOAEL (NOEL) repeat dose toxicity = 20 mg/kg/day (both sexes)

NOAEL (NOEL) reproduction = 20 mg/kg/day (dam and offspring)

Conclusions:

5-Ethylidene-2-norbornene administered to rats by oral gavage for 45 days, induced both parental systemic and reproduction/developmental toxic ty at 100 mg/kg/day. Treatment did not appear to affect mating capabilities or fertility index but did affect the embryo and fetus at this high dose t at inhibited body wt gain and food consumption in parental animals. However, the lack of effect on the live birth index, day 4 neonatal viability, exter al appearance and necropsy findings in offspring suggests that the test material does not affect postpartum neonatal growth.

Executive summary:

MHW, Japan (1999) reported results of a guideline (OECD 421) and GLP reproductive/developmental toxicity screening study in Sprague-Dawley rats at doses of 0, 4, 20, and 100 mg/kg/day of the substance ethylidene norbornene (ENB). ENB was administered for 46 days in males and from 14 days before mating to day 4 of lactation in female rats. Two male rats in the 100 mg/kg group died. Suppressed body weight gain and decreased food consumption was observed in both sexes in this group. The relative liver weights were increased in the 100 mg/kg male group, and histopathological examination revealed hypertrophy and vacuolation of hepatocytes in these animals. Among dams, prolongation of the gestation period, and a trend for a decrease in the number of implantation and delivery indices were observed in the 100 mg/kg group. No other changes attributable to the compound were observed in any parameters including the mating index, the fertility index, the gestation index, number of corpora lutea, parturition state and lactation behavior. Among offspring, total number of births and number of live offspring on day 4 of lactation were decreased in the 100 mg/kg group. No other changes attributable to the compound were observed in parameters including the sex ratio, the live birth index, the viability index on day 4, necropsy findings or external examination. The NOAEL for parental toxicity and for reproductive and developmental toxicity is considered to be 20 mg/kg/day.

This result can be considered representative of the reproductive toxicity of the close structural analogue vinyl norbornene.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

20 mg/kg bw/day

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Justification for selection of Effect on fertility via oral route:
Only study available in dossier

Effects on developmental toxicity

Description of key information

NOAEL (maternal toxicity, inhl): 25 ppm
NOAEL (developmental toxicity, inhl): 100 ppm

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Comparable to Guideline study. Well conducted and reported study.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

other: CD (Sprague-Dawley)

Details on test animals or test system and environmental conditions:

Each animal was assigned a unique number and was ear tagged for identification.

TEST ANIMALS
- Virgin male and female CD (Sprague Dawley).
- Age not recorded; acclimated for 2 weeks before exposure commenced.
- Weight at study initiation: females ~235 g.
- Housing: 2 (1M/!F) to a cage in stainless steel wire-mesh cages.
- Diet: Prolab Certified Rodent Food@, ad libitum except during exposure period
- Water: tapwater
- Acclimation period: two weeks during which time they were examined by the Clinical Veterinarian and representative animals were subjected to a full necropsy, examination for intestinal parasites, histologic examination of selected tissues and serum viral antibody analysis.

ENVIRONMENTAL CONDITIONS
- Temperature (exposure chamber): 20.4-22.2 Celsius
- Humidity (exposure chamber): 47.5-49.6%
- Photoperiod: 12-hour

Route of administration:

inhalation

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Details on exposure:

For generation of atmospheres, liquid ENB was metered from a heated glass evaporator similar in design to that described by Carpenter et al. (1975) and, more recently, Snellings and Dodd (1990). The temperature in the evaporator(s) was maintained at the lowest level sufficient to vaporize the liquid (31-52°C). The resultant vapor was carried into the chamber by passage of conditioned air through the evaporator(s). Concentrations of the ENB vapor in the exposure chambers were monitored using a gas chromatograph equipped with a flame ionization detector.

Chamber volume: 3220litres, airflow 1000litres/min.

Chamber temperature, relative humidity, and airflow rate were recorded approximately every 30 minutes during each six-hour exposure.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analytical chamber concentrations were measured by gas chromatography. Calibration of the gas chromatograph was done using a series of standards which encompassed the entire range of vapor concentrations generated in the exposure chambers. Each chamber atmosphere was monitored for concentration verification approximately once every 25 minutes during each daily six-hour exposure. Daily nominal concentrations (an estimated concentration calculated from the amount of test material delivered and the chamber airflow during the exposure period) were calculated for each chamber. In a preliminary study on the distribution of vapur in the exposure chamber, each chamber was sampled at 5 different positions in triplicate. The variation seen was deemed acceptable.

Details on mating procedure:

- If cohoused:
- M/F ratio per cage: 1:1 (one male at least 300 g:one female at least 200 g) mating cages (22.5 x 31.0 x IS cm high)
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
- Plug-positive females-were housed individually for the duration of the study. 

Duration of treatment / exposure:

Gestation days (GD) 6-15

Frequency of treatment:

6 hours/day

Dose / conc.:

25 ppm (analytical)

Remarks:

equivalent to 123mg/m3

Dose / conc.:

100 ppm (analytical)

Remarks:

equivalent to 492mg/m3

Dose / conc.:

354 ppm (analytical)

Remarks:

equivalent to 1740mg/m3

No. of animals per sex per dose:

25

Control animals:

other: yes, air-exposed only

Details on study design:

Sex: female
Duration of test: females sacrificed on GD21

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Maternal animals were observed daily for mortality, morbidity, and signs of toxicity

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were recorded on GD 0, 6, 9, 12, 15, 18, and 21.

FOOD CONSUMPTION : Yes, Maternal food consumption was measured at 3-day intervals.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21
- Organs examined: general abdominopelvic gross pathology, gravid uterine weight, liver and kidney weights. Maternal thyroid glands were weighed and prepared for light microscopic examination and morphometric measurements.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: not reported

Fetal examinations:

All fetuses were weighed, sexed, and examined for external variations and malformations.
- Soft tissue examinations: Yes: half per litter were examined for thoracic and abdominal abnormalities ; these fetuses were decapitated and the heads fixed in Bouin's solution for examination of craniofacial structures by sectioning. 
- Skeletal examinations: Yes: All fetuses were eviscerated and processed for skeletal staining with alizarin red S to examine for skeletal malformations and variations.
- Head examinations: Yes: half per litter

Statistics:

Quantitative continuous variables were intercompared between ENB groups and the corresponding air-control groups using Levene's test for equal variances,analysis of variance, and t-tests. The t-test was used when the F value from the ANOVA was significant. Non-parametric data were statistically analyzed using the Kruskall-Wallis test followed by the Mann-Whitney U test. Incidence data were compared using Fisher's Exact Test. A probability value of <0.05(two-tailed) was used as the critical level of significance.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weight: Significantly reduced in top dose group (-8.5% compared to controls by GD15). Showed evidence of reversal after exposure ceased.
Body weight gain: Significantly reduced in top (-62%) and mid (-25%) dose groups, but for the mid dose group this was only over the period GD6-9. There was again evidence of this effect disappearing after exposure ceased.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Significantly reduced by 21% in high dose group and 10% in mid dose group. In the latter case, this is an average figure over the whole exposure period, but the effect was more marked at the start of exposure (-17% compared to the end of exposure (-8%).

Immunological findings:

no effects observed

Description (incidence and severity):

No changes to thyroid weight, T3 or T4 levels.

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Relative liver weight increased in mid and high dose animals. No other significant organ weight changes noted.

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Colloid depletion in thyroid gland, characterised by small, collapsed or angular-shaped follicles containing minimal colloid. A dose response was seen in all dose groups.

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): effects observed, non-treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): One dam at 100ppm delivered early.

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

Rates at 83-100% were equivalent across all groups.

Other effects:

no effects observed

Description (incidence and severity):

Gravid uterine weight unaffected. No effects on number of corpora lutea, total number of non-viable and viable implants

Dose descriptor:

NOAEC

Effect level:

< 25 ppm (analytical)

Based on:

test mat.

Basis for effect level:

histopathology: non-neoplastic

Dose descriptor:

NOAEC

Effect level:

25 ppm (analytical)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

food consumption and compound intake

organ weights and organ / body weight ratios

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

External malformations:

no effects observed

Skeletal malformations:

effects observed, treatment-related

Description (incidence and severity):

In 100ppm and 354ppm groups there was an increase in the number of fetuses showing bilobed twelfth thoracid centrum. In high dose group only, there was also an increase in split twelfth thoracic centrum and poorly ossified second sternebra. This are all considered variations rather than malformations and are seen as an increase in frequency compared to spontaneous occurence in control animals.

Visceral malformations:

no effects observed

Details on embryotoxic / teratogenic effects:

.

Dose descriptor:

NOAEC

Effect level:

100 ppm (analytical)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

skeletal malformations

Abnormalities:

effects observed, treatment-related

Localisation:

skeletal: vertebra

Description (incidence and severity):

minor variations - increase in frequency compared to spontaneous occurence in control animals

Developmental effects observed:

no

There were no maternal deaths or abortions. One dam at 100 ppm delivered early. Pregnancy rates ranged from 83.3 to 100% and were equivalent across all groups. Between 20 and 25 litters were available for examination in each group. There were no exposure-related clinical signs of toxicity. Gestational body weights were reduced GD 9, 12, 15, and 18 at 354 ppm and on GD 15 at 100 ppm. Gestational body weight gains were statistically significantly reduced (p< 0.01) 61.5% over GD 6-15 at 354 ppm and 25.2% over GD 9-15 at 100 ppm, both accompanied by decreased food consumption (21.4% and 10.4%, respectively, p< 0.01). At 100 ppm, food consumption was less markedly affected, being reduced 16.5% for GD 9-12 and 8.0% for GD 12-15. Food consumption was similar to controls in the post expsoure period.  

Necropsy: There were no effects on the number of corpora lutea. The corrected body weights and corrected body weight changes were reduced in the 354 ppm group. Liver weights showed a nonstatistical trend for increase at 100 and 354 ppm. Relative liver weight was increased at 100 and 354 ppm. There were no statistically significant differences among the groups for number of live fetuses per litter, percent malformations per litter, placental or fetal body weights, or sex ratio. Three skeletal variants were increased in litters of the 354 ppm group (bilobed 12th thoracic centrum, split 12th thoracic centrum, and poorly ossified second sternabra) and one variant (bilobed 12th thoracic centrum) was increased in the 100 ppm group litters, but these occurred in the presence of maternal toxicity and were not seen in the 25 ppm group. Whilst the incidence of bilobed 12th thoracic centrum was statistically increased relative to controls, there was no clear dose response relationship - incidence at all three doses was similar and the effect did occur in controls. The biological significance is therefore questionable in the absence of any other significant findings. Both absolute and relative thyroid weights were unaffected by maternal exposure to ENB. There was no difference in thyroid hormones compared to controls. Histology evaluation confirmed vacuolar colloid depletion in all groups, (including controls) that was more marked and numerous in ENB groups. Morphometric evaluation confirmed concentration-related depletion of thyroid colloid in the ENB groups. There were no clinical signs suggestive of thyroid dysfunction.

Executive summary:

Neeper-Bradley et al. (1995) reported results of a teratogenicity test of ethylidene norbornene (ENB) conducted in CD (Sprague-Dawley) rats by inhalation of 0, 25, 100 and 354 ppm (0, 123, 492, 1740 mg/m3) during days 6-15 of pregnancy. There was no maternal mortality. Maternal body weights, body weight gain, and food consumption were reduced over the exposure period at 100 and 354 ppm, with partial or complete recovery post exposure. Increased relative liver weights were measured for the 100 and 354 ppm groups. Vacuolar depletion of thyroid follicular colloid was present in all groups of pregnant animals, including air-only controls, but the incidence and extent was greater in ENB vapor-exposed rats. There were no effects on tri-iodothyronine (T3), tetra-iodothyronine (T4) or T3 uptake. There were no increases in the incidence of malformations or external and visceral variations. Three skeletal variants (bilobed 12th thoracic centrum, split 12th thoracic centrum, and poorly ossified second sternabra) were increased at 354 ppm, and one (bilobed 12th thoracic centrum) was increased at 100 ppm. Thus, minimal developmental toxicity in the form of skeletal variants was observed in the 100 and 354 ppm group litters in the presence of maternal toxicity but analysis of the results suggests no dose response relationship and, in the absence of other findings, this change may not be biologically significant. On this basis, it is concluded that the NOAEL for maternal toxicity is 25ppm (123 mg/m3) whilst that for developmental toxicity/teratogenicity is 100 ppm (492 mg/m3).

This result can be considered representative of the likely developmental toxicity of the close structural analogue vinyl norbornene.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

492 mg/m³

Species:

rat

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

A teratogenicity test of ENB was conducted in CD (Sprague-Dawley) rats by inhalation of 0, 25, 100 and 354 ppm (0, 123, 492, 1740 mg/m3) during days 6-15 of pregnancy (Neeper-Bradley, et al. 1995). A NOAEL of 25 ppm (123 mg/m³) was established for both maternal toxicity and a NOAEL of 100ppm (492 mg/m3) for developmental toxicity/teratogenicity.

Justification for selection of Effect on developmental toxicity: via inhalation route:
Only study available.

Justification for classification or non-classification

Reliable animal data show no evidence of reproductive of developmental effects at levels below those producing toxicity, therefore, no classification is proposed.