3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-indene

Endpoint summary

Description of key information

3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-indene (TCDE) is considered to be irritating to skin and the respiratory system and slightly irritating to eyes. 

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Eye irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

Non human information

As detailed in section 5.1.3 of the CSR (IUCLID 7.1.1), 3a,4,7,7a-tetrahydro-4,7-methanoindene (DCPD) is considered an appropriate read-across candidate where data are not available for 3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-indene (TCDE). This section summaries the available data for TCDE and also includes that for DCPD for comparison.Where data are available for TCDE these are considered key.

Skin

Groups of 5 male and 5 female New Zealand white rabbits rats were dosed with 2000 mg/kg of 3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-indene (TCDE) as a 24- hour dermal application to abraded skin (under a semi-occlusive dressing) and were observed daily for 14 days after dosing (FDRL, 1980b). One male died on day 12 of the observation period. Redness of the back was seen clinically in 4 males and 5 females and the skin sites were assessed for erythema and oedema, using the Draize scoring system, at the end of the exposure period. The mean scores were 3.7 for erythema and 3.5 for oedema for the 10 rabbits. TCDE was irritant to the abraded skin of rabbits following a 24 hour dermal application.

Considering the read-across substance, DCPD, this also is moderately irritating to skin. The skin irritation potential of DCPD was assessed in a study in New Zealand White rabbits (Safepharm, 1989c). 0.5 mL of DCPD 75% was applied to an area of clipped, intact skin under a semi-occlusive dressing for 4 hours. Animals were observed at 1 and 4 hours after removal of the patch and then daily for 7 days. Well-defined erythema and slight to severe oedema was present at all sites and for all rabbits at 24, 48 and 72 hour observation times. On day 7, no oedema was noted but there were signs of possible hyperkeratinisation. No other adverse dermal reactions were noted during the study. The overall mean scores (24, 48 and 72 h) were 2 for erythema and 2.3 for oedema; dicyclopentadiene 75% was a therefore considered to be a moderate irritant of rabbit skin.

In an older supporting study New Zealand white rabbits were used to assess skin irritation following a 24 hour, uncovered, application of 0.01 mL undiluted dicyclopentadiene (Smyth 1962).  The overall irritation score (on a scale of 1 -10) was 5 and confirmed that undiluted DCPD was moderately irritating to rabbit skin.

Eye

There is no information available for TCDE therefore data from the read-across substance, DCPD, are considered to address this endpoint.

In what is considered to be the key eye irritation study in New Zealand White rabbits (Safepharm 1989d) 0.1 mL DCPD 75% was instilled into the conjunctival sac and the eyes were scored for irritation responses at 1, 24, 48 and 72 hours and at 7 days after instillation. Moderate irritation was present at 1 hour in all 3 rabbit eyes; iridial inflammation and conjunctival irritation were present in all cases and corneal dulling was present in 2. However, signs of irritation regressed to minimal in 2 eyes at 24 hours. Although corneal redness persisted in 1 animal at 72 hours, all effects were fully reversible within 7 days.

In a supporting study (Litton Bionetics, 1976a) using undiluted dicyclopentadiene, initial conjunctival irritation was present in 7 out of 9 rabbits but had recovered by day 3. Undiluted dicyclopentadiene was practically non-irritating at 24, 48 and 72 hours in this study. 

Respiratory

Whilst there are no specific studies assessing respiratory irritation, significant clinical signs (seen in animals at all doses) included decreased activity, laboured respiration, nasal discharge and/or salivation were reported in the acute inhalation toxicity study (FDRL, 1980)

For the read-across candidate, DCPD, similar findings of laboured/ irregular breathing, nasal discharge and haemorrhagic lungs post mortem were evident in acute inhalation exposures of rats and mice (Bushy Run, 1981) and dose-dependent eye irritation was observed in a variety of species during acute inhalation exposures to neat dicyclopentadiene vapour (Kinkead et al, 1971).

Human information

No information is available relating to the irritative effects of TCDE to humans and very little information has been reported for DCPD. However, in a study in volunteers to determine the human sensory response to dicyclopentadiene vapour, 2 subjects inhaled analysed concentrations of 1 ppm and 5.5 ppm for 30 minutes (Kinkead et al, 1971). Both concentrations caused sporadic eye and throat irritation and one subject could taste dicyclopentadiene for 1 hr after the 5.5 ppm exposure. Human exposure to vapours of dicyclopentadiene is considered likely to result in respiratory and ocular irritation. The literature was reviewed (Amoore et al, 1983) to provide quantitative data on the odour thresholds of 214 chemicals including dicyclopentadiene. Data on the volatility, solubility, ionisation and water-air distribution ratio at 25ºC were collected and a safe dilution factor and an odour safety factor were calculated. For dicyclopentadiene the threshold limit value was 5 ppm v/v, the volatility at 25ºC was 3600 ppm v/v, the air odour threshold was 0.0057±1.9 ppm. The calculated safe dilution factor was 720 and the odour safety factor was 870. On the basis of these results, dicyclopentadiene was placed in odour safety class A (i. e. more than 90% of distracted persons perceived warning of TLV concentration in the air).

Effects on skin irritation/corrosion: moderately irritating

Effects on eye irritation: slightly irritating

Effects on respiratory irritation: irritating

Justification for classification or non-classification

Animal studies with 3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-indene (TCDE) demonstrate skin irritation and justify the classification of "Xi" R38 "Irritating to skin" under DSD and Category 2 (Irritant) with the hazard statement" H315 causes skin irritation" under CLP.

Considering read-across to the structurally similar DCPD, classification as Xi, "R36 Irritating to eyes" is proposed, with corresponding classification as Category 2 "H319 Causes serious eye irritation" under CLP. 

Similarly, the observations of respiratory tract irritation in animals and humans seen with TCDE (acute inhalation study) and DCPD imply that TCDE warrants classification as Xi "R37 Irritating to respiratory system" under DSD and Category 3 for transient target organ toxicity under STOT-RE under CLP.