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 of slight - moderate acute toxicity by the oral and inhalation routes (oral LD50 670 mg/kg, inhalation 4 hour LC50 2,750 mg/m3) and is practically non-toxic by the dermal route (dermal LD50 > 2000 mg/kg). 

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Dose descriptor:

LD50

Value:

670 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Dose descriptor:

LC50

Value:

2 750 mg/m³ air

Acute toxicity: via dermal route

Endpoint conclusion

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

Non human information

As detailed in section 5.1.3 of the CSR (IUCLID Section 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.

Acute toxicity : oral

In the key study (FDRL, 1980a), groups of 5 male and 5 female Sprague Dawley rats (fasted overnight) were dosed by gavage at levels of 430, 660, 1020, 1560 or 2400 mg/kg of 3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-indene (TCDE) and were observed daily for 14 days after dosing. Significant clinical signs (seen in animals at all doses) included decreased activity, ataxia, tonic convulsions, tremors, paralysed hind-quarters (1 female at 1560 mg/kg), staub tail (1 female at 2400 mg/kg), diarrhoea, urinary incontinence and/or salivation. All mortalities occurred one or two days after dosing. Gross necropsy findings, seen in animals at all dose levels, included dark and/or mottled lungs; dark, blanched and/or mottled liver; pale, blanched kidneys; vascularisation of stomach and/or gastro-intestinal tract; granular, pale and/or dark spleen. The LD₅₀was calculated to be 670 (100 - 1920) mg/kg bw for males and females combined.

This is supported by the acute oral toxicity data on DCPD with the overall LD50 of 590 mg/kg being very similar to the LD50 for TCDE. For DCPD the studies are summarised as follows. In the key study for DCPD (Safepharm, 1989a), groups of fasted Sprague Dawley rats were dosed by gavage at dose levels of 500, 794, 1260 or 2000 mg/kg of resin grade DCPD with a purity of 75% DCPD and observed daily for 14 days after dosing.  Signs of toxicity (including lethargy and decreased respiratory rate) were seen after dosing with 1260 or 2000 mg/kg bw, with ptosis and occasional signs of ataxia seen 4 hours after dosing with 2000 mg/kg bw. All rats dosed with 1260 or 2000 mg/kg bw died one or two days after dosing.  Haemorrhagic lungs, dark liver and sloughing of the non-glandular gastric epithelium were seen in decedents. The LD50 was calculated to be 590 mg/kg bw (male/female); 512 mg/kg for males and 676 mg/kg/bw for females.

In supporting studies by Litton Bionetics (1976c) the oral LD50 in the Sprague Dawley rat was 449 mg/kg (male/female); 520 mg/kg for males and 378 mg/kg for females. Slightly lower LD50 values were found in Swiss Webster mice: 220 mg/kg (male/female); 190 mg/kg for males and 250 mg/kg for females

 

Acute toxicity : inhalation

Groups of 5 male and 5 female Sprague Dawley rats were exposed to aerosols of 3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-indene (TCDE) at nominal concentrations of 7960, 10050, 12670 or 19950 mg/m3 for 1 hour and were observed daily for 14 days after exposure (FDRL, 1980b).  Mortalities, which all occurred during exposure, were 0/10, 3/10, 8/10 and 10/10 at concentrations of 7960, 10050, 12670 or 19950 mg/m3,

respectively.  Significant clinical signs (seen in animals at all doses) included decreased activity, laboured respiration, decreased coordination, nasal discharge and/or salivation. Reduced body weight gain was seen in females at all exposure levels and in males exposed to 10050 mg/m3 and higher.  The only treatment related gross necropsy findings were enlarged salivary glands and cervical lymph nodes in animals exposed to 12670 or 19950 mg/m3 TCDE. The 1 hour LC₅₀was calculated to be 11000 mg/m3 (95% CI 9.2 – 12.2 mg/L) for males and females combined.  Using Haber’s law (n=1) this corresponds with a 4 hour LC50 of 2750 mg/m³.

Considering the read-across candidate, DCPD, studies assessing the acute inhalation toxicity of exposure in rats and mice for 6 hours have been reported (Bushy Run, 1981). These studies were conducted to obtain a definitive LC50 value that was not confounded by fracturing of the DCPD (previous publications have given conflicting LC50 values that might have been caused by loss of DCPD via fracturing). Chamber concentrations of DCPD and cyclopentadiene were monitored by gas chromatography/flame ionization detection with a detection limit for both chemicals of 0.05 ppm; cyclopentadiene was below the detection limit in both studies.  

In the rat study, groups of Fischer 344 rats were exposed for 6 hours to vapours containing 46, 130, 260 or 557 ppm and then observed daily for up to 14 days. At 557 ppm, all females were found dead on the day after exposure and all males died within 24 hours of exposure. At 260 ppm, two males were found dead on the day after exposure, all females survived. Clinical signs included loss of righting reflex, impaired gait, stereotypic behaviour, laboured breathing, nasal discharge and convulsions. The 6 hour LC50 was 284 ppm for males and 353 ppm for females, equivalent to 1723 mg/m3 (male/female). Conversion of this result using Haber's rule (n=3) gives a 4 hour LC50 equivalent of 1972 mg/m3 for males and females.  The NOAEC for irregular breathing and stereotypic behaviour was 46 ppm (248.74 mg/m3).

In the mouse study, groups of B6C3F1 mice were exposed for 6 hours to the same vapour concentrations of DCPD and then observed daily for up to 14 days. At 557 ppm, all mice died within 24 hours of exposure. At 260 ppm, all males were found dead on the day after exposure and all females died during exposure or within 24 hours. At 130 ppm, 2 males and 3 females died within 24 hours of exposure. There were no deaths at 46 ppm. Clinical signs included loss of righting reflex, impaired gait, stereotypic behaviour, laboured breathing, clear nasal discharge, loss of coordination and convulsions prior to death. The 6 hour LC50 was 143 ppm for males and 126 ppm for females, equivalent to 738.5 mg/m3 (male/female). The NOAEC for irregular breathing and stereotypic behaviour was 46 ppm (248.74 mg/m3).

Supporting studies assessed the acute inhalation toxicity of DCPD exposure for 4 hours in rats, mice, dogs and rabbits (Kinkead et al, 1971).  The LC50 in the male albino rat was 359.4 ppm (1943 mg/m3) and in the female was 385.2 ppm (2083 mg/m3). These values are consistent with the LC50 equivalent of 1972 mg/m3 for males and female rats calculated using Haber's rule from the Bushy Run, (1981) study. For the male mouse the 4 hour LC50 was 145.5 ppm (787 mg/m3) and for the male rabbit was 771 ppm (4171mg/m3).  For the female dog, the 4 hour LC50 was between 458 and 773 ppm (2473-4174 mg/m3).  Poor coordination and convulsions were seen in all species, especially prior to death and eye and nose irritation, lachrymation and tremors were observed in the dog study.

Acute toxicity : dermal

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, 1980c).  One male died on day 12 of the observation period. Decreased activity and ataxia was seen in all animals after dosing and redness of the back was seen in 4 males and 5 females.  Diarrhoea and/or soft stools were seen in some animals.  Weight loss or reduced weight gain was seen in 3/5 males and all females over the 14-day observation period. Gross necropsy findings, seen in several animals, included pale and/or granular spleen and/or pale kidneys. The LD50 was greater than 2000 mg/kg to rabbits following dermal application to abraded skin. 

The results of the TCDE study concur with those for the read-across candidate, DCPD. The acute dermal toxicity of resin grade DCPD with a purity of 75% DCPD was assessed in a group of 5 male and 5 female rats (Safepharm 1989b). 2000 mg/kg bodyweight of the chemical was applied to an area of clipped, intact dorsal skin and held in place with an occlusive dressing. Animals were observed at 1 and 4 hours after dosing and then daily for 14 days. Clinical signs present in all animals on day 1 included vocalisation for up to 30 minutes, hunched posture, lethargy, piloerection, erythema and oedema.  All animals showed signs of eschar by day 3 which persisted until days 10 or 12 but all treatment sites appeared normal by the end of the study. The acute dermal LD50 of dicyclopentadiene 75% to the rat was greater than 2000 mg/kg bodyweight.  In two rabbit studies, the acute dermal LD50 of undiluted DCPD was 4460 mg/kg bw (Smyth et al, 1962) and 6720 mg/kg bw (Smyth et al, 1954). No observations of systemic toxicity were reported.

Human information

No relevant human information is available

Justification for classification or non-classification

3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-indene (TCDE) is not included in Annex I of the DSD.

TCDE is harmful by the oral route with an LD50 value of 670 mg/kg which justifies classification R22 (Harmful if swallowed) under DSD and Category 4 (H302) under CLP.

Considering the data presented, the calculated 4 hr LC50 of 2750 mg/m³ justifies classification as Harmful, R 20 (Harmful by inhalation) under DSD with the corresponding Category 3 H331 (Toxic if inhaled) under CLP.

TCDE is of low acute toxicity by the dermal route with an LD50 greater than 2000 mg/kg and therefore does not warrant classification under DSD or CLP for dermal exposure.