1,4,5,6,7,7-hexachloro-8,9,10-trinorborn-5-ene-2,3-dicarboxylic anhydride

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
A summary of the toxicokinetic characters of chlorendic anhydride was completed based on the results of the studies undertaken and is attached below.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

A summary of the toxicokinetic characters of Chlorendic Anhydride was completed based on the results of the studies undertaken and is attached here below.

Summary

Chlorendic Anhydride has been assessed under REACH for registration at greater than 1000tonnes per annum for use in a variety of industrial applications.  A CSR has been prepared.

 

It is considered likely that chlorendic anhydride hydrolyses to chlorendic acid in water and acid media and any oral exposure to the anhydride can be considered to lead to exposure to the acid.

 

The toxicokinetics of chlorendic acid has been assessed [ref 1] and it was shown to be absorbed orally, and distributed through to various tissues through use of radiolabelling. The major site of radiolabelling recovery was the liver, with background levels in the blood, skin, and kidneys. Excretion was considered to be primarily through the bile, with limited findings in the urine. At least 75% of total radioactivity was excreted within 24 hours, mainly as metabolites.

 

In the absence of specific findings form toxicity testing of the anhydride, this reference should be treated as possibly the best source of information.

 

Chemical composition

The substance Chlorendic Anhydride is a mono constituent substance (origin: organic) having the following characteristics.

 

The following public name is used: Chlorendic Anhydride.

Table1. Substance identity

 

EC number:		204-077-3
EC name:		1,4,5,6,7,7-hexachloro-8,9,10-trinorborn-5-ene-2,3-dicarboxylic anhydride
CAS number:		115-27-5
CAS name:		1,4,5,6,7,7-hexachloro-8,9,10-trinorborn-5-ene-2,3-dicarboxylic anhydride
Molecular formula:	C9H2Cl6O3
Molecular weight:	370.83

 

 

Physico-chemical properties

 

Property	Results	Value used for CSA / Discussion
Physical state at 20°C and 1013 hPa	solid Form:crystalline Colour: White Odour: characteristic of aromatic compounds
Melting / freezing point	The melting temperature was found to be 235 - 239°C.	Value used for CSA:237 °C
Boiling point	The boiling temperature was found to be 266.5 - 322°C.	Value used for CSA:294.25 °C
Relative density	The relative density of Chlorendic anhydride was found to be 1.76.	Value used for CSA:1.76 at 20°C
Vapour pressure	The vapour pressure was determined using a vapour pressure balance. The vapour pressure of chlorendic anhydride was found to be 2.68E-03 Pa at 25°C.	Value used for CSA:0.003 Pa at 25 C
Surface tension	The surface tension of a 90% saturated aqueous solution of Chlorendic anhydride was found to be 72.0 mN/m. As the result was greater than 60 mN/m, the test substance was not considered to be surface active.	Value used for CSA:72 mN/m at 20°C and 450 mg/L
Water solubility	The water solubility of chlorendic anhydride in the form of chlorendic acid is 0.499 g / l at 20°C. The water solubility of chlorendic anhydride in its unhydrolysed form is less than 25 mg/l	Value used for CSA:2.5 mg/LChlorendic anhydride hydrolyses to chlorendic acid in contact with water and hence the water solubility has been reported as the hydrolysis product and a less than value for the anhydride.
Partition coefficient n-octanol/water (log value)	Chlorendic anhydride hydrolyses to chlorendic acid in contact with water and hence the partition coefficient of chlorendic acid has been determined in this study. Pow = 24.5	Value used for CSA:Log Kow: 1.39 at 20 °C
Dissociation constant	Study not undertaken.	Study not undertaken as substance readily hydrolyses.

 

 

Environmental Fate and Effects Summary

 

Hydrolysis:

It can be concluded that on dissolving in water Chlorendic Anhydride undergoes immediate hydrolysis to the corresponding di-acid. It is claimed that it is not possible to determine a half-life time for Chlorendic Anhydride in water, but this does indicate that if ingested, the anhydride will quickly convert to the acid and the oral toxicity of the anhydride and acid will need to be considered in the same way.

 

A report from the US National Toxicity Program [ref 2] on chrorendic acid shows that this will itself undergo further abiotic degradation in water and sunlight.

 

Biodegradation:

There are no evidence of biodegradation when tested at ca 160 mg/l by manometric method. A concurrent toxicity control suggested that there was no toxicity to the culture.

 

Toxicity summary

Extensive testing has been performed on the anhydride and acid and it needs to be noted that in view of the apparent instability of the anhydride in water, the toxicity of the acid and anhydride can be expected to be very similar.

 

Acute oral toxicity, rats, discriminating dose > 1281 mg/kg. Mortality seen at > 2034 mg/kg with 100% mortality at 3229 mg/kg. Most pathological changes related to effects to the GI tract and most deaths were within the first day.  

 

Inhalation study, rats, no adverse effects at limit of exposure of 203 mg/l atmosphere of dust

Acute dermal toxicity, no effect at 10000 mg/kg, but mortality seen at 20000 mg/kg. No indication of local skin affects.

 

Not classified irritating to the skin, with slight/moderate skin irritation. Note that the sample was applied dry and not moistened prior to administration. 

 

Irritating to the eyes

 

Considered to be a potential sensitiser in view of response at challenge. Administered by solution in saline, so exposure will have been to the hydrolysis product (acid). 

 

28 day rat feeding study showed no effects at up to 10 000 ppm in feed. No evidence of absorption.

 

Oral teratorgenicity test with administration in corn oil resulted in no significant effects.

90 day rat feeding study at up to 2500 ppm showed some lower weight gain at higher levels and associated variations in some organ weights. No evidence of adsorption or metabolic activity.

3-week rabbit skin toxicity resulted in adverse clinical signs and dose related effects on the stomach. Biochemistry parameters were unchanged and there was no evidence of metabolic activity. There was only mild skin irritation. The substance was applied in wetted form in saline. 

 

28 day rat inhalation at up to 10 mg/l atmosphere resulted in respiratory irritation and some changes in blood parameters that could have been in response to general stress of animals.

An oral in-vivo dominant lethal assay in mice showed no adverse effects on reproductive viability

 

Negative Ames, not toxic with no impact of S-9 fraction

 

Mouse lymphoma gene mutation assay cultures resulted in lower toxicity in the presence of S-9

 

In an in-vitro UDS assay, there was toxicity with and without S-9, with a suggestion of higher inhibitory effect without S-9 at 0.1 mg/ml. Possible DNA damage seen in both groups.

 

In conclusion, there were limited findings from toxicity testing to help in this assessment of toxicokinetics. 

 

There is no evidence that the test material is absorbed by the oral route and the lethality seen in the oral studies at levels above 2000 mg/kg and the dosage-related effects on bodyweight apparent within the treated groups in the 28 and 90-day oral toxicity study may be a result of local effects to the GI tract and adaptive changes. 

 

However, absorption via the dermal route was possible from the signs in the 3-week dermal toxicity study in rabbits. Systemic toxicity following dermal exposure was apparent at the high dosage level in view of the adverse clinical signs and decrease in bodyweight seen, although some of this may be due to ingestion from grooming. The topical challenge in the sensitisation study led to positive responses showing dermal penetration.

 

The 28-day toxicity study in rats by inhalation exposure also resulted in findings, such as clinical signs, decrease weight gain in high dose (9.97 mg/L) males, differences in haematological and blood chemistry parameters, which could be indicative that the material was absorbed by the inhalation route, of may be adaptive changes as a result of distress from local respiratory irritation.

 

Although there were effects reported in the organ weights (lower than control heart and liver weights in the 90-day study), possibly indicating distribution of the test material, there was no associated macroscopic pathology or histopathological findings. These organ weight effects are likely to be a result of lower than control terminal bodyweights for these animals rather than indicative of direct toxicity or distribution. However, in 28-day inhalation study in rats there were pathological inflammatory changes in the lungs, trachea, nasal turbinates and stomach mucosa in all treated groups. This was partially a result of the irritant nature of the test material.

 

In two in-vitro mutagenicity studies with mammalian cells, the presence of S-9 appeared to reduce the toxicity to the cell cultures, indicating possible metabolic action. The substance showed no indication of biodegradation; this can itself be an indicator or metabolic potential.

 

The changes in the enzyme activities in the treated groups throughout the rat 90-day oral and in the 28-day inhalation study (primarily at the high dose level) may indicate increased metabolic activity in the liver, which would assist in the excretion of the test material, but could be other adaptive changes as a result of local irritation. 

 

There was no indication, in the studies available, of bioaccumulation of the test material.

In summary, there was limited evidence that Chlorendic Anhydride was absorbed by various exposure routes, with some possible evidence of metabolism, in the toxicity studies. The treatment-related pathological findings seen in the repeat dose toxicity studies were mainly a result of the irritant properties of the material test, but may also indicate distribution. 

         

Absorption

There was no evidence of systemic effects reported in the data provided on the acute oral or dermal toxicity studies, but blood parameter changes observed in the repeat dose oral toxicity study could suggest that absorption takes place orally, although the changes could be adaptive in response to local irritation effects.

 

There is conflicting information relating to the speed of hydrolysis and more work is perhaps needed to confirm the rate of conversion to chlorendic acid on ingestion and whether administration in corn oil or as a feeding study will lead to exposure to the acid.

 

It is assumed that in the stomach, conversion to the acid will occur quickly (minutes – hours) and a the results of work with metabolism of chlorendic acid can be cited as a read-across assessment [ref 1]. This study show rapid absorption (hours) following oral administration of radiolabelled material

 

 

Distribution

Limited systemic effects were observed in the subacute oral toxicity study with changes in blood chemistry and minor findings possibly related to adaptive responses from local irritation to the GI tract. Effects in the GI tracts following dermal exposure may be a result of grooming and were inconclusive.

 

Testing on chlorendic acid demonstrated rapid distribution to the liver, skin, muscle and blood of radiolabelled material, including metabolites.

 

Based on chlorendic acid data, it is therefore possible to conclude that the substance and metabolites, are transported. 

 

 

Metabolism

The substance is not biodegradable suggesting biological stability, but in the mutagenicity studies, the presence of S-9 metabolic activation seemed to reduce the cell toxicity in in-vitro systems, suggesting rapid metabolism to less toxic metabolites. 

 

A metabolism study on the acid form [ref 1] confirmed rapid metabolism. 

 

Excretion

There is no evidence from testing performed that there is subsequent excretion of the absorbed substance or any metabolites formed. However, the metabolism study on the acid form showed rapid excretion (75% in one day), mainly through faeces.

 

 

Conclusion

The absence of specific toxicokinetic data from animal testing on the anhydride means that it is not possible to make firm conclusions concerning the absorption, distribution, metabolism or excretion.

 

However, there is sufficient evidence from the fact that the anhydride rapidly hydrolyses to the acid form to read-across to the data on the acid. A reliable study demonstrates rapid (hours) absorption, distribution, metabolism and excretion. 

 

There is no suggestion that the substance will accumulate in the body.

 

 

References

 

1 Disposition and excretion of chlorendic acid in Fischer 344 rats.

Decad GM,Fields MT.J Toxicol Environ Health.1982 May-Jun;9(5-6):911-20.

 

2 Report on Carcinogens, Twelfth Edition(2011),National Toxicology Program, Department of Health and Human Services