Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.88 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
170
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Modified dose descriptor starting point:
NOAEL
AF for differences in duration of exposure:
6
AF for interspecies differences (allometric scaling):
10
AF for intraspecies differences:
5
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

For the calculation of the DNELs read across has been carried out from the substance Cashew (Anacardium occidentale) Nutshell Extract, Decarboxylated, Distilled (“Distilled Grade”). The justification for read-across from the studies for Distilled and Distillation Residue grades to Technical grade is given below:

Under Annex XI of the REACH Regulation “General rules for adaptation of the standard testing regime set out in Annexes VII to X”, in addition to the specific rules set out in Column 2 of Annexes VII to X, a registrant may adapt the standard testing regime in accordance with the general rules set out in Section 1 of the Annex. One approach that may be used is the grouping of substances and the read-across approach (Section 1.5 of Annex XI). An overall grouping and read-across rationale has been developed for the three grades of cashew nutshell extract. This has involved using data for two source substances Distilled and Distillation Residue grades to read-across the required data for Technical grade by interpolation. In this context interpolation is “the estimation of a value for a member of the group using measured values from other members on both sides of that member within the defined group spectrum”.

The justification for the read-across approach results from the commonality of the constituents and functional groups in the three grades and the common modes of action for specific localised endpoints that are manifest in physico-chemical, environmental fate and toxicological properties that are similar or follow a regular pattern as a result of structural similarity. Further details on the justification for using the interpolation based read-across approach are given in the accompanying document “Report on the development of an updated grouping and read-across rationale for the three grades of processed Cashew Nutshell extract”. The following points are relevant:

•       The three grades are manufactured using a common process in which the unprocessed cashew nutshell extract is heated, which produces Technical grade. Subsequent distillation does not result in the formation of any new constituents in the resulting Distilled and Distillation Residue grades, but rather changes in the proportion of certain constituents relative to those present in Technical grade.

•       In all the three grades the proportions of three out of the five key constituents namely the low boilers, C17 phenolics and high boilers (cardol and 2-methylcardol) are similar. Whilst the lightest, lower molecular weight non-polymeric constituents (such as cardanol) and the highest molecular weight polymeric constituents vary between the grades, Technical grade compositionally lies between Distilled and Distillation Residue grades.

•       For all the physico-chemical parameters for which measured data are available (relative density, vapour pressure, water solubility, octanol-water partition coefficient, flash point and flammability) the values estimated for the target substance Technical grade from the results generated in tests on the source substances Distilled and Distillation Residue grade are consistent with the actual measured values for Technical grade. The consistency of the estimated and measured values for these endpoints for Technical grade indicate that the read-across approach is appropriate and that reliable results can be generated by interpolation from the source substances (Distilled and Distillation Residue grades). In particular, there is consistency for the key physico-chemical parameters which influence toxicological behaviour of the three grades of processed cashew nutshell extract, namely: water solubility, octanol-water partition coefficient (logKow) and vapour pressure.

•       Based on mammalian toxicity studies conducted with Distilled grade, the following points can be concluded regarding the substance. Systemic effects following repeated dosing indicate that Distilled grade is absorbed via the gastro-intestinal tract. The rate and extent of absorption cannot be elucidated from the data available. Only local effects were observed from an acute dermal toxicity study, and also a skin irritation and sensitisation studies. It is likely that the skin barrier will be compromised by the irritation/sensitisation observed following application of Distilled grade, and that some absorption via this route will occur. Systemic effects in the lung, mesenteric lymph nodes, stomach and duodenum were observed, indicating that Distilled grade is distributed throughout the body, however, the extent of such distribution is unknown. There is no data available regarding metabolism or excretion of the Distilled grade.

The conclusions discussed above suggest similar local and systemic toxicity profiles for all the three substances. The use of data from two source substances (Distilled and Distillation Residue grades) to read-across to Technical grade is considered to provide greater confidence in the predicted data for the target substance, as testing at the two ends of the compositional spectrum will reveal the toxicity or lack of toxicity of all the key constituents (including those of their degradation products) which are present in Technical grade.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.25 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Modified dose descriptor starting point:
NOAEL
AF for differences in duration of exposure:
6
AF for interspecies differences (allometric scaling):
10
AF for intraspecies differences:
10
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.25 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Modified dose descriptor starting point:
NOAEL
AF for differences in duration of exposure:
6
AF for interspecies differences (allometric scaling):
10
AF for intraspecies differences:
10
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

For the calculation of the DNELs read across has been carried out from substance is Cashew (Anacardium occidentale) Nutshell Extract, Decarboxylated, Distilled (“Distilled Grade”). The justification for read-across from the studies for Distilled and Distillation Residue grades to Technical grade is given below:

Under Annex XI of the REACH Regulation “General rules for adaptation of the standard testing regime set out in Annexes VII to X”, in addition to the specific rules set out in Column 2 of Annexes VII to X, a registrant may adapt the standard testing regime in accordance with the general rules set out in Section 1 of the Annex. One approach that may be used is the grouping of substances and the read-across approach (Section 1.5 of Annex XI). An overall grouping and read-across rationale has been developed for the three grades of cashew nutshell extract. This has involved using data for two source substances Distilled and Distillation Residue grades to read-across the required data for Technical grade by interpolation. In this context interpolation is “the estimation of a value for a member of the group using measured values from other members on both sides of that member within the defined group spectrum”.

The justification for the read-across approach results from the commonality of the constituents and functional groups in the three grades and the common modes of action for specific localised endpoints that are manifest in physico-chemical, environmental fate and toxicological properties that are similar or follow a regular pattern as a result of structural similarity. Further details on the justification for using the interpolation based read-across approach are given in the accompanying document “Report on the development of an updated grouping and read-across rationale for the three grades of processed Cashew Nutshell extract”. The following points are relevant:

•       The three grades are manufactured using a common process in which the unprocessed cashew nutshell extract is heated, which produces Technical grade. Subsequent distillation does not result in the formation of any new constituents in the resulting Distilled and Distillation Residue grades, but rather changes in the proportion of certain constituents relative to those present in Technical grade.

•       In all the three grades the proportions of three out of the five key constituents namely the low boilers, C17 phenolics and high boilers (cardol and 2-methylcardol) are similar. Whilst the lightest, lower molecular weight non-polymeric constituents (such as cardanol) and the highest molecular weight polymeric constituents vary between the grades, Technical grade compositionally lies between Distilled and Distillation Residue grades.

•       For all the physico-chemical parameters for which measured data are available (relative density, vapour pressure, water solubility, octanol-water partition coefficient, flash point and flammability) the values estimated for the target substance Technical grade from the results generated in tests on the source substances Distilled and Distillation Residue grade are consistent with the actual measured values for Technical grade. The consistency of the estimated and measured values for these endpoints for Technical grade indicate that the read-across approach is appropriate and that reliable results can be generated by interpolation from the source substances (Distilled and Distillation Residue grades). In particular, there is consistency for the key physico-chemical parameters which influence toxicological behaviour of the three grades of processed cashew nutshell extract, namely: water solubility, octanol-water partition coefficient (logKow) and vapour pressure.

•       Based on mammalian toxicity studies conducted with Distilled grade, the following points can be concluded regarding the substance. Systemic effects following repeated dosing indicate that Distilled grade is absorbed via the gastro-intestinal tract. The rate and extent of absorption cannot be elucidated from the data available. Only local effects were observed from an acute dermal toxicity study, and also a skin irritation and sensitisation studies. It is likely that the skin barrier will be compromised by the irritation/sensitisation observed following application of Distilled grade, and that some absorption via this route will occur. Systemic effects in the lung, mesenteric lymph nodes, stomach and duodenum were observed, indicating that Distilled grade is distributed throughout the body, however, the extent of such distribution is unknown. There is no data available regarding metabolism or excretion of the Distilled grade.

The conclusions discussed above suggest similar local and systemic toxicity profiles for all the three substances. The use of data from two source substances (Distilled and Distillation Residue grades) to read-across to Technical grade is considered to provide greater confidence in the predicted data for the target substance, as testing at the two ends of the compositional spectrum will reveal the toxicity or lack of toxicity of all the key constituents (including those of their degradation products) which are present in Technical grade.

A well conducted oral study combining a repeat dose toxicity study with reproduction/developmental toxicity screening has been performed in the rat (Dhinsaet al,2005) using Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade). Sprague-Dawley rats (10/sex/dose) were administered 0, 15, 150 or 1000 mg/kg bw/day via gavage for up to 49 days. The study was conducted to OECD Guideline 422 and to GLP requirements.

Clinical signs, functional observations, bodyweight development and food and water consumption were monitored during the study. Haematology and blood chemistry were also evaluated prior to mating and termination on selected animals from each dose group. Following mating and subsequent gestation, offspring development was monitored up to Day 4post partum.All animals were subject to gross necropsy and histopathological examination.

Increased salivation was detected prior to dosing and up to 5 hours after dosing for animals of either sex treated with 1000 mg/kg bw/day from Day 9 onwards. One female treated with 150 mg/kg bw/day developed clinical signs consistent with inappropriate dosing on Day 5 and was subsequently terminated. One female treated with 1000 mg/kg bw/day had given birth to a number of pups of which the majority were found dead. Several clinical signs were observed in this animal, and the animal and litter were terminated. There were no toxicologically significant deaths during the study.

A slightly reduced bodyweight gain was observed for 1000 mg/kg bw/day males during the first two weeks of the study. Reduced bodyweight gain was also observed for 1000 mg/kg bw/day females during the later stages of the gestation period. Females treated with 1000 mg/kg bw/day showed elevated liver weights. No changes were noted in food consumption, efficiency or water consumption.                               

Haematological assessments revealed elevated platelet counts for animals of either sex treated with 1000 mg/kg bw/day. Elevated haemoglobin, erythrocyte and haematocrit was also evident for males treated at 1000 mg/kg bw/day. No such effects were detected at 150 and 15 mg/kg bw/day. An increase in aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase levels were observed for 1000 mg/kg bw/day animals of either sex, together with elevated inorganic phosphorus, bilirubin and urea, and reduced cholesterol levels.

Open field arena observations revealed increased salivation for individual animals of either sex treated with 1000 mg/kg bw/day from Week 3.                                     

Groups of alveolar macrophages were seen with a higher incidence for females treated with 1000 mg/kg bw/day. A higher incidence of sinus histiocytosis and/or foamy histiocytes was observed in relation to treatment with 1000 mg/kg bw/day. Hyperkeratosis, frequently associated with acanthosis was seen in the forestomach of animals of either sex treated with 1000 mg/kg bw/day. Focal ulceration of the forestomach epithelium was also seen in one high dose female. Mucosal hypertrophy was seen in three males at the top dose group. A low incidence of mucosal hypertrophy was observed in females in all dose groups.

Reproductive and developmental parameters were similar for treated animals and controls.

The observation of changes in the lungs, mesenteric lymph nodes, stomach and duodenum in rats treated with 1000 mg/kg bw/day resulted in a systemic NOAEL of 150 mg/kg bw/day being identified. No adverse effects on reproduction or development were noted, therefore, an arbitrary NOAEL of 1000 mg/kg bw/day has been identified for these endpoints from this study.

         

Information on the toxicokinetics and toxicodynamics of Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade) are not available, therefore assessment (uncertainty) factors for interspecies and intraspecies variation cannot be specifically derived, and therefore, default factors as prescribed in the ECHA guidance will be used.

 

    

A sub-acute (short-term) No Observed Adverse Effect Level (NOAEL) of 150 mg/kg bw/day has been identified from a 28 day repeat dose oral study combined with a reproductive screening test.

Oral

General population

Long-term

A safety assessment factor of 10 will be applied to account for interspecies (rat to human) variation, as per the ECHA Guidance (ECHA, 2008).

A safety assessment factor of 10 will be applied to account for intraspecies variation (between humans in the general population, to include sensitive sub-populations) as per the ECHA Guidance.

In the absence of any long-term repeat dose studies, a safety assessment factor of 6 will be applied to account for use of a sub-acute NOAEL for a chronic DNEL, as per the ECHA Guidance.

Derived No Effect Level (DNELLong-term) for oral exposure = 150/10/10/6 = 0.25 mg/kg bw/day

Worker

Long-term

A safety assessment factor of 10 will be applied to account for interspecies (rat to human) variation, as per the ECHA Guidance (ECHA, 2008).

A safety assessment factor of 5 will be applied to account for intraspecies variation (between workers, therefore not including sensitive sub-populations), as per the ECHA guidance.

In the absence of any long-term repeat dose studies, a safety assessment factor of 6 will be applied to account for use of a sub-acute NOAEL for a chronic DNEL, as per the ECHA Guidance.

Derived No Effect Level (DNELLong-term) for oral exposure = 150/10/5/6 = 0.5 mg/kg bw/day

Dermal

Data obtained indicate that in 2 out of 4 tests, Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade) samples are irritating to the skin and sensitising. A sub-acute or chronic dermal study is not available.

The United Kingdom Interdepartmental Group on Health Risks from Chemicals document entitled ‘Guidelines on route-to-route extrapolation of toxicity data when assessing health risks of chemicals’ (IGHRC, 2006) states that oral to dermal extrapolation is common for industrial chemical and pesticide exposure. This document assumes that dermal bioavailability is less than oral (i.e. less substance will be absorbed via the skin due to its barrier properties), therefore, using the oral data is precautionary, providing that the skin is not compromised by the substance being a severe irritant and causing increased absorption through a more permeable barrier. Although a skin irritant and sensitiser, Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade) is not considered to be a ‘severe irritant’, therefore, equivalent bioavailability can be assumed for oral and dermal exposure to provide a precautionary DNEL. The approach used in the IGHRC document is that used in the ECHA Guidance and is widely referenced.

A sub-acute (short-term) NOAEL of 150 mg/kg bw/dayhas been identified from a 28 day repeat dose oral study combined with a reproductive screening test.

General population

Long-term

A safety assessment factor of 10 will be applied to account for interspecies (rat to human) variation, as per the ECHA Guidance (ECHA, 2008).

A safety assessment factor of 10 will be applied to account for intraspecies variation (between in the general population, to include sensitive sub-populations) as per the ECHA Guidance.

In the absence of any long-term repeat dose studies, a safety assessment factor of 6 will be applied to account for use of a sub-acute NOAEL for a chronic DNEL, as per the ECHA Guidance.

Derived No Effect Level (DNELLong-term) for dermal exposure = 150/10/10/6 = 0.25 mg/kg bw/day

Worker

Long-term

A safety assessment factor of 10 will be applied to account for interspecies (rat to human) variation, as per the ECHA Guidance (ECHA, 2008).

A safety assessment factor of 5 will be applied to account for intraspecies variation (between workers, therefore not including sensitive sub-populations), as per the ECHA guidance.

In the absence of any long-term repeat dose studies, a safety assessment factor of 6 will be applied to account for use of a sub-acute NOAEL for a chronic DNEL, as per the ECHA Guidance.

Derived No Effect Level (DNELLong-term) for dermal exposure = 150/10/5/6 = 0.5 mg/kg bw/day

It should be recognised that in addition to defining a dermal DNEL, consideration should be given to whether it would be more relevant to assess and control the risk(s) of dermal exposure.

Inhalation

A sub-acute or chronic inhalation study is not available. In order to derive an inhalation DNEL, data can be converted from oral studies.

A sub-acute (short-term) NOAEL of 150 mg/kg bw/day has been identified from a 28 day repeat dose oral study combined with a reproductive screening test.

General population

Long-term

To convert the rat NOAEL (NoObservedAdverse Effect Level) to human NAEL (No Adverse Effect Level) for interspecies variation (rat to human), a factor of 1.15 will be applied to account for the standard breathing volume of the rat for 24 hours, as per the ECHA Guidance (ECHA, 2008).

An adjustment of x10/100% (oral absorption/inhalation absorption) will be applied to account for assumed bioavailability via the inhalatory route compared with the oral route (i.e. low oral absorption as low toxicity seen via this route and has to pass into blood stream from the intestines versus high absorption straight from the lungs) (IGHRC, 2006).

A safety assessment factor of 10 will be applied to account for intraspecies variation (between humans in the general population, to include sensitive sub-populations) (ECHA, 2008).

In the absence of any long-term repeat dose studies, a safety assessment factor of 6 will be applied to account for use of a sub-acute NOAEL for a chronic DNEL, as per the ECHA Guidance.

Derived No Effect Level (DNELLong-term) for inhalation exposure = 150/1.15x0.1/10/6 = 0.2mg/m3

General population (consumers with 4 hours exposure per day)

Long-term

To convert the rat NOAEL (NoObservedAdverse Effect Level) to human NAEL (No Adverse Effect Level) for interspecies variation (rat to human), a factor of 0.19 will be applied to account for the standard breathing volume of the rat for 24 hours, as per the ECHA Guidance (ECHA, 2008).

An adjustment of x10/100%(oral absorption/inhalation absorption) will be applied to account for assumed bioavailability via the inhalatory route compared with the oral route (i.e. low oral absorption as low toxicity seen via this route and has to pass into blood stream from the intestines versus high absorption straight from the lungs) (IGHRC, 2006).

A safety assessment factor of 10 will be applied to account for intraspecies variation (between humans in the general population, to include sensitive sub-populations) (ECHA, 2008).

In the absence of any long-term repeat dose studies, a safety assessment factor of 6will be applied to account for use of a sub-acute NOAEL for a chronic DNEL, as per the ECHA Guidance.

Derived No Effect Level (DNELLong-term) for inhalation exposure = 150/0.19x0.1/10/6 = 1.32mg/m3

Worker

Long-term

To convert the rat NOAEL (NoObservedAdverse Effect Level) to human NAEL (No Adverse Effect Level) for interspecies variation (rat to human), a factor of 0.38 will be applied to account for the standard breathing volume of the rat for 8 hours, as per the ECHA Guidance (ECHA, 2008).

An additional conversion for workers of 6.7m3/10m3to account for caloric demand during light activity will be applied.

An adjustment of x10/100% (oral absorption/inhalation absorption) will be applied to account for assumed bioavailability via the inhalatory route compared with the oral route. (i.e. low oral absorption as low toxicity seen via this route and has to pass into blood stream from the intestines versus high absorption straight from the lungs) (IGHRC, 2006).

A safety assessment factor of 5 will be applied to account for intraspecies variation (between workers, therefore not including sensitive sub-populations) (ECHA, 2008).

In the absence of any long-term repeat dose studies, a safety assessment factor of 6will be applied to account for use of a sub-acute NOAEL for a chronic DNEL, as per the ECHA Guidance.

Derived No Effect Level (DNELLong-term) for inhalation exposure = 150/0.38x0.67x0.1/5/g = 0.88mg/m3