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
Overall assessment factor (AF):
300
Modified dose descriptor starting point:
NOAEL
AF for differences in duration of exposure:
6
AF for other interspecies differences:
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

Analogue Justification:

For the calculation of the DNELs read across has been carried out from Cashew (Anacardium occidentale) Nutshell Extract, Decarboxylated, Distilled (“Distilled Grade”). The studies for distilled grade are considered relevant for read across to distillation residue grade since the two substances:

•Contain the same constituents (cardanol, cardol, 2-methyl cardol, C13 and unidentified phenolics, C17 phenolics and polymeric species), generally in similar proportions.

•Have similar physico-chemical properties in terms of their water solubility, vapour pressure and octanol-water partition coefficient.

Cashew (Anacardium occidentale) Nutshell Extract, Decarboxylated, Distilled (“Distilled Grade”) has a higher proportion of lower molecular weight, more potentially toxicologically active components, (principally cardanol) and lower proportion of more inert polymeric species compared to Distillation Residue Grade. The relative typical proportions of the cardanol and polymeric species in Distilled and Distillation Residue Grades are 78% versus 35% and 2% versus 50% respectively. Therefore, it is considered that distilled grade has the potential to exert greater toxicity within the group of distilled, technical and distilled residue grades (see Section 3.1 - Technological Process) for endpoints relevant to human health and environmental effects. On this basis within the group of distilled, technical and distilled residue grades, the substance Cashew (Anacardium occidentale) Nutshell Extract, Decarboxylated, Distilled represents the potentially most (eco)toxicologically active form.

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
Overall assessment factor (AF):
600
Modified dose descriptor starting point:
NOAEL
AF for differences in duration of exposure:
6
AF for other interspecies differences:
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 other interspecies differences:
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

Analogue Justification:

For the calculation of the DNELs read across has been carried out from Cashew (Anacardium occidentale) Nutshell Extract, Decarboxylated, Distilled (“Distilled Grade”). The studies for distilled grade are considered relevant for read across to distillation residue grade since the two substances:

•Contain the same constituents (cardanol, cardol, 2-methyl cardol, C13 and unidentified phenolics, C17 phenolics and polymeric species), generally in similar proportions.

•Have similar physico-chemical properties in terms of their water solubility, vapour pressure and octanol-water partition coefficient.

Cashew (Anacardium occidentale) Nutshell Extract, Decarboxylated, Distilled (“Distilled Grade”) has a higher proportion of lower molecular weight, more potentially toxicologically active components, (principally cardanol) and lower proportion of more inert polymeric species compared to Distillation Residue Grade. The relative typical proportions of the cardanol and polymeric species in Distilled and Distillation Residue Grades are 78% versus 35% and 2% versus 50% respectively. Therefore, it is considered that distilled grade has the potential to exert greater toxicity within the group of distilled, technical and distilled residue grades (see Section 3.1 - Technological Process) for endpoints relevant to human health and environmental effects. On this basis within the group of distilled, technical and distilled residue grades, the substance Cashew (Anacardium occidentale) Nutshell Extract, Decarboxylated, Distilled represents the potentially most (eco)toxicologically active form.

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