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Survey and health assesment of chemicals substances in pleasure gel

5 Health Assessment

• 5.1 Introduction
• 5.2 Method
• 5.3 Selected substances
  • 5.3.1 Camphor
  • 5.3.2 Cinnamaldehyde
  • 5.3.3 Eugenol
  • 5.3.4 D-Limonene
  • 5.3.5 Linalool
  • 5.3.6 2-Phenoxyethanol
  • 5.3.7 α-Pinene
• 5.4 Overall Assessment
  • 5.4.1 Substances
  • 5.4.2 Products

5.1 Introduction

In this section, the potential health effects from identified and selected substances are assessed. The assessment is aimed at adults only.

For each of the identified and quantified substances information of the substances’ identity as well as chemical and physical properties are presented. This will include data on material state, melting point, boiling point, density, vapour pressure and solubility.

A search in the open literature has been performed with focus on the ability of skin absorption and effects by oral intake and the most important test results, the effects, and circumstances are presented in this report. The aim has been to find data for NOAEL/LOAEL (No or Low Observed Adverse Effect Levels) for the selected substances or other relevant data, if available.

Based on NOAEL or similar data and the amount of the substances the margin of safety (MOS) can be calculated, and it can be assessed whether the substances of the tested products may cause a negative health effect.

5.2 Method

It is assumed that the substances can be absorbed in the body by oral intake and by penetration through skin and mucous membranes.

None of the product labellings give directions on recommended amounts to use. For assessment and comparison purposes it is assumed that the same amount of product is used per day. The amount used is based on the TGD (2003) setting 1 g product per day for general purpose creams.

Regarding exposure, two scenarios have been selected:

A.     One scenario, where 1 gram of product is ingested per day. It is assumed that 100 percent of the substances are absorbed to the body.

B.     One scenario, where 1 gram of the product is absorbed through the skin or mucous membranes. It is assumed that 100 percent of the substances are absorbed by the body.

The exposure scenarios are defined according to the EU's Technical Guidance Document (TGD, 2003).

The uptake is calculated as:

Intake per day per kg body weight =

Content of substance × [mg/gram] * 1 gram per day / body weight [kg]

The body weight (b.w.) is assumed to be 70 kg.

There is no variable for “fraction absorbed” because is it assumed to be “1” (100 %) in all scenarios.

The equation can be reduced to:

Intake per day per kg b.w. = 0.0143 * Content of substance × [mg/kg b.w.]

The intake per day has then to be compared with data for oral intake and, if available, with data for absorption through skin and mucous membranes.

Evaluation of risk

In the evaluation of health risks the calculated intake has to be compared with the NOAEL or similar values. As NOAEL typically is based on tests on animals a safety factor (MOS:Margin of safety) is introduced by dividing NOEAL in mg/kg b.w by the intake.

If the data for animals is a chronic long term study of high quality the safety factor in the risk assessment is typically MOS=100. This is based on a factor of 10 for extrapolation between species (interspecies) and a factor of 10 meant to protect sensitive individuals like children (intraspecies). If the data is of less quality etc. based on LOAEL or a subchronic study an additional safety factor is applied (typically 10). The total safety factor is the combined product of the individual safety factors.

5.3 Selected substances

The substances described in the following subsections are selected as the most significant substances for potential health risks.

5.3.1 Camphor

5.3.1.1 Identity

Name	Bornan-2-one
CAS-number	76-22-2
EINECS number	200-945-0
Molecular formula	C10H16O
Molecular structure
Molecular weight	152.23
Synonyms	Bicyclo(2.2.1)heptan-2-one, 1,7,7-trimethyl- 1,7,7-Trimethylbicyclo(2.2.1)heptan-2-one 2-Bornanone Gum camphor Spirit of camphor

The substance consists of colourless or white crystals. It has a boiling point of 204°C and a melting point of 179°C (The Merck Index, 1983).

The substance is more soluble in organic solvents than in water. Yalkowsky and Yan (2003) state that 1.6 gram of camphor can be dissolved in 1 litre water at 25°C. In another reference the following is given: At 25°C one gram dissolves in about 800 ml water, in 1 ml alcohol, 1 ml ether, 0.5 ml chloroform. The substance is freely soluble in carbon disulphide, petroleum, fixed and volatile oils. It is also soluble in concentrated mineral acids, in phenol, in liquid ammonia, and in liquid sulphoxide (O'Neil, M.J., 2001).

The partition coefficient Log K_OW is determined to be 2.38 (Daylight Chemical Information Systems, 2004).

Vapour pressure is determined to be 0.65 mm Hg @ 25°C (Jones AH, 1960).

Some values are given for odour threshold values. The lowest odour value is 0.0026 ppm and the highest is 0.96 ppm. Both odour values are below TLV (Haz-map, 2005).

5.3.1.2 Detected quantities

The substance is detected in two products. In sample no. 6, 900 mg/kg has been detected and in sample no. 25 only 3.9 mg/kg.

5.3.1.3 Function of substance

The substance is included in the INCI-database. Here it is stated that the function of the substance can be denaturants / film formers and as a fragrance. O'Neil, M.J. (2001) states that the substance is normally used as an odorant and flavourant and it can be used as emollient in cosmetics and as a preservative.

5.3.1.4 Classifications and TLV’s

This chemical substance is not classified in the Annex I of Directive 67/548/EEC.

The Danish threshold limit value is 2 ppm equal to 12 mg/m³. The same limit is set in USA (ACGIH, 2005).

5.3.1.5 Health Effects

Data regarding health effects has been retrieved from TOXNET and the databases related to this host. The substance is not included in IUCLID.

Acute toxicity

The substance is irritating to the eyes, the skin, and the respiratory tract (IPCS, 2003). Camphor applied to the skin of volunteers as a 20% solution in alcohol produced no significant sensation of irritation or pain at normal skin temperatures. It did appear to have a slight sensitising effect on the perception of temperature change during heating and cooling, and increased the sensation of burning at high temperatures (National Poisons Information Service Center, 1996).

Acute toxicity by ingestion based on test with animals indicates that camphor may be slightly toxic:

• LD₅₀ Mouse oral 1,310 mg/kg  (Lewis, R.J. 1996)
• LD₅₀ Rat subcutaneously 70 mg/kg  (Lewis, R.J. 1996)
• LD₅₀ Mouse ip 3,000 mg/kg (ACGIH, 2001)

Several exposure studies with humans have been reported. In one study, 1.5 g camphor has been ingested in an adult, who recovered. In children 0.7 to 1.0 g has proved fatal. Urinary retention, albuminuria, and anuria are described in non-fatal cases, but kidney lesions in fatal poisonings are not always prominent. Mild and transient hepatic derangements may occur and widespread hemorrhages are described in one fatal case. Fetal death resulted after camphor ingestion by mother and postmortem exam revealed severe atelectasis and central neuronal necrosis (Gosselin et al., 1984).

Camphor remains in over 950 products listed in Poisindex. A review of all camphor ingestions estimated to be 2 mg/kg or greater was made. Seventy-three patients (90%) remained asymptomatic, three (4%) developed minor symptoms, and five (6%), all ingesting over 59 mg/kg, developed major symptoms. There were no deaths reported (Geller RJ et al., 1984).

From IPCS, Poisons Information Monograph the following has been retrieved

• Camphor crosses the placenta and has been implicated in fetal and neonatal death. It has been used to induce abortions. Camphor poisoning during pregnancy was reported in four cases and, in each case, camphorated oil was mistaken for castor oil. The topical use of camphorated oil in pregnancy was not associated with teratogenic effects.
• Deafness has been reported in association with camphor. Ulceration of the mucous membranes has been reported following the use of toothache solutions containing camphor (along with menthol, phenol, clove oil and chloroform).
• Camphor administered in doses of 60 mg to 4 g was reported to cause flickering, darkening or veiling of vision along with noises in the ears. Corneal erosions have been reported in association with the use of inhalant capsules containing camphor.

Sub-chronic toxicity

D-Camphor elicited no evidence of teratogenicity when administered orally during the fetal period of organogenesis to pregnant rats at doses up to 1,000 mg/kg b.w./day, and to pregnant rabbits at doses up to 681 mg/kg b.w./day. The NOEL for the fetal organism for the rat was above 1,000 mg/kg b.w., and for the rabbit above 681 mg/kg b.w. (Leuschner J, 1997).

Chronic toxicity

With chronic dermal exposure, systemic effects and contact dermatitis can occur as well as significant allergic responses. Ocular exposure results primarily in irritation only, although oral intake has been associated with visual problems (Ford MD et al., 2001).

Camphor is classified as “A4; Not classifiable as a human carcinogen” (ACGIH, 2005).

Summary

Only values for NOEL for teratogenicity are given for short term studies with animals. The lowest value was 680 mg/kg b.w. per day.

Observations on humans showed that ingestion of 2 mg/kg b.w. gave none or minor symptoms.

References show that camphor may cause irritation by skin contact and may by chronic exposure cause allergies.

5.3.1.6 Exposure scenarios

The maximum content in a sample was 900 mg/kg equal to 0.9 mg per gram.

Intake per day per kg b.w. = 0.0143 * 0.9 = 0.013 mg/kg b.w.

It is assumed that the estimated amount can either be ingested or absorbed through skin or membranes.

5.3.1.7 Assessment

Camphor is a substance that may cause irritations and allergies by skin contact. It may be toxic if ingested in relative large amounts - more than 1 mg/kg b.w. Camphor may cause teratogenic effects; NOEL based on a subacute test is estimated to 680 mg/kg. Indications for other long term effects have not been found.

Camphor has been detected in two samples. Based on intake of 1 gram of product the maximum daily uptake will be 0.01 mg per kg b.w.

Based on the data for teratogenicity a marginal of safety (MOS) is more than 50,000. Compared with the observations on humans with 2 mg/kg b.w. MOS is 200. From this it can be concluded that oral ingestion will cause no health risks.

Based on the available data there is a risk that camphor may cause irritations and allergic reactions.

5.3.2 Cinnamaldehyde

5.3.2.1 Identity

Name	Cinnamaldehyde
CAS-number	104-55-2
EINECS number	203-213-9
Molecular formula	C9H8O
Molecular structure
Molecular weight	132.15
Synonyms	2-Propenal, 3-phenyl- 3-Phenyl-2-propenal Cinnamaldehyde Cinnamic aldehyde

Cinnamaldehyde is a yellow oily liquid with a strong odour of cinnamon (Budavari, S. 1989). The boiling point is 253°C at 760 mm HG and the melting point is -7.5°C (Lide, DR 1990).

The partition coefficient Log K_OW is estimated to be 1.90 (Hansch et al., 1995).

The vapour pressure is 1 mmHg at 25°C. The substance is soluble in most organic solvents. Water solubility is 1.42 g/l at 25°C (Valvani, 1981).

5.3.2.2 Detected quantities

The substance is detected in large amounts in two products and in small amounts in one product.

In sample no. 4 6,200 mg/kg equal to 0.62 weight percent has been detected. In sample no. 6 17,000 mg/kg equal to 1.7 weight percent has been detected. In sample no. 7 only 270 mg/kg has been detected.

5.3.2.3 Function

In general, cinnamaldehyde is added to food and beverage as a cinnamon flavour and as a perfume.

Cinnamaldehyde is included in INCI as a denaturant, which means that the substance is mostly added to products containing ethanol in order to render them unpalatable.

5.3.2.4 Classifications and TLV’s

This chemical substance is not classified in the Annex I of Directive 67/548/EEC.

The substance is included in the EU-list of allergenic perfumesubstances (SCCNFP, 1999).

Cinnamaldehyde is included in the Danish advisory list for classification (Vejledende liste ,2001) with the classification:

R43        May cause sensitization by skin contact.

N;R50    Hazardous to the environment; Very toxic to aquatic organisms.

DSM Special products BV advises a provisional TLV of 5 ppm to prevent irritation and toxic effects (IUCLID, 2000). No other data for TLV was found.

5.3.2.5 Health Effects

Data regarding health effects has been retrieved from TOXNET and the databases related to this host. Data from IUCLID has been included as well as from other sources.

Acute toxicity

Cinnamaldehyde is known to be an irritant and causes allergy. From the EU-study on allergens (SCCNFP, 1999) it is concluded:

• The substance causes allergic reactions in 2-3 percent of the tested patients.
• It causes allergic reactions in 1-30 percent in patients with eczema from cosmetic products.
• The test concentration is 1 percent - higher concentrations may cause irritations.

Test for irritation has shown that the highest non-irritating concentration of cinnamaldehyde was 0.5 percent in vaseline and 1 percent in acetone (IUCLID, 2000).

Regarding oral intake a few older data is reported in IUCLID. LD₅₀ is determined to be between 1,160 to 3,400 mg/kg for rats, mice and guinea pigs. For acute dermal toxicity values of more than 2,000 mg/kg was reported for rats and rabbits.

Cinnamaldehyde is regarded as moderately toxic (Gosselin et al., 1984). Probable oral lethal dose for humans is 0.5 to 5 gram per kg b.w.

Sub-chronic toxicity

In a 16 weeks test from 1964 rats were orally fed with 1, 2.5 and 10 gram per kg bw (IUCLID, 2000). NOAEL was determined to be 2.5 gram per kg b.w. LOAEL was determined to be 10 gram per kg b.w. At this dose level hyperkeratosis of the fore stomach and light swelling of hepatic cells were observed.

Cinnamaldehyde was evaluated for developmental toxicity in a short-term in vivo animal bioassay. In this assay, pregnant mice were dosed with the test agent in mid-pregnancy and allowed to go to term. Observations were then made on litter size as well as the birth weight, neonatal growth, and survival of pups as indicators of developmental toxicity. Forty-nine pregnant CD-1 mice were given 1200 mg/kg/day cinnamaldehyde in corn oil by gavage on days 6-13 of gestation and were allowed to deliver. No toxic effect was observed in the dams or in their offspring for the parameters assayed (Hardin et al., 1987).

In another short-term for developmental toxicity, rats were exposed from day 7 to day 17 of gestation with doses of 5, 25 and 250 mg/kg. NOAEL for the adult was determined to be 5 mg/kg and less than 5 mg/kg for the foetuses, because they were slightly more sensitive (IUCLID, 2000).

Chronic toxicity

In the database NCI Chem. Carcinogenesis Res Info System 5 negative results of Ames test is reported.

A two-generation study on reproduction toxicity from 1965 is reported in IUCLID. Based on exposure for 433 days with a dose of 5 mg/kg b.w. NOAEL for the parents were 5 mg/kg and less than 5 mg/kg for first and second generation offspring’s. Only observed effects were increased lipid content in the liver of the offspring’s.

The Joint FAO/WHO Expert Committee on Food Additives (1967) published a monograph and specifications, given a conditional Acceptable Daily Intake of 0 to 1.25 mg/kg.

Summary

Cinnamaldehyde causes irritations to skin in concentrations of more than 1 percent. The substance also causes sensitization by skin contact.

Sub-acute and chronic test for reproduction toxicity shows a NOAEL of 5 mg/kg b.w. for the adults (parental generation) and less than 5 mg/kg for foetus / 1^st and 2^nd generation of offspring.

No other data on long term effects has been found.

A value for ADI is referred to be from 0 to 1.25 mg/kg.

5.3.2.6 Exposure scenarios

The maximum content in sample no. 6 was 17,000 mg/kg equal to 17 mg per gram.

Intake per day per kg b.w. = 0.0143 * 17 = 0.243 mg/kg b.w.

For sample no. 4:

Intake per day per kg. b.w. = 0.089 mg/kg b.w.

It is assumed that the estimated amount can either be ingested or absorbed through skin or membranes.

5.3.2.7 Assessment

Regarding skin irritation the content of 0.6 w% and 1.7 w% may cause irritation. It is shown that skin contact causes allergic reactions in 2-3 percent of all people. People with eczema from cosmetic products are more sensitive.

Regarding intake of products with cinnamaldehyde the maximal intake is less than 0.1 mg/kg b.w. The ADI is 0-1.25 mg/kg.

NOAEL for reproductive toxicity is 5 mg/kg b.w., which gives a marginal of safety of more than 500.

It can be concluded that cinnamaldehyde in sample 4 and 6 may cause irritation to skin and mucous membranes. It is also likely to expect that skin contact may cause allergies. Intake will not cause any major health problems and no long term effects besides allergies can be expected.

5.3.3 Eugenol

5.3.3.1 Identity

Name	Eugenol
CAS-number	97-53-0
EINECS number	202-589-1
Molecular formula	C10H12O2
Molecular structure
Molecular weight	164.2
Synonyms	2-Methoxy-4-(2-propenyl)phenol Allylguaiacol Phenol, 2-methoxy-4-(2-propenyl)-

Eugenol is a colourless or pale yellow liquid with an odour of cloves. The substance has a boiling point of 253°C and a melting point of -9.2°C. (Budavari, 1989).

The partition coefficient Log K_OW is 2.27 (Sangster, 1994).

Eugenol has a solubility in water of 2.43 gram per litre (Yalkowsky, 1992).

The substance is soluble in most organic solvents.

5.3.3.2 Detected quantities

Eugenol is detected in 4 products. In sample no. 6 was found 18 000 mg/kg equal to 1.8 weight percent. 3 samples held relatively small amounts, - sample no. 4 500 mg/kg, no. 7 380 mg/kg and sample no. 27 830 mg/kg.

5.3.3.3 Function

Eugenol is principally used as a fragrance and flavouring agent, as an analgesic in dental materials and non-prescription drug products, as an insect attractant, and as a chemical intermediate (IARC, 1985).

Eugenol is included in INCI as a denaturant, which means that the substance is mostly added to products containing ethanol in order to render them unpalatable.

5.3.3.4 Classifications and TLV’s

This chemical substance is not classified in the Annex I of Directive 67/548/EEC.

The substance is included in the EU-list of allergenic perfume substances (SCCNFP, 1999).

With respect to the Statutory Order on cosmetic products (Cosmetics, 2006) it has to be mentioned, that eugenol must be specified on the product contents list, when the concentration of eugenol exceeds

-        0.001% in products which are not cleaned off after use

-        0.01% for products which are cleaned off

5.3.3.5 Health Effects

Acute toxicity

In IARC (1985) data for acute oral intake is given. LD₅₀ for rats is 1,930 mg/kg, for mice it is 3000 mg/kg and for guinea pigs it is 2,130 mg/kg. It means that eugenol is slightly harmful by ingestion.

Dogs given oral doses of 0.25 g/kg of eugenol demonstrated vomiting, weakness, lethargy, and ataxia. At 0.5 g/kg eugenol is capable of causing coma and death within 24 hr. The LD₅₀ in eugenol in rats has been determined to be 1.8 ml/kg (1.93 g), with post-mortem findings consistent with sudden cardiovascular collapse (Haddad, 1990).

No relevant data for irritations caused by skin contact has been found.

Eugenol is one of 8 constituents of a fragrance mix that is used for diagnosing contact allergy to fragrances (SCCNFP, 1999). 1.2 percent of a group of test patients had a positive reaction to 1% eugenol. People with eczema from cosmetic products are more likely to react positively with allergic reactions to eugenol.

Sub-chronic toxicity

Some sub-chronic tests are briefly described in Patty’s Industrial Hygiene (Clayton and Clayton, 1981).

• A test with rats given daily doses of 900 mg/kg b.w. showed minor liver damages. No liver damages were observed in rats fed with 1% eugenol in the diet for about 4 month. Exposure to 0.1 or 1% in the diet to rats for 19 weeks exhibited no effects. No effects were seen in rats fed 79.3 mg/kg per day for 12 weeks. NOAEL is 79.3 mg/kg with liver damages as the critical effect.
• Twenty male rats were given an oral dose of 1.4 gram per kg, gradually increasing to 4 gram per kg. Fifteen of the rats lived long enough to receive maximal dose. Enlargement of liver and adrenal glands were observed.

In a survey of lip care products (Larsen JR and Holmberg RD, 2005) it is stated that LOAEL is 960 mg/kg b.w. also based on liver effects.

Chronic toxicity

IARC (1987) has classified eugenol as group 3: The agent is not classifiable as to its carcinogenicity to humans.

In the database Gene-tox, 3 tests are mentioned. One micro-nucleus test was positive. A Sister-chromatid exchange (SCE) in vitro showing no conclusion and a Forward and reverse gene mutation, also showed no conclusion. Therefore, the substance has a slight risk of gene-toxic effects.

No other data regarding long-term effects has been found.

Summary

Eugenol is a substance that by skin contact may cause allergy. It may be harmful if swallowed in large quantities. No indications for long-term effects have been seen. NOAEL is estimated to 79 mg/kg b.w. per day based on liver effects. LOAEL is estimated to 960 mg/kg b.w. per day.

5.3.3.6 Exposure scenarios

The maximum content in sample no. 6 was 18,000 mg/kg equal to 18 mg per gram.

Intake per day per kg b.w. = 0.0143 * 18 = 0.26 mg/kg b.w.

The content in sample 27 was 830 mg/kg:

Intake per day per kg. b.w. = 0.01 mg/kg b.w.

It is assumed that the estimated amount can either be ingested or absorbed through skin or membranes.

5.3.3.7 Assessment

Regarding skin contact, the content of 1.8 w% may cause allergy. It is shown that skin contact causes allergic reactions in 1-2 percent of all people. People with eczema from cosmetic products are more sensitive.

NOAEL for liver damages is 79 mg/kg b.w. which gives a margin of safety of 300 for sample no. 6 and a margin of safety for the other samples of 8,000 or more.

It can be concluded that eugenol may cause allergies by skin contact for sample no. 6. Intake will not cause any major health problems and no long-term effects besides allergies can be expected.

5.3.4 D-Limonene

5.3.4.1 Identity

Name	D-Limonene
CAS-number	5989-27-5
EINECS number	227-813-5
Molecular formula	C10H16
Molecular structure
Molecular weight	136.23
Synonyms	(+)-(4R)-Limonene (+)-4-Isopropenyl-1-methylcyclohexene (+)-Dipentene (+)-Limonene Citrene (+)-alpha-Limonene (+)-p-Mentha-1,8-diene

D-Limonene is a liquid with a fresh citrus odour. The substance has a boiling point of 176°C (Budavari, 1989) and a melting point of -74.35°C (Lide, 1992).

The vapour pressure is 1.44 mmHg (Hansen and Eggert, 2003). Solubility in water is 13.8 mg/litre at 25°C. The partition coefficient Log K_OW is measured to 4.57.

5.3.4.2 Detected quantities

D-Limonene was found in 9 products. The largest amount was found in sample 6, where 400 mg/kg equal to 0.04 w% was detected. In two other samples the amount was also relative high, - sample no. 27 150 mg/kg and sample no. 30 220 mg/kg. In sample no. 3, 4, 7, 15 29 and 32 between 5 and 100 mg/kg were detected.

5.3.4.3 Function

D-Limonene is used as a fragrance in cosmetics and as a flavouring agent in food and beverage.

D-Limonene is included in INCI as a fragrance.

5.3.4.4 Classifications and TLV’s

D-Limonene is included in the list of dangerous substances and classified as:

R10                Flammable

Xi; R38          Irritant; Irritating to skin.

R43                May cause sensitization by skin contact.

N; R50/53      Dangerous for the environment; Very toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment.

A general TLV is given for terpenes, 25 ppm equivalent to 140 mg/m³ (C.0.1, 2005). No specific values have been found for d-limonene.

The substance is included in the EU-list of allergenic perfume substances (SCCNFP, 1999).

5.3.4.5 Health Effects

D-Limonene is included in IUCLID, but the data sheet consists of relatively few data. The following is based on the data sheet, data bases in TOXNET and two previous survey reports, - one on printed matter (Hansen OC and Eggert T, 2003) and one on stain removers (Engelund et al., 2004).

Acute toxicity

Data for acute toxicity by ingestion is determined by LD₅₀ to more than 4000 mg/kg. This indicates no major potential health risk (Hansen and Eggert, 2003).

Oxidisation products of d-limonene are strong allergens. A number of cases of contact allergy from occupational exposures to d-limonene are reported. The frequency of contacts allergy to oxidised limonene is 1-2 % in consecutive eczema patients. The relationship between contact allergy to oxidised d-limonene and fragrances in cosmetic products need to be further examined (SCCNFP, 1999).

Chronic toxicity

There is inadequate evidence for carcinogenicity in humans. There is evidence for carcinogenicity in animals, but the mechanism is not relevant for humans. Therefore D-Limonene is not classifiable as to its carcinogenicity to humans (Group 3) (IARC, 1999).

Data for NOAEL and LOAEL is included in the report on stain removers (Engelund et al., 2004). Data are given for ingestion with liver damage as the critical effect.

        NOAEL: 250 mg/kg b.w. per day

        LOAEL:  500 mg/kg b.w. per day

The type of test that the data is based upon is not described in the reference.

IUCLID do no provide data for estimating NOAEL or similar threshold limits for ingestion or dermal uptake. The same applies for TOXNET data bases.

Summary

D-Limonene is a substance that by skin contact may cause allergy. It is not harmful by ingestion and there has been found no indication for long-term effects. NOAEL is 250 mg/kg (liver damages) and LOAEL is 500 mg/kg (liver damages).

5.3.4.6 Exposure scenarios

The maximum content in sample no. 6 was 400 mg/kg equal to 0.4 mg per gram.

Intake per day per kg b.w. = 0.0143 * 0.4 = 0.006 mg/kg b.w.

Because of the relative high value of Log K_OW (>4) it seems reasonable to expect that not 100% of the substance will be absorbed by skin contact.

5.3.4.7 Assessment

After oxidation of D-Limonene the substances formed are allergens. The relative low content of d-limonene (0.04 w%) may cause allergy.

NOAEL for liver damages is 250 mg/kg b.w. which gives a margin of safety of more than 4000 for sample no. 6 and higher for the remaining samples.

It can be concluded that D-Limonene might cause allergies by skin contact. It is assumed that the risk is minor because of the relative low concentrations. Intake will not cause any major health problems and no long-term effects besides allergies can be expected.

5.3.5 Linalool

5.3.5.1 Identity

Name	Linalool
CAS-number	78-70-6
EINECS number	201-134-4
Molecular formula	C10H18O
Molecular structure
Molecular weight	154.24
Synonyms	1,6-Octadien-3-ol, 3,7-dimethyl- 2,6-Dimethyl-2,7-octadien-6-ol 2,7-Octadien-6-ol, 2,6-dimethyl- 3,7-Dimethyl-1,6-octadien-3-ol Linalyl alcohol

Linalool has an odour similar to bergamot oil and French lavender. It has a boiling point of 195°C (Lewis, 1993). The melting point is less than 25°C.

The partition coefficient Log K_OW is 2.97 (Li J, Perdue EM, 1995). The water solubility of linalool is 1590 mg/litre (Yalkowsky and Dannenfelser, 1992). The vapour pressure is 0.16 mm Hg 25°C (ChemIDplus).

5.3.5.2 Detected quantities

Linalool was found in 9 products. The largest amount was found in sample no. 2 and 30, where 1400 mg/kg equal to 0.14 w% was detected. In two other samples the determined amounts were also relative high, - sample no. 6 1200 mg/kg and sample no. 27 1300 mg/kg. In sample no. 4, 7, 15, 29 and 32 between 10 and 100 mg/kg were detected.

5.3.5.3 Function

Linalool is used in perfume, as a synthetic flavouring agent, and modifier in citrus and carbonated beverages and by natural occurrence. The general population can be exposed dermally and by inhalation to linalool through foodstuffs and various household products.

Linalool is included in INCI as a deodorant and additive.

5.3.5.4 Classifications and TLV’s

This chemical substance is not classified in the Annex I of Directive 67/548/EEC.

The substance is included in the EU-list of allergenic perfume substances (SCCNFP, 1999).

With respect to the Statutory Order on cosmetic products (Cosmetics, 2006) it shall be mentioned that linalool must be specified on the product declaration, when the concentration of linalool is more than

-        0.001% in products which are not cleaned off after use

-        0.01% for products which are cleaned off

5.3.5.5 Health Effects

For linalool an IUCLID data-set, data in HSDB, CCRIS and ChemIDplus in TOXNET and a description of the substance in Survey of lip care products has been detected (Larsen & Holmberg, 2005).

Acute toxicity

Acute oral toxicity for rats, LD₅₀ is determined to be between 2,790 and 4,180 mg/kg. For acute dermal toxicity, LD₅₀ is more than 5,000 mg/kg (IUCLID, 2000).

Linalool is absorbed through the skin and effectively excreted, mainly through the kidneys. A 60 kg man was massaged 10 minutes with lavender oil (amount not given) at a 376 cm² skin area resulted in a calculated absorption of 7.24 mg linalool. After 5 minutes linalool was detected in the blood and after 20 minutes the concentration was 211ng/ml. After 90 minutes no linalool was detected in the blood stream (IUCLID, 2000).

In IUCLID several tests for skin irritation were reported - some positive and some negative. Reported tests for eye irritation showed no irritation.

Linalool was evaluated for primary dermal irritation (Rhone-Poulenc Inc, 1992). The test substance was applied (0.5 ml) to the occluded-shaved skin of 6 New Zealand white rabbits per concentration at 100%; 30%; 10%; or 3% for 24 hours. The test substance was slightly irritating at 100% and 30%; and no irritation was noted at 10% and 3%. Linalool was also evaluated for primary eye irritation. The test substance was applied (0.1 ml) to the conjunctive sac of 6 New Zealand white rabbits per concentration at 100%; 30%; 10%; or 3%. Irritation was moderate at 100%, slightly at 30%; very slightly at 10%; and no irritation at 3%.

Linalool is a potential allergen. One study with one case and one study with 3 cases of contact allergy to linalool were found among patients with eczema from cosmetic products (SCCNFP, 1999).

Chronic toxicity

In the survey of lip care products (Larsen & Holmberg, 2005), a description of tests based on repeated exposure is given. The main results from this description are:

• Oral exposure of 500 mg/kg b.w. per day and more led to enzyme changes in liver and increased liver weight.
• A NOAEL of 50 mg/kg b.w. per day is based on a 90 day oral exposure study with rats. Reduced food intake and growth was observed. These effects were attributed to poor tasting food.
• A 13 week dermal exposure study with rats established a NOAEL of 250 mg/kg b.w. per day with effects such as momentary blushing and reduced activity as critical effects.
• A study with mice exposed orally 5 days with 375 mg/kg b.w. per day no effects were observed.
• Linalool has been stated as possibly having effects on the liver in humans at chronic or repeated exposure.
• No data for mutagenicity or other long-term effects has been found.

Summary

Linalool may be irritating by skin and eye contact and the substance causes allergy. NOAEL is 50 mg/kg b.w. per day with liver damage as the critical effect. No data for other long-term effects has been found.

5.3.5.6 Exposure scenarios

The maximum content in sample no. 2 and 30 was 1,400 mg/kg equal to 1.4 mg per gram.

Intake per day per kg b.w. = 0.0143 * 1.4 = 0.02 mg/kg b.w.

It is assumed that the estimated amount can either be ingested or absorbed through skin or membranes.

5.3.5.7 Assessment

The concentrations vary from 0.001 w% to 0.14 w% and there is a potential risk for allergy, - especially for the highest concentrations.

It is not expected that the amounts of linalool detected will cause irritations.

NOAEL for liver damages is 50 mg/kg b.w., which gives a marginal of safety of more than 2,500 for sample no. 2 and 30 and higher for the other samples.

5.3.6 2-Phenoxyethanol

5.3.6.1 Identity

Name	2-Phenoxyethanol
CAS-number	122-99-6
EINECS number	204-589-7
Molecular formula	C8H10O2
Molecular structure
Molecular weight	138.16
Synonyms	Hydroxy-2-phenoxyethane 2-Fenoxyethanol 2-Hydroxyethyl phenyl ether 2-Phenoxyethanol 2-Phenoxyethyl alcohol Ethylene glycol phenyl ether Arosol Dowanol EP Dowanol EPH EGMPE

The substance 2-phenoxyethanol is a colourless liquid with a faint aromatic odour. Boiling point is 245.2°C and melting point is 14°C (Budavari, 1989)

The partition coefficient Log K_OW is measured to 1.16 (Leo, 1985). 2-phenoxyethanol is freely soluble in alcohol, ether and sodium hydroxide. The solubility in water is 26.7 gram per litre (Budavari, 1989).

The vapour pressure for 2-phenoxyethanol is measured to be 0.07 mm Hg at 25°C (Dow Chem Co, 1990).

5.3.6.2 Detected quantities

2-Phenoxyethanol was found in 9 products. The largest amount was found in sample 24, where 100,000 mg/kg equal to 10 w% was detected.

Sample no. 8, 11, 12 and 13 consists of 5-8,000 mg/kg equal to 0.5 to 0.8 w%. Sample no. 1, 2 and 23 consists of 1-2,500 mg/kg equal to 0.1 to 0.25 w%. For sample no. 18 only 61 mg/kg was detected.

5.3.6.3 Function

2-Phenoxyethanol is used for a number of purposes. It is common as fixative for perfumes, as solvent for inks, textile dye carrier and as bactericide.

The substance is included in INCI as a preservative and can as a preservative be used in concentrations up to 1 percent in cosmetics.

5.3.6.4 Classifications and TLV’s

2-Phenoxyethanol is included on the list of dangerous substances and classified as:

Xn;R22  Harmful; Harmful if swallowed.

Xi;R36   Irritating; Irritating to eyes.

With respect to the Statutory Order on cosmetic products (Cosmetics, 2006) it can be used as a preservative in up to 1 percent. It can also be used with others functions than preservation in cosmetics if the purpose is stated on the product.

5.3.6.5 Health Effects

For 2-Phenoxyethanol an IUCLID data-sheet is found, data in TOXNET and a description of the substance in Screening for health effects from chemical substances in textile colorants (Hansen OC, 2005).

Acute toxicity

In IUCLID a number of tests with rats where LD₅₀ by oral exposure was determined have been reported. The data range is between 1,200 mg/kg and 5,500 mg/kg. By dermal exposure LD₅₀ was determined to 2,300 mg/kg and up to more than 10,000 mg/kg.

Several negative tests for skin irritation on animals are reported (IUCLID, 2000). Also a 3 week patch-test on humans did not cause irritations. Test on rabbits showed eye irritation. Several tests for sensitizing were reported, - all with a negative result.

Sub-chronic toxicity

Several sub-chronic studies are reported in IUCLID. Some of these are briefly referred in the following:

• In a 13 week study with rats orally exposed NOAEL was determined to 200 mg/kg b.w. per day based on changes in blood parameters and weight loss.
• In another 13 week study with rats orally exposed NOAEL was determined to 80 mg/kg b.w. per day based on kidney damages.
• A 13 week study with dermal exposure to rabbits showed no adverse effects at the doses 50, 150 and 500 mg/kg per day. NOAEL was determined to be 500 mg per kg b.w. per day.

Chronic toxicity

• determined to be 500 mg per kg b.w. per day.

Chronic toxicity

Pregnant New Zealand white rabbits were treated dermally with 300, 600, or 1,000 mg/kg/day of undiluted 2-phenoxyethanol on days 6 through 18 of gestation (25 animals per dose group). 2-Phenoxyethanol was toxic to the dams (maternal death) at the 600 and 1,000 mg/kg doses. No adverse effects on pregnancy rate, resorptions, or foetal body measurements were observed at any dose. 2-Phenoxyethanol did not cause malformations in the foetuses as compared with controls (Scortichini et al., 1987).

2-Phenoxyethanol was tested for reproductive toxicity in Swiss CD-1 mice in a 2 generation test. The dose levels were 0.0, 0.25, 1.25, 2.5% in feed equal to 0, 375, 1875 and 3700 mg/kg/day. 2-Phenoxyethanol produced significant reproductive and developmental toxicity. Liver weight increased in treated F0 mice. The substance caused significant toxicity in growing animals, as evidenced by the reduced body weight in neonates and the large increase in post-natal lethality as the F1 animals grew to the age of mating (Department of Health & Human Services, 1984).

Teratogenicity was evaluated in pregnant New Zealand White rabbits. They were (25/group) dermally exposed to 2-phenoxyethanol at treatment levels of 0, 300, 600, and 1000 mg/kg/day on gestation days (GD) 6-18. Surviving animals were sacrificed on GD 28. Significant differences were observed between treated and control animals in the following: slight to moderate reddening of the skin at the application site (all treated animals), maternal mortality with dead animals exhibiting kidney damages, evidence of anorexia, changes in the gastric mucosa, decreased feed and fecal material in the intestines as well as changes in the blood parameters (high- and mid-dose groups). No significant differences were observed between treated and control animals in the following (mid- and low-dose groups) unless otherwise noted. No statistical evaluations were performed on the five high-dose groups of rabbits which survived until GD 28 (Dow Chemicals, 1984).

Summary

The substance will cause irritation by eye contact and may be harmful when ingested. NOAEL based on oral intake was determined to be 80 mg per kg b.w. per day based on kidney damages. Test showed reproductive and developmental effects in long-term studies with dermal exposure.

5.3.6.6 Exposure scenarios

The maximum content in sample no. 24 was 100,000 mg/kg equal to 100 mg per gram.

Intake per day per kg b.w. = 0.0143 * 100 = 1.43 mg/kg b.w.

For the sample no. 8, 11, 12 and 13 with of 5-8.000 mg/kg equal to 0.5 to 0.8 w% the intake per day will be 0.07 to 0.1 mg/kg b.w. per day.

It is assumed that the estimated amount can either be ingested or absorbed through skin or membranes.

5.3.6.7 Assessment

One sample contains 10 percent 2-phenoxyethanol, would be prohibited according to the Statutory Order on cosmetics.

Compared with NOAEL of 80 mg/kg b.w. per day for kidney damages for sample no. 24 it results in a margin of safety of 56 and for the other samples of at least 800. The assessments shows that there might be a heath risk for product 24.

Besides sample no. 24 it is assessed that the content of 2-phenoxyethanol will cause no or minor health problems.

5.3.7 α-Pinene

5.3.7.1 Identity

Name	α-Pinene
CAS-number	80-56-8
EINECS number	201-291-9
Molecular formula	C10H16
Molecular structure
Molecular weight	136.24
Synonyms	2-Pinene 2,6,6-Trimethylbicyclo(3.1.1)-2-hept-2-ene 2,6,6-Trimethylbicyclo(3.1.1)hept-2-ene 4,6,6-Trimethylbicyklo(3,1,1)hept-3-en Bicyclo(3.1.1)hept-2-ene, 2,6,6-trimethyl Acintene A Monoterpenes

α-Pinene is a colourless liquid with a characteristic odour of pine. The boiling point is 156°C and melting point is -62.5°C (Fenaroli, 1975).

Log K_OW for α-Pinene is determined to 4.83 (Li and Perdue, 1995).

The solubility of the substance in water is 2.49 gram/l at 25°C. α-Pinene is soluble in alcohol, chloroform, ether and concentrated acetic acid. It is almost insoluble in propylene glycol and glycerine (Fenaroli, 1975).

The vapour pressure of α-Pinene is 4.75 mm Hg at 25°C (Daubert and Danner, 1989).

5.3.7.2 Detected quantities

α-Pinene was detected in two samples, sample no. 5, where 260 mg/kg was found and sample no. 21, where 560 mg/kg was found.

5.3.7.3 Function

a -Pinene has many functions and is widely used. Common uses are as solvent, emollient, in pesticides as base for synthetic oils and perfumes

The substance is included in INCI as a fragrance.

5.3.7.4 Classifications and TLV’s

α-Pinene is not classified in the Annex I of Directive 67/548/EEC. The substance is included in the Danish advisory list for classification (Vejledende liste, 2001) with the classification:

R43                May cause sensitization by skin contact.

N;R50/53       Dangerous for the environment; Very toxic to aquatic organisms, may cause long-term adverse effects in aquatic environments..

No TLV are given for α-Pinene. For terpenes in general like turpentine TLV in Denmark is 140 mg/m³ or 25 ppm (C.0.1, 2005). In USA TLV as a 8 hr Time Weighted Avg (TWA) is set to 20 ppm (ACGIH, 2003).

5.3.7.5 Health Effects

Data for α-Pinene is relatively limited. The following is based on a data set from IUCLID, the databases in TOXNET and a general search at the internet. A general search of terpenes is also included.

Acute toxicity

Acute oral toxicity has been tested in studies with rats, which showed LD₅₀ of 2,100 mg/kg and up to 5,100 mg/kg. Dermal toxicity based on test with rabbits showed results of LD₅₀ of more than 5,000 mg/kg (IUCLID).

α-Pinene has essentially the same toxicity as turpentine (Gosselin et al., 1984). Fatal dose for humans is about 180 gram orally as turpentine, which contains 58-65% α-Pinene (The Merck Index, 1976).

It is mentioned that α-Pinene irritates skin and mucous membranes and cause skin eruption and irritation of the respiratory system (Budavari, 1989). In IUCLID it is mentioned some tests on rabbits, mice and rats, where some were positive and some negative. A patch test on 5 humans tested with 10% α-Pinene in petrolatum for 48 hours showed no effects.

In IUCLID a test of eye irritation with the result “moderate irritation” is described. Another source states that α-Pinene is an eye, mucous membrane, and severe human skin irritant (Lewis, 1996).

Several tests on sensitizing on humans have been reported (IUCLID, 2000). Most of the patch tests showed that several people reacted positive. Turpentine oil, which normally has a high content of α-Pinene is labelled R43: May cause sensitization by skin contact.

Sub-chronic toxicity

In a 14 day test rats were orally exposed daily with 0, 250 and 500 mg/kg. In the group exposed to 500 mg per kg reduced body weight and increased weight of liver was observed.

No relevant data for turpentine oil were found.

Chronic toxicity

No data on chronic toxicity for α-Pinene were found.

From OSHA’s Health Guidelines (2005) the following information has been retrieved for turpentine and it is assumed to be valid for α-Pinene as well.

• In one study, dermal application of turpentine produced skin tumours in rabbits but not in mice. In another experiment, however, painting the skin of mice with 240 g/kg turpentine did cause tumours
• Turpentine is a skin, eye, mucous membrane, and upper respiratory tract irritant in humans. It may also cause skin sensitization and central nervous system, gastrointestinal, and urinary tract effects. The lowest estimated oral dose reported to be lethal in humans is 441 mg/kg.
• A case-control study of workers in particle-board, plywood, sawmills, and formaldehyde glue factories demonstrated a statistically significant association between chronic exposure (longer than 5 years) to terpenes (the principal component of turpentine) and the development of respiratory tract cancers.

Summary

α-Pinene causes irritation by skin and eye contact and may cause allergies by skin contact.

Data on long-term effects are very limited and risk of cancer and other longterm effects from skin contact and ingestion are very uncertain.

Based on the one sub-chronic test NOAEL is determined to be 250 mg/kg with increased liver weight as the critical effect.

5.3.7.6 Exposure scenarios

The maximum content in sample no. 30 was 560 mg/kg equal to 0.56 mg per gram.

Intake per day per kg b.w. = 0.0143 * 0.56 = 0.008 mg/kg b.w.

5.3.7.7 Assessment

In two samples, no. 65 and 30, the contain of α-Pinene is less than 0.06 percent. α-Pinene is a potential skin sensitizer and therefore there is a minor risk of allergic reaction when contact with the two products.

NOAEL is estimated to 250 mg/kg based on limited data for increased liver weight.

The marginal of safety is more than 30,000. Despite the limited data the MOS is acceptable and it can be concluded that the risk for uptake of the substance is minimal.

5.4 Overall Assessment

5.4.1 Substances

In the following an overview of the assessments of the substances in section 5.3 is given. Data in the tables are given for the sample with the highest determined concentration of the actual substance.

Table 5.1 Irritation and allergy effects for selected substances in pleasure-gels

From Table 5.1 can be seen that one sample contained an extreme high amount of 2-phenoxyethanol. The sample contained 10% - according to the Statutory Order on cosmetics only 1% is allowed. Other samples contained less than 1% of the substance.

Most of the selected substances can cause sensitization to skin almost at all levels of concentration.

Table 5.2 Toxic effects for selected substances in pleasure-gels

From Table 5.2 it also can be seen that the amount of 2-phenoxyethanol in sample no. 24 is very high. The effects seen are kidney damages.

In sample no. 6 a relatively high content of eugenol (18g/kg) is found and for the other 3 samples the content is max. 0.8 g/kg. The critical effect for eugenol is liver damages.

5.4.2 Products

Among the 22 test products one product should be classified and labelled according to the Statutory Order on classification. Further, for 5 products a marking is required with a sentence specifying that an allergic reaction can arise as specified in appendix 2 point 2.13 of the statutory order on classification.

The Statutory Order on cosmetics does not regulate pleasure-gels. If pleasure-gels were covered by the Statutory Order certain requirements for declaration of ingredients should be met as well as observing restrictions on certain substances. If the Statutory Order were in force the following were found:

• The declaration for 8 out of 22 products were insufficient
• Too much of the preservative 2-phenoxy-ethanol was found in one product

With respect to irritation this effect is seen for camphor and 2-phenoxyethanol. The amounts of camphor are so limited that there is no risk of this effect for any of the products. With respect to 2-phenoxyethanol it will cause risk of irritation in product number 24.

The substances Cinnamaldehyde, eugenol, d-limonene and linalool can cause sensitization by skin contact. In general there is no lower limit for risk of sensitization and therefore all products, where the substances are found will be potential sensitizers. The products for which this is particular relevant is:

• Product no. 2
• Product no. 4
• Product no. 6
• Product no. 27
• Product no. 30

With respect to the toxic effects for the selected substances especially eugenol and 2-phenoxyethanol are problematic. For both substances the margin of safety is determined to be less than 1000. For eugenol there is a minor potential health risk for product number 6. For 2-phenoxyethanol, there is a potential health risk for product number 24.

Conclusion

Product no. 24 is identified as giving a potential health risk (kidney damage) by oral intake or intake through the skin due to the content of phenoxyethanol .

Several products contain substances that may cause sensitization by skin contact and about 25% of the tested products contain a relatively large amount of these substances (products no.2, 4, 6, 27 and 30).

According to the Statutory Order on classification, all products containing more than 0.1% of a substance classified or estimated to be sensitizing (allergy-causing) have to be marked with "Contains (substance). Allergic reaction can arise".

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Version 1.0 September 2006, © Danish Environmental Protection Agency