A survey and health assessment of cosmetic products for children

6 Health assessment

6.1 Selection of substances for health assessment

As basis for the selection of substances for the health assessment the list of the most frequently used substances in cosmetic products for children is used. However, in the selection emphasis has been on substances with the most worrisome properties and primarily it has been chosen to emphasize on the risk of developing allergy.

Earlier health assessments of a number of the 26 fragrances mandatory to déclassé have been conducted for which reason these are not repeated in this project. Furthermore, parabens are under risk assessment in the EU for the moment and therefore they are also deselected at the health assessment of this project.

In the selection of fragrances for the health assessment emphasis has been on the analysis results and a fragrance is selected which is identified in the analyses in a concentration which requires a separate declaration of the substance. Therefore, the substances stated in the table below have been chosen for health assessment.

INCI name CAS No. Function In number of mapped products
Benzyl alcohol 100-51-6 Preservative. Fragrance.
Solvent.
20
Sodium benzoate 532-32-1   13
Methylchlorisothiazolinone and Metyhlisothiazolinone MI 2682-20-4
CMI 26172-55-4
MI/CMI
55965-84-9
Preservative 15
Phenoxyethanol 122-99-6 Preservative 50
5-Bromo-5-nitro-1,3-dioxane 30007-47-7 Preservative 15

6.2 Fragrances

6.2.1 Benzyl alcohol

Occurrence and application

Yearly, 40,000 tons of benzyl alcohol are produced worldwide. The majority (30%) is applied as hardening agent in epoxy paints where it is chemically combined after reaction. Other important applications are as solvents in low concentrations in water-based paints (10%), as constituent in paint remover (10%), and as chemical intermediate in the synthesis of benzyl esters which are applied in aroma and in the perfume industry (10%) (OECD SIDS, 2001). Finally, benzyl alcohol is applied in many different cosmetic products as fragrance, preservative, solvent and viscosity decreasing agent (SCF 78, 2002). Benzyl alcohol has a bacteriostatic impact and therefore it is also applied as a preservative (Jensen AA, 1999).

In the mapped cosmetic products for children benzyl alcohol occurs in 20 of the 208 products, distributed on six hair dyes, six bath confetti/caviar/fizzle salt products, one tooth paste, one eau de toilette, one body shampoo/bath gel, one shampoo, one bobble bath products, one body lotion/cream and finally one product in the category others (body splash), that means in nearly all kind of cosmetic products being investigated in this project.

Benzyl alcohol is applied as a local anesthetic and a pharmaceutical remedy. Benzyl alcohol is a natural constituent in a number of different plants, including jasmine. Benzyl alcohol occurs naturally in for instance some edible fruits (up to 5 mg/kg) and in green and black tea (1-30 and 1-15 mg/kg respectively). Benzyl alcohol is also added to some food products and beverages as a flavouring agent (up to 400 mg/kg – however, for chewing gum 1,254 mg/kg) (SCF 78, 2002; Jensen AA, 1999). In Europe the yearly application of benzyl alcohol as an additive in food products is about 110 tons. WHO estimates that the daily intake of benzyl alcohol is 16,000 µg/day corresponding to 270 µg/kg bw/day in Europe (WHO, 2002).

Identification

Chemical name Benzyl alcohol
Synonyms (Hydroxymethyl)benzene
Benzenecarbinol
a-Hydroxytoluene
Phenylmethanol
Phenylmethyl alcohol 
INCI name Benzyl alcohol
CAS No. 100-51-6
EINECS No. 202-859-9
Gross formula C7H8O
Molecular structure Molecular structure
Legislation:
The list of dangerous substances
(Stat. Ord. 923, 2005)
The list of harmful substances
(Orientation from the Danish EPA no. 8, 2004)
The Danish EPA’s self classification
(Environmental project no. 635, 2001)
Cosmetics Statutory Order
(Stat. Ord. 422 , 2006)
XN; R20/22. Conc. = 25%: XN; R20/22
R20/22 = ”Dangerous if inhaled and if swallowed”.
Yes
No.
Maximum permitted concentration as preservative in cosmetic products is 1% (Appendix 5, serial number 4 VI, 1, 34).
Is one of the 26 fragrances which by SCCNFP* is assessed to be allergenic in case of contact with skin. As fragrance the presence of the substance must be stated in the declaration of content when the concentration is higher than 0.001% in products which are not to be cleansed and when the concentration is higher than 0.01% in products which are to be cleansed.
International Fragrance Association (IFRA) No guidelines from IFRA for this substance.

*             The Scientific Committee on Cosmetic Products and Non-Food Products

Physical chemical properties

The physical chemical properties of benzyl alcohol are found via the ChemIDplus database of TOXNET, Chemfinder and the OECD report on benzoates (OECD SIDS, 2001).

Physical structure Colourless liquid
Molar weight (g/mol) 108.14
Melting point -15 °C
Boling point 205 °C
Steam pressure 0.13 hPa at 20 °C
0.3 hPa at 20 °C (according to IUCLID, 2000b)
0.02 kPa at 250 °C
Octanol water distribution coefficient (log POW) 1.1
Water solubility 42.9 g/L
35 g/L at 20 °C

According to HSDB the odour threshold of benzyl alcohol is 5.5. ppm.

Absorption and distribution

Benzyl alcohol is easily absorbed via the skin – the quantity which is not evaporated at first. In animal trials with rhesus monkeys, benzyl alcohol was applied to the skin of the monkeys. Under normal application only 32% was absorbed via the skin during 24 hours because the substance evaporated. Under circumstances where the benzyl alcohol was not able to evaporate so easily 56-80% of the substance was absorbed (IUCLID, 2000b).

Benzyl alcohol is easily absorbed in the gastrointestinal tract. After the absorption it is quickly transformed in the liver to benzoic acid which is separated within 24 hours, mainly as hippuric acid in the urine. At very high dosages (> 500 mg/kg/day via oral intake) a saturation of this process of metabolism might occur (Jensen AA, 1999; Nair B, 2001; OECD SIDS, 2001; WHO, 2002).

Acute toxicity

Earlier benzyl alcohol has been applied in concentrations of about 1% as preservative in infusion liquids with physiological salt water and in a number of injection preparations. In 1983 the Danish National Board of Health warned against this use as in the USA in the early 1980’ies reports told about brain damages, blood changes and several deaths among premature babies which were caused by these applications. Total dosage applied to the children who died was 130-405 mg benzyl alcohol per kg body weight per day. This corresponds to the intravenous LD50 value found in test animals. If swallowed benzyl alcohol is 25 times less acutely toxic (Jensen AA, 1999).

Intake of large quantities of benzyl alcohol leads to vomiting and diarrhea and depression of the central nervous system (HSDB). Similarly five premature babies got several injections added bacteriostatic water with 0.9% benzyl alcohol. Daily dosages were 99-234 mg benzyl alcohol per kg body weight. The seen impacts were gradually neurological destruction, serious acidosis (abnormally strong acidification in the body), severely gasping breathing, destruction of the skin, impacts on the blood, impact on liver and kidney function, low blood pressure and collapse of the cardiovascular system (Gershenk et al, 1982).

According to “The list of dangerous substances” benzyl alcohol is assessed to be harmful to health when inhaled and swallowed. Tabel 6-1 states the acute toxicity in test animals.

Tabel 6-1: Acute toxicy (LD50) of benzyl alcohol

Species Exposure LD50
(mg/kg bw)
Reference
Rabbit Oral 1000 Graham & Kuizenga, 1945
Rat Oral 1600 Procter & Gamble, 1992
Rat Oral 3100 Smyth et al., 1951
Rat Oral 2080 Opdyke, 1973. Graham & Kuizenga, 1945
Moapply Oral 1580 Opdyke, 1973. Jenner et al, 1964.
Rat Oral 1610 Loeser, 1978.
Rat Oral 1230 RTECS
Rat Oral 1610 IUCLID, 2000b
Rat Oral 1230 IUCLID, 2000b
Moapply Oral 1150 IUCLID, 2000b
Rabbit Oral 1040 IUCLID, 2000b
Rabbit Dermal 2000 NPIRI, 1974.
Guinea pig Dermal < 5000 IUCLID, 2000b

WHO has set the limit for the acceptable daily intake of benzyl alcohol to 5 mg/kg/day. In general, US FDA (US Food and Drug Administration) sees benzyl alcohol to be safe for apply in food products (Nair B., 2001). A WHO working group has examined benzyl alcohol and other similar additives for food products and concludes that benzyl alcohol does not give cause for concern in relation to the health at a continuous use at the present level (WHO, 2002).

In tests with rats no effects were seen at a dose of 500 mg/kg body weight/day (375 mg/kg body weight/day when adjustment is made for dose only given five times a week). The value is based on a study of 16 days where the effects at higher doses were increased mortality, reduction in body weight, haemorrhage and lethargy. Correspondingly, no effects were seen at a dose of 400 mg/kg body weight/day (286 mg/kg body weight/day adjusted for five-day dosing schedule) in a subchronic study of 13 weeks. There were neurotoxic effects at higher doses. At a corresponding test of 16 days and a subchronic test (13 weeks) with mice no effects were seen at 250 (188 when adjusted for five-day dosing schedule) and 400 (286 when adjusted for five-day dosing schedule) mg/kg body weight/day respectively. In the test of 16 days the effects were lethargy at a higher dose and at the test of 13 weeks there were neurotoxic effects at a higher dose (NTP, 1989). Based on these tests 400 (286) mg/kg body weight/day can be regarded as NOAEL value.

Local irritation

Benzyl alcohol is irritating on skin (in a 0.5% solution), mucous membranes and eyes (at 100 mg per animal) and is affecting the central nervous system (Jensen AA, 1999; IUCLID, 2000b; OECD SIDS, 2001).

Allergy

In patch tests on humans benzyl alcohol has shown sensitizing properties in some tests but also ambiguous and negative results are seen (IUCLID, 2000b; OECD SIDS, 2001). Scientific Committee on Cosmetic Products and Non-Food Products (SCCNFP) evaluates that benzyl alcohol is one of the fragrances which most frequently is reported as allergenic to consumers (SCCNFP 0017, 1999). Benzyl alcohol is one of the 26 fragrances mandatory to declare which according to the Cosmetics legislation must be declared separately, with the purpose that allergic persons can avoid the substance.

Prolonged, repeated impact and gene damaging effects

Generally, benzyl alcohol shows low toxicity at repeated impact (OECD SIDS, 2001). Long-term tests with rats and mice showed no serious impacts of benzyl alcohol – the impacts were limited to be reduced food intake and reduced growth at doses of more than 400 mg/kg body weight/day.

In a reproduction study with mice the impacts were lower maternal body weight and decreasing mean litter weights. In another study a decreasing fetal weight in relation to the control group was noted while a third study showed no difference between the control group and the group of animals exposed to benzyl alcohol (Nair B., 2001).

In animal tests with mice and rats there were no signs that benzyl alcohol is carcinogenic (Jensen AA, 1999; Nair B., 2001; WHO, 2002; NTP, 1989).

In long-term tests on mice and rats there were no signs of carcinogenic impact of benzyl alcohol neither in female nor male rats at dosages of 200 and 400 mg/kg in the feed. Correspondingly there were no signs of carcinogenic impact of benzyl alcohol neither in female nor male rats at a dosage of 100 and 200 mg/kg for two years (NTP, 1989). In the OECD SIDS report on benzoates, a NOAEL value for benzyl alcohol of =400 mg/kg/day for the rat test and =200 mg/kg/day for the mouse test is stated, based on the above NTP report (OECD SIDS, 2001).

In the OECD SIDS report, a NOAEL value for benzyl alcohol of 550 mg/kg bw/day for developmental toxicity for mice is stated (OECD SIDS, 2001).

Benzyl alcohol has not shown to be mutagenic in the Ames test and other bacterial tests or in cell cultures (Jensen AA, 1999; Nair B., 2001; WHO, 2002; NTP, 1989).

Critical impact

At prolonged exposure the critical impact of benzyl alcohol is assessed to be neurotoxic effects. Here a NOEAL value of 400 mg/kg body weight/day is stated. With regard to the acute toxicity of benzyl alcohol mortality is seen at dose of down to 100 mg/kg body weight/day for premature babies. Here the dose was given intravenously. If swallowed benzyl alcohol is 25 times less acute toxic. In tests with mice a NOAEL value of 188 mg/kg body weight/day is stated where the acute toxicity at higher levels was lethargy. The critical impact of benzyl alcohol is thus lethargy (NOAEL value 188 mg/kg body weight/day). This value is used in the risk assessment despite the fact that mortality is seen at intravenous influence at lower doses as the acute effect of benzyl alcohol intravenously is 25 times higher than if swallowed.

6.3 Preservatives

6.3.1 Sodium benzoate

Sodium benzoate is the sodium salt of benzoic acid which is also preserving (WHO, 2000). Sodium benzoate is transformed into benzoic acid in acidic environments. In general benzoic acid and sodium benzoate are assessed together in one health assessment – and this is also the case for the fragrance/preservative benzyl alcohol which is described above. Sodium benzoate and benzoic acid belong to a comparatively similar chemical group and benzyl alcohol can be oxidated into benzoic acid. Therefore, the three substances have similar health properties (OECD SIDS, 2001).

Restrictions of sodium benzoate in relation to cosmetic products are set as a maximum limit for “salts of benzoic acid” where the maximum permissible content in percentages is calculated as benzoic acid (Stat. Ord. 422, 2006). Therefore the physical chemical parameters are stated for both sodium benzoate and benzoic acid.

Occurrence and application

In the mapped cosmetic products for children sodium benzoate occurs in 13 of the 208 products, distributed on five tooth pastes, three shampoos, two bobble bath products, one body shampoo/bath gel, one solid soap and one balsam.

OECD estimates that yearly 75,000 tons of sodium benzoate are produced worldwide. The majority[13] is applied as a preservative in food products and beverages and a large part is applied as rust-preventative agent, especially as an additive to anti-freeze fluid for cars or other coolant. Sodium benzoate is applied for many other purposes too, such as stabilizer in photo processing, in medical drugs, in plastic as for instance polypropylene to improve strength and brightness, as well as in cosmetic products. In most applications the primary function is preservative (OECD SIDS, 2001; WHO, 2000).

Sodium benzoate is applied as preservative (E211 – “Atamon”) in marmalade, jam, juice, vegetables in pickle, soft drinks, fish products such as marinated herrings and caviar, surface treatment of dried meat products, fluid egg products etc. Sodium benzoate occurs naturally in fruits and berries. The only fruits which have a natural content of sodium benzoate of importance are cranberries and cloudberries. They contain between about 600 and 2,000 mg/kg (Biosite, 2006; the E number guide, 2004; the Danish Veterinary and Food Administration, 2004).

According to the Positive list the content of benzoic acid and its salts must not be more than 6 g/kg in special crustaceans and mollusks. Other examples of restrictions for benzoic acid in food products are 200 mg/l in juice, non-alcoholic beer and alcohol (below 15% alcohol), 500 mg/kg in jelly, dried fruit butter and marmalade, 600 mg/l in fluid fruit tea, 1 g/kg in spices, 1.5 g/kg in food products for special medical purposes, chewing gum and slimming diet products, 2 g/kg in diet supplement and fish, and 5 g/kg in fluid egg products (The Positive list, 2005).

HSDB gives an example of a concentration of sodium benzoate of 0.125% in a body lotion (HSDB).

According to JECFA (Joint FAO/WHO Expert Committee on Food Additives) we consume between 0.18 and 2.3 mg benzoate per kg body weight per day. The low value is from Japan and the high value illustrates the daily intake in the USA (WHO, 2000).

Identification

Chemical name Sodium benzoate Benzoic acid
Synonyms Benzoic acid, sodium salt
Antimol
Benzoate of soda
Benzenecarboxylic acid
Benzenemethanoic acid
INCI name Sodium benzoate Benzoic acid
CAS-No. 532-32-1 65-85-0
EINECS No. 208-534-8 200-618-2
Gross formela C7H5NaO2 C7H6O2
Molecular structure Molecular structure Molecular structure
Legislation:
The list of dangerous substances
(Stat. Ord. 923, 2005)
The list of harmful substances
(Orientation from the Danish PA no. 8, 2004)
The Danish EPA’s self classification
(Environmental project no. 635, 2001)
No
No
No
No
No
No
Cosmetics Statutory Order
(Stat. Ord. 422 , 2006)
Salts of benzoic acid are permitted in cosmetic products but in a maximum concentration of 0.5% ranked as acid (Appendix 5, serial number 3m VI, 1, 1).

Physical chemical properties

Information about the physical chemical properties of sodium benzoate is found via Chemfinder, the ChemIDPlus database of TOXNET, a report from OECD SIDS on benzoates and via safety data sheet on sodium benzoate (OECD SIDS, 2001; Malinckrodt Chemicals, 2004; Safety Emporium, 2004).

  Sodium benzoate Benzoic acid
Physical structure White crystallic powder White crystallic powder
Molar weight (g/mol) 144.11 122.12
Melting point 331 °C 122 °C
Boiling point 465 °C 249 °C
Steam pressure < 0.001 hPa 0.0004 mmHg at 25 °C
Octanol water distribution (log POW) -2.27 1.87
Water solubility 556 g/l at 25 °C 3,4 g/l at 25 °C

Absorption and disribution

Sodium benzoate is easily absorbed in the gastrointestinal tract. Sodium benzoate is expected to ionize immediately to benzoic acid in acid environments and also in the stomach. The benzoic acid is bound to the amino acid glycine and is mainly separated as hippuric acid in the urine within 24 hours (Nair B, 2001; OECD SIDS, 2001).

Acute toxicity

WHO has set a limit for the acceptable daily intake (ADI) of sodium benzoate of 5 mg/kg/day. In general US FDA (US Food and Drug Administration) regards sodium benzoate as being safe for apply in food products (Nair B, 2001).

There is a limited amount of data on the acute toxicity of sodium benzoate and the available studies are not completed according to the present guidelines (WHO, 2000). The found LD50 values for sodium benzoate are stated in Table 6.2. The stated values mean that sodium benzoate shall not be classified as harmful to health if swallowed.

Table 6.2: Acute toxicity (LD50) of sodium benzoate

Species Exposure LD50
(mg/kg bw)
Reference
Rat Oral 3140 Loeser, 1977.
Rat Oral 4070 Smyth & Carpenter, 1948.
Rat Oral 2100* Deuel HJ et al, 1954
Rat Oral 3450* Deuel HJ et al, 1954

*             Calculated as benzoic acid

The primary effect at intake of moderate amounts of benzoates is irritation of gastrointestinal systems. Intake of large amounts of benzoates (> 1 mg/kg body weight/day) can cause low pH level in the blood (acidosis) (HSDB).

Local irritation

Sodium benzoate is not assessed to be irritating on skin but slightly irritating for the eyes (OECD SIDS, 2001; WHO, 2001).

Allergy

There are reported cases of urticaria, asthma, rhinitis (a year-round cold) and anaphylactic shock (intense allergic response with skin rash and breathing difficulties) after oral exposure, skin exposure or inhalation of sodium benzoate (WHO, 2000).

Sodium benzoate is not skin sensitizing in tests with animals but in humans exposed to patch tests there is a low incidence of skin sensitization (5 of 2,045 cases (0.2%) were positive) (OECD SIDS, 2001; WHO, 2000). It is estimated that there shall be an exposure of 50 mg benzoate at one time to provoke an allergic response at sensitive persons (The Danish Veterinary and Food Administration, 2004).

Prolonged, repeated impact and gene damaging effects

In long-term tests with rats and mice, the impacts were limited to be reduced food intake and reduced growth. No damaging impacts to reproduction or carcinogenic impacts of sodium benzoate are observed in tests with rats and mice.

In the literature, different NOAEL values of 1000, >1090, 1310 and 3145 mg/kg bw/day are stated (Deuel HJ et al, 1954; Onodera et al, 1978; Sodemoto & Enomoto, 1980; IUCLID, 2000c; SCCNFP 0532, 2002). The highest value is the oldest.

There are no reports about serious side-effects after therapeutic use of sodium benzoate at doses of between 250 and 500 mg/kg bw/day in humans even if a few cases of anorexia and vomiting have been observed (WHO, 2000).

The Scientific Committee on Cosmetic Products and Non-Food Products (SCCNFP) has assessed whether it is safe to use benzoic acid and its salts and esters for non-preserving purposes in a maximum concentration of 2.5% in cosmetic products which are rinsed off after use. SCCNFP concluded that the data were not sufficient to be able to conduct a risk assessment of benzoic acid and sodium benzoate for these non-preserving purposes in cosmetic products (SCCNFP0532, 2002).

Sodium benzoate has shown not to be mutagenic in Ames tests and other tests (Nair B., 2001; OECD SIDS, 2001; WHO, 2000).

Critical impact

The critical impact of sodium benzoate is assessed to be irritation of gastrointestinal system if swallowed. No exact NOAEL value for this impact is found but the NOAEL value is between 250 and 500 mg/kg body weight/day even if a single case of vomiting is seen here.

6.3.2 Kathon

Kathon is the commercial name and a collective designation for the two substances methylchlorisothiazolinone and methylisothiazolinone which are often abbreviated CMI and MI respectively. According to the Cosmetics Statutory Order (Stat. Ord. 422 §25, 2006) the highest permissible concentration of Kathon in cosmetic products is 0.0015% of a mixture in the ratio 3:1 of methylchlorisothiazolinone and methylisothiazolinone.

When Kathon is applied in the CMI/MI ratio 3:1 in cosmetic products it is also this mixture that is primarily assessed in the health assessment. Most studies have also been carried out on the mixture and not on the individual isothiazolinones.

Earlier a health assessment of Kathon in Environmental Project No. 615 from the Danish Environmental Protection Agency 2001 has been conducted. This health assessment has been updated with new data (Madsen T et al, 2001).

Occurrence and application

Kathon is applied in cosmetic products as preservative. Kathon is applied in both “leave-on” products (primarily body lotions and other kinds of creams) and “rinse-off” products, such as shampoo and body shampoo (SCCNFP 0625, 2003).

In the studied cosmetic products for children Kathon is in 15 of the 208 products, distributed on eight body shampoo/bath gel products, two shampoos, two bobble bath products, one liquid soap, one eau de toilette and one body lotion/cream.

Identification

In the table below the chemical identification of methylisothiazolinone, methylchlorisothiazolinone and a mixture of these two substances are summarized.

Table 6.3: Identification of Kathon

Chemical name 2-Methyl-4-isothiazolin-3-one 5-Chloro-2-methyl-4-isothiazolin-3-one Chloro-2-methyl-3(2H)-isothiazolone with 2-methyl-3(2H)-isothiazolone
Synonyms 2-Methyl-3(2H)-isothiazolone
2-Methyl-2H-isothiazol-3-one
2-Methyl-2,3-dihydroisothiazol-3-one
MI
5-Chloro-2-methyl-2H-isothiazol-3-one
3(2H)-Isothiazolone, 5-chloro-2-methyl-
Kathon CG 5243
Kathon DP
Kathon LX
Kathon UT
Kathon WT
MCI
CMI
Kathon 886
Kathon 886 W
Kathon 886MW
Kathon CG
Kathon CG/ICP II
Kathon LX
Kathon RH 886
Kathon WT
Kathon biocide
MCI/MI
CMI/MI
INCI name Methylisothiazolinone Methylchloroisothiazolinone -
CAS No. 2682-20-4 26172-55-4 55965-84-9
EINECS No. 220-239-6 247-500-7 -
Gross formula C4H5NOS C4H4ClNOS  
Molecular structure Molecular structure Molecular structure Molecular structure
Classification according to the List of dangerous substances
(Stat.Ord. 923, 2005)
The List of unwanted substances (Orientation from the Danish EPA no. 8, 2004)
Danish EPA Self-classification
(Environmental project no. 635, 2001)
The Cosmetics Statutory Order
(Stat. Ord. 422 , 2006)
No
No
R43
Highest permissible concentration of 0.0015% (15 ppm) (of a mixture in the ratio 3:1 of 5- chlor-2-methyl-4- isothiazolin- 3-on and 2- methyl-4-isothiazolin-3-on).
No
No
R43
Highest permissible concentration of 0.0015% (15 ppm) (of a mixture in the ratio 3:1 of 5- chlor-2-methyl-4- isothiazolin- 3-on and 2- methyl-4-isothiazolin-3-on).
T;R23/24/25 C;R34 R43 N;R50/53
In concentrations above 0.0015%, but below 0.06% the classification is Xi, R43
No
No
Highest permissible concentration of 0.0015% (15 ppm) (of a mixture in the ratio 3:1 of 5- chlor-2-methyl-4- isothiazolin- 3-on and 2- methyl-4-isothiazolin-3-on).

Physical chemical properties

In the table below the physical chemical properties of Kathon are summarized. The information is based on information from SCCNFP (SCCNFP 0805, 2004) and (SCCNFP 0625, 2003) as well as information from the IUCLID database which only covers the properties for the mixture of the two substances.

Table 6.4: Physical chemical properties of Kathon

  Methylisothiazolinone Methylchlorisothiazolinone Kathon (the mixture)
Physical structure Raw white or light brown solid substance at room temperature   Fast stof
Molar weight (g/mol) 115.16 149.59  
Density 1,35 g/cm³ at 25 °C   1,2556 g/cm³ at 20 °C
Melting point 46,7 – 48,3 °C   Ca. 50-55 °C
Boiling point Thermal decomposition at 155 °C   106,5 °C at 1000 hPa
Steam pressure 0,73 Pa at 20 °C   20,8 hPa at 20 °C
Octanol water distribution (log POW) -0,486 at 24 °C   -0,71 – 0,75 at 20 °C
Water solubility > 1000 g/l at 20 °C   > 5000 mg/l at 20 °C
Flame point     > 100 °C

Absorption and distribution

Kathon is readily excreted after absorption in the body. After oral administration of Kathon 886 to rats, the majority of MI and CMI was excreted without troubles with the urine or faeces (CIRP, 1992). Tests with C14 labelling of the chlorinated compound (CMI) have shown that more than 50% is excreted with faeces or the urine after 24 hours and about 70% (faeces 35%, urine 31% and CO2) after 96 hours (Debethizy et al, 1986).

Kathon 886 is distributed quickly to blood, liver, kidneys and testicles after an intravenous dose (0.8 mg/kg bw) (CIRP, 1992).

The half-life period for dermally absorbed compounds is found to be 13.1 days. This indicates an increased potential for accumulation in the body at repeated application or use (Conner et al, 1996).

Acute toxicity

Kathon (CMI og MI) is from moderate to very poisonous when swallowed (Table 6.5). Signs of toxicity are among others drowsiness, ataxia (loss of full control of body mobility) and serious gastric irritation. Signs of intoxications at doses from 75 mg MI/kg body weight/day are seen in female rats (150 mg MI/kg body weight/day for male rats) (Rohm and Haas, 1999; Rohm and Haas, 2000a; SCCNFP 0625, 2003; CIRP, 1992).

In vitro tests with normal human ceratinocyte cell cultures showed that a short exposure (10 minutes) with CMI/MI in concentrations between 0.001% and 0.1% causes a cytotoxic (cell-destroying) impact which is dependent on concentration (Ettorre A et al, 2003).

Table 6.5: Acute toxicity (LD50) of Kathon

Substance Species Exposure LD50
(mg/kg bw)
Reference
MI Rat Oral 183-235 Rohm and Haas, 1999
MI Rat Oral 106-275 Rohm and Haas, 2000a
MI Rat Dermal > 485 Rohm and Haas, 2000b
Neolone 950
(calculated as MI)
Rat Oral 104 - 269 Rohm and Haas, 2004b
Neolone 950 (calculated as MI) Rat Dermal > 475 Rohm and Haas, 2004b
Kathon CG (calculated as CMI/MI total) Rat Oral 39,5-50,3 Rohm and Haas, 2004a
Kathon CG (calculated as CMI/MI total) ? Dermal 75 Rohm and Haas, 2004a
CMI Rat Dermal > 1008 IUCLID, 2000a
CMI Rat Oral 481 IUCLID, 2000a
CMI Rat/moapply Oral 53-60 DFG, 1993
Kathon CG Rat Oral 3350* CIRP, 1992
CMI Rabbit Dermal 80 DFG, 1993

*             Suggests that the value is of the sold product Kathon CG and is not calculated for the total content of CMI/MI.

Local irritation

Kathon is in its pure form corrosive for both skin and eyes. Solutions containing more than 0.5% active isothiazolinones are very skin irritating on humans and can cause corrosion of mucous membranes and corneas (DFG, 1993; CIRP, 1992).

It also applies to the two individual substances in Kathon that they individually are corrosive in pure form. MI is neither skin nor eye irritating (on rabbits) at 100 ppm (0.01%) active constituent. No found data indicate how irritating CMI is in undiluted form (Rohm and Haas, 2000d; IUCLID, 2000a; Rohm and Haas, 2000e).

Allergy

The sensitizing potential for Kathon (CMI/MI) for humans is well-described in the literature. There is a general agreement that CMI/MI is a sensitizer. At the beginning of the 1980’ies CMI/MI was introduced as a preservative in cosmetics and gave cause for an empidemic of allergy cases in Europe. The many cases of allergy have led to limitation of the use of CMI/MI. In 2005 1.6% of the eczema patients in Denmark were allergic to CMI/MI. On the whole this figure is unchanged from 2003 and 2004 and CMI/MI is still considered as one of the most frequent causes for preservative allergy in Denmark (Denmark’s National Allergy Research Centre, 2006b). The picture in Germany was the same when CMI/MI was introduced as a preservative in the 1980’ies. Here 5.2% of the patients were allergic to CMI/MI. Since reduction in the applied concentration of CMI/MI has halved this figure (Alexander BR, 2002).

In a memorandum to ECB (European Chemicals Bureau) on CMI/MI three tests with patch tests on children are described. The studies carried out in Norway (in 1991), in Germany (in 1990-1995) and in Italy (in 1988-1994) show that 5.2%, 1.1% and 5.7% respectively reacted positively to Kathon CG. The studies demonstrate that Kathon CG is sensitizing and that occupational exposure might be excluded. Kathon from cosmetic products is the most probable cause for the sensitization. In the same memorandum a survey in Japan is described where 0.9% reacted positively to a patch test in the period 1989 to 1992 and this despite the fact that Kathon CG is only applied in products being rinsed after use and in a maximum concentration of 15 ppm. A concentration of 15 ppm in products being rinsed after use represents thus a risk for sensitization of Kathon CG (ECB, 1999). Today Kathon is permitted in a maximum concentration of 15 ppm but also in product with the purpose of staying on the skin.

Dermatological studies have shown isothiazolone concentrations below 20 ppm may cause sensization and that allergic responses can be provoked in already sensitized persons with concentrations of 7-15 ppm (DFG, 1993).

It is primarily CMI which is the sensitizing substance in Kathon (CMI/MI) but MI has also sensitizing properties. SCCNFP (Scientific Committee on Cosmetic Products and Non-Food Products) assesses that there is at least a factor 30 in difference between the mixture CMI/MI and MI in the sensitizing potential of the two products (SCCNFP 0625, 2003). ECB (2002b) and characterizes the mixture CMI/MI as an extreme sensitizer and MI as a strong sensitizer based on the EC3 values[14] which are found in LLNA tests (Local Lymph Node Assay).

ECB’s Working Group on Sensitisation has set up a treshold limit of sensitization for Kathon CG of < 3 ppm based on several published Guinea Pig Maximazation Tests (ECB, 2002a). Correspondingly, Alexander (2002) has set up a threshold limit of sensitization for CMI/MI of 58 ppm based on animal tests and 10-20 ppm based on human tests. Regarding MI the corresponding threshold value of sensitization is 800 ppm, based on animal tests. The highest tested dose of the mixture CMI/MI not being sensitizing is found to be 36 ppm and 500 ppm for MI in animal tests (Alexander BR, 2002).

An article in the weekly journal of the Danish Medical Association describes that persons with known Kathon allergy got severe allergic responses when being in a room painted with water-based plastic paint preserved with Kathon (30 ppm). It is unknown whether the Kathon responses are due to inhalation or skin contact with Kathon in the air (The weekly journal of the Danish Medical Association, 2002).

Prolonged, repeated impact and gene damaging effects

In long-term tests with rats no effects are seen in oral tests with MI alone. In similar long-term tests with rats only a slight gastric irritation for the Kathon mixture is seen (Kathon 886) (Rohm and Haas, 2000c; CIRP 1992).

No damaging impacts on reproduction or carcinogenic impacts of Kathon are found in the relatively few tests which are referred in the literature (CIRP, 1992). No information about the damaging potential on reproduction or carcinogenic potential of the two individual substances MI and CMI is found.

In a long-term test where rats were exposed to MI via the drinking water there was no mortality at any of the doses. No treatment related impacts on body weight and food intake at up to the second-highest dose were found. Based on this test a NOAEL of 250 ppm active constituent was set up, equivalent to 19.0 and 24.6 mg a.i./kg bw/day for male and female rats respectively for MI (Rohm and Haas, 2000c). In view of this NOAEL the Scientific Committee on Cosmetic Products and Non-Food Products (SCCNFP) has assessed that MI (as single substance) will not present a risk for the consumers’ health when used as preservative in cosmetic products in a maximum concentration of 100 ppm (0.01%) (SCCNFP 0805, 2004).

A three months’ test on rats with CMI via dermal exposure showed only weak skin responses at the highest dose of 18.75 mg/kg/day (IUCLID, 2000a).

For the Kathon mixture (Kathon 886) a three months’ test on rats with oral intake via the drinking water showed only a slight gastric irritation at a dose of 20 mg/kg/day. NOEL was set to 8 mg/kg/day (CIRP, 1992).

Kathon mixtures (Kathon CG and Kathon) have been through a number of tests regarding the mutagenic properties. Several tests show that Kathon is mutagenic in Ames test whereas there are negative results in studies investigating the DNA damaging potential of Kathon (Madsen T et al, 2001). Similarly, the single substance CMI is tested mutagenic according to Ames test (IUCLID, 2000a) whereas MI does not show any signs of mutagenicity in test with bacteria. Based on in vitro tests (in vitro) SCCNFP assesses MI to be clastogenic. That means it may cause damages or changes on chromosomes (SCCNFP 0625, 2003).

Critical impact

The critical impact of Kathon if swallowed is ataxia and serious gastric irritation. NOEL value coming from a test at oral intake through drinking water is found to 8 mg/kg body weight/day. This value is used in the risk assessment of Kathon as it is the lowest value where impacts of Kathon are seen.

In the total scenario of the toxicity of Kathon the attention is drawn to the point that Kathon is assessed to be sensitizing. ECB’s Working Group on Sensitisation has set a threshold value for Kathon CG of < 3 ppm based on animal tests. Others state a threshold value for Kathon of 10-20 ppm based on human tests.

6.3.3 Phenoxyethanol

Occurrence and application

OECD has investigated the production of phenoxyethanol and has not identified more than one American producer. In 1999 6,400 tons phenoxyethanol were produced in the USA. A large number of applications of phenoxyethanol is reported in both the USA and Europe (see the table below). Paints, detergents and dyes seem to be the largest application areas (OECD SIDS, 2004). In cosmetics phenoxyethanol is used as a preservative (INCI, 2006).

The OECD report estimates that about 60% of the produced amount of phenoxyethanol is used in consumer products (OECD SIDS, 2004).

In the mapped cosmetic products for children phenoxyethanol is found in 50 of the 208 products, distributed on 22 body shampoo/bath gel, 10 shampoos, eight booble bath products, six body lotion/cream, two hairstyling products, one balsam and one facial cream. Thus phenoxyethanol is one of the most used preservative in the mapped products. Only methyl paraben and propyl paraben are more frequently used (in 79 and 70 of the mapped products respectively).

Table 6.6: Application areas reported for phenoxyethanol

USA Europa
Solvent for cellulose acetate
Dyes
Printing inks
Resins
Organic synthesis of plasticizers
Germicides
Pharmaceuticals
Preservative for human anatomical specimens for dissection
Fixative for perfumes
As bactericide and insect repellant in organic synthesis
Fixative for cosmetic products
Textile dye carrier
Chemical intermediate product
Solvent for detergents
Solvent for frimærkepuder
Specialty inks and ball points
Detergents
Paints and varnishes
Cutting fluids
Non-agricultural pesticides and preservatives
Reprographic substances
Surfactant
Cosmetic products
plasticizer
Glue and binder
Surface treatment
Welding and soldering agents
Pharmaceuticals
Colouring agents
corrosion inhibitor
Lubricant
Stabilizer
Solvent

Identification

Chemical name 2-phenoxyethanol
Synonyms 1-Hydroxy-2-phenoxyethane
2-Hydroxyethyl phenyl ether
2-Phenoxyethyl alcohol
Ethylene glycol phenyl ether
Phenoxethol
Phenoxyethanol
Phenoxyethyl alcohol
Phenyl cellosolve
Phenylmonoglycol ether
Rose ether
INCI name Phenoxyethanol
CAS No. 122-99-6
EINECS No. 204-589-7
Gross formula C8H10O2
Molecular structure Molecular structure
Legislation:
The List of dangerous substances
(Stat. Ord. 923, 2005)
The List of unwanted substances
(Orientation from the Danish EPA no. 8, 2004)
Danish EPA Self-classification
(Environmental project no. 635, 2001)
The Cosmetics Statutory Order
(Stat. Ord. 422 , 2006)
XN; R22 XI; R36
R22 = Dangerous if swallowed. R36 = Irritates the eyes.
No
No
Is permitted as a preservative in cosmestics products in a maximum concentration of 1.0%. (Appendix 5, serial number 39 VI, 1, 29). The substance may be used in other concentrations and for other purposes than preservation, for instance as deodorant in soaps or in dandruff hair shampoo. In such cases the purpose of the use of the substance must appear from the product itself.

Physical chemical properties

Data on the physical chemical properties of phenoxyethanol are found via Chemfinder, ChemIDplus database of TOXNET, OECD SIDS report on phenoxyethanol as well as IUCLID data sheet for 2-phenoxyethanol. (Chemfinder; TOXNET; IUCLID, 2000d; OECD SIDS, 2004).

Physical structure Clear, colourless, thick liquid
Molar weight (g/mol) 138.17
Melting point 14 °C
Boiling point 245 °C
Steam pressure 0.013 hPa at 20 °C
Octanol water distribution (log POW) 1.16
Water solubility 26,700 mg/l at 20 °C

Absorption and distribution

Human skin absorption of phenoxyethanol is tested in vitro and shows that about 60% of the substances is absorbed after 6 hours (Roper et al, 1997). OECD notes that it is uncertain whether the apply af methanol as a solution has had an impact on the absorption of phenoxyethanol in one or another direction (OECD SIDS, 2004).

Tests with rats show that more than 75% and up to 99% of the phenoxyethanol after either oral or dermal exposure can be found unchanged in the urine together with small quantities of two substances to which the phenoxyethanol has metabolized. One of the metabolism products is phenoxyacetic acid (Breslin et al, 1991).

Acute toxicity

Symptoms of poisoning with phenoxyethanol in animal tests are a slight to more serious reduction in activity, weakness, reflex impairment and breathing difficulties. At high doses comatose before death or recovery is seen and also lethargy, ataxia (loss of full control of bodily movements) and body tremors at high doses are seen. No abnormalities are found in the animals which died (Hill Top Research, 1980; Richold et al, 1982).

The found LD50 values (Table 6.7) support the classification of phenoxyethanol as harmful to health if swallowed.

Table 6.7: Acute toxicity (LD50) of phenoxy ethanol

Species Exposure LD50
(mg/kg bw)
Reference
Rat Oral 1386 - 2563 Hill Top Research, 1980
Rat Oral 2937 - 4013 Gollapudi et al, 1988
Rat Oral 1260 Smyth et al, 1941.
Rat Dermal 14.300 Davies, 1970

Local irritation

Phenoxyethanol is not skin irritating for humans but irritating for eyes in animal tests with rabbits. Phenoxyethanol must also be classified Xi R36 ”Irritates the eyes” (IUCLID, 2000d; OECD SIDS, 2004; BEK 923, 2005).

A survey of 2,736 patients who underwent patch tests with 1% phenoxyethanol in petrolatum showed that none of the patients had signs of irritating effects two or four days after exposure (Lovell et al, 1984).

Allergy

Both human data and data from animal tests show that phenoxyethanol is not sensitizing. A survey with patch tests showed only one positive response to phenoxyethanol (5% in petrolatum) corresponding to 0.2% out of the 501 patients (IUCLID, 2000d; De Groot et al, 1986). In another survey with patch test with 5% phenoxyethanol in petrolatum on 3,726 patients, only one patient showed allergic responses (CIR Review, 1990a). In the above-mentioned survey of 2,736 patients with patch tests none of the patients got allergic responses (Lovell et al, 1984).

Prolonged, repeated impact and gene damaging effects

No studies regarding the carcinogenic properties of phenoxyethanol are found but the Danish Environmental Protection Agency has applied FDA’s cancer models on phenoxyethanol with a negative result (OECD SIDS, 2004). This means that phenoxyethanol is not expected to be carcinogenic.

Phenoxyethanol has shown damaging impacts on reproduction and developmental toxicity in animal tests with mice. In several reproduction studies with mice the impacts were decreasing body weight on the mice and their progeny as well as increased liver weight at high doses of between 1,875 and 4,000 mg/kg bw/day. At the highest dose of between 3,700 and 4,000 mg/kg bw/day, phenoxyethanol showed damaging impacts on reproduction in the form of decrease in both the number of young per litter and young born alive (NTP, 1984; Heindel et al, 1990; OECD SIDS, 2004).

Heindel et al. (1990) states a NOAEL for impacts on both parents and foetus of 400 mg/kg bw/day in reproduction studies with mice. A 90 days’ repeated test with oral exposure of rats with the doses 80, 400 and 2,000 mg/kg bw/day showed no impacts at 80 mg/kg bw/day (NOAEL value). At 400 mg/kg bw/day kidney toxicity and changes in grooming behavior were seen. At a dose of 2,000 mg/kg bw/day toxicity towards red blood corpuscles was seen (Ben-Dyke et al, 1977).

A 90 days’ repeated test with skin exposure on rabbits showed no impacts besides erythema of the skin on the test spot at doses of 50 to 500 mg phenoxyethanol/kg bw/day. From this a NOAEL for systemic toxicity of 500 mg/kg bw/day is derived (Breslin et al, 1991).

Phenoxyethanol has shown not to be mutagenic in the Ames test. Other gene mutation tests were also negative (IUCLID, 2000d; OECD SIDS, 2004).

The recommendations in an OECD SIDS report on phenoxyethanol are that the substance is a candidate for future work regarding human health as the substance has properties indicating a hazard for human health (eye irritation and developmental toxicity at high doses which also gives maternal toxicity) (OECD SIDS, 2004).

Critical impact

The critical impact of phenoxyethanol is assessed to be kidney toxicity if swallowed. The NOAEL value is found to 80 mg/kg body weight/day.

6.3.4 5-bromo-5-nitro-1,3-dioxane

Occurrence and application

5-bromo-5-nitro-1,3-dioxane is used as a stabilizer, surfactant and bactericide, and in the immunology it is used to preserve antibodies in concentrations of between 0.1 and 0.5% (Wikipedia, 2006). According to the SPIN database 5-bromo-5-nitro-1,3-dioxane is used in detergents, in cosmetic products and for surface treatment in Denmark (SPIN2000).

Since the middle of the 1970’ies 5-bromo-5-nitro-1,3-dioxane has been used in cosmetic products as a preservative in shampoos, bobble bath etc. (Wikipedia, 2006). According to the Cosmetics Statutory Order the permitted maximum concentration is 0.1% and only in products which are cleansed after apply (Stat. Ord. 422, 2006).

In the mapped cosmetic products for children 5-bromo-5-nitro-1,3-dioxane occurs in 15 of the 208 products, distributed on 13 body shampoos/bath gels and two bobble baths.

Identification

Chemical name 5-Bromo-5-nitro-1,3-dioxan
Synonyms 1,3-Dioxane, 5-bromo-5-nitro-
5-Bromo-5-nitro-m-dioxane
Bronidox
INCI name 5-Bromo-5-nitro-1,3-dioxane
CAS No. 30007-47-7
EINECS No. 250-001-7
Gross formula C4H6BrNO4
Molecular structure Molecular structure
Legislation:
The List of dangerous substances
(Stat. Ord. 923, 2005)
The List of unwanted substances
(Orientation from the Danish EPA no. 8, 2004)
Danish EPA Self-classification
(Environmental project no. 635, 2001)
The Cosmetics Statutory Order
(Stat. Ord. 422 , 2006)
No
No
Xn; R22 R43
R22 = Dangerous swallowed
R43 = Might give allergic reactions at contact with the skin
Is permitted as a preservative in cosmetic products in a maximum concentration of 0.1%. May only be used in products which are cleansed of after apply. Formation of nitrosamines shall be avoided. Compulsory user’s instruction and warning on the label is: “Contains formaldehyde” if the concentration in the end product is above 0.05%.

Physical chemical properties

Data on the physical chemical properties of 5-bromo-5-nitro-1,3-dioxane are found in various safety data sheets on the Internet (ChemicalLand21.com, 2006), (Wikipedia, 2006), as well as The Danish Information Centre for Environment & Health (The Danish Information Centre for Environment & Health, 2004).

Physical structure White crystallic powder
Molar weight (g/mol) 212.06
Melting point 60 °C
Boiling point -
Steam pressure -
Octanol water distribution (log POW) 0.25
Water solubility Insoluble

Acute toxicity

In general, only few data on the toxicity of 5-bromo-5-nitro-1,3-dioxane are available. According to the list of dangerous substances 5-bromo-5-nitro-1,3-dioxane shall not be classified as hazardous but according to the guiding list for self-classification of the Danish Environmental Protection Agency the substance is hazardous to health (dangerous if swallowed) (Orientation from the Danish Environmental Protection Agency no. 8, 2004).

Table 6.8: Acute toxicity (LD50) of 5-Bromo-5-nitro-1,3-dioxan

Species Exposure LD50
(mg/kg bw)
Reference
Rat Oral 590 (Wikipeida, 2006)
Rat Oral 455 (Fette, Seifen, Anstrichmittel, 1976)
Moapply Oral 455 (Wikipeida, 2006)
Rat Dermal 2.5 mg/24 hours (Wikipeida, 2006)

In safety data sheets 5-bromo-5-nitro-1,3-dioxane is described as being dangerous if swallowed. Reactions of toxicity when swallowed are impacts on the central nervous system, such as tremor, convulsions and excitement (ScienceLab, 2005; Wikipedia, 2006).

Local irritation

5-bromo-5-nitro-1,3-dioxane is skin irritating and irritating for the eyes in concentrations above 0.1% (ScienceLab, 2005; Wikipedia, 2006; CIR Review, 1990b).

Allergy

5-bromo-5-nitro-1,3-dioxane is assessed to be sensitizing for human even if the substance is not sensitizing in studies with guinea pigs (CIR Review, 1990b; Madsen T et al, 2001). According to the guiding list for self-classification of the Danish Environmental Protection Agency, 5-bromo-5-nitro-1,3-dioxane is allergenic and therefore the substance ought to be labelled with R43 “Might cause allergic reactions at contact with the skin (Environmental project no. 635, 2001).

5-bromo-5-nitro-1,3-dioxane is a so-called formaldehyde releaser, this means that the substance separates out formaldehyde. This is the way that 5-bromo-5-nitro-1,3-dioxane is preserving as formaldehyde is a preservative. According to the Danish Knowledge Centre for Allergy, about 2% of the persons with eczema are allergic towards formaldehyde (The Danish Knowledge Centre for Allergy, 2006c).

Prolonged, repeated impact and gene damaging effects

Only a little information about the carcinogenic, damaging to reproduction and gene damaging effects is available but according to the little found information 5-bromo-5-nitro-1,3-dioxane is neither carcinogenic, damaging to reproduction nor mutagenic (negative Ames test), (Roche Applied Science 2005; CIR Review, 1990b).

5-bromo-5-nitro-1,3-dioxane can react with amines and amides and form nitrosamines or nitrosamides which are assessed to be carcinogenic and may penetrate the skin (Madsen T et al, 2001, US FDA). Special guidelines regarding this substance are found in the Cosmestics Statutory Order stating that formation of nitrosamines should be avoided (Stat. Ord. 422, 2006). In practice this means that 5-bromo-5-nitro-1,3-dioxane must not be mixed with amines and amides in cosmetic products. Furthermore, the substance is only permitted to be used in cosmetic products being cleansed after use.

Critical impact

Detailed information about 5-bromo-5-nitro-1,3-dioxane is missing in order to assess the critical impact of the substance but there is no doubt that contact allergy at skin contact is a substantial impact.

[13] The different sources disagree a little on how large quantities of sodium benzoate that are applied for the different purposes but preservative for food products and beverages seems to be more than 50% of the total produced quantity.

[14] EC3 value is the estimated concentration which is needed to provoke a three times increase in the activity of lymph gland cell.

 



Version 1.0 October 2007, © Danish Environmental Protection Agency