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Mapping and health assessment of chemical substances in shoe care products

6 Toxicological profiles

6.1 Turpentine oil
     6.1.1 Use
     6.1.2 Identification
     6.1.3 Physical-chemical data
     6.1.4 Toxicological data
6.2 Mineral turpentine (stoddard solvent)
     6.2.1 Use
     6.2.2 Identification
     6.2.3 Physical-chemical data
     6.2.4 Toxicological data
6.3 C_9-12 isoalkanes
     6.3.1 Use
     6.3.2 Identification
     6.3.3 Physical-chemical data
     6.3.4 Toxicological data
6.4 Propan-2-ol
     6.4.1 Use
     6.4.2 Identification
     6.4.3 Physical-chemical data
     6.4.4 Toxicological data
6.5 Heptane
     6.5.1 Use
     6.5.2 Identification
     6.5.3 Physical-chemical data
     6.5.4 Toxicological data

This section contains toxicological profiles for the selected critical ingredients. The toxicological data identified in this chapter are used in the following exposure evaluation as well as in the evaluation of whether there is any risk connected with consumers using the products.

6.1 Turpentine oil

6.1.1 Use

Previously, the most common use was as thinner in pain and other products for surface coating {8} which is still partly its use. In addition, turpentine oil is used in ointments, in wax, in polishers and similar products as well as in the synthesis of camphor and menthol.

6.1.2 Identification

Turpentine oil is a complex mixture of substances defined as: ”Any of the volatile mainly turpentine fractions or destillates found through solvent extraction of rubber collection from or crushing of blood tree. Consists primarily of the C₁₀H16-terpencarbonhydrids: alfa-pinen, beta-pinen, limonen, 3-caren, camphen. May contain other acyclic, monocyclic or bicyclic terpenes, oxygenated terpenes and anethol. The exact composition varies with refining methods and age, origin and species of the blood tree source”.

Vapour destillated turpentine oil is composed of 81.3% a-pinen, 2.1% ß-pinen, 11.4% camphen 3.4% related terpenes and less than 1% of a number of other compounds including 3-caren, dipenten and cymen {4}.

As it is a complex misture it is not possible to state an exact mol-weight or an unambiguous molecule structure.

Turpentine oil is a clear volatile liquid with a characteristic odour described as aromatic, unpleasant and penetrating. The odour limit is 100 ppm {8}.

1 ppm = 5.6 mg/m³

6.1.3 Physical-chemical data

6.1.4 Toxicological data:

6.1.4.1 Absorption

Easily absorbed through the lungs, gastrointestinal tract {7}. Ingredients in turpentine oil is easily absorbed through the skin.

6.1.4.2 Acute effects, humans:

Irritating to skin, eyes and mucous membranes.

Splashes of the liquid in the eyes may cause inflammation of the conjunctiva of the eye (conjuctivitis) and thickening of the horny layer. Skin contact causes a risk of allergy {2}.

Ingestion causes irritation of gastrointestinal tract and may cause kidney damage. CNS depression including coma may occur after ingestion {7}. Lethal dose by ingestion for humans is estimated at 150 ml. {2}.

Vapours in concentrations of 70-200 ppm (396-1130 mg/m³) are slightly irritating {2}. Another source establishes the threshold for airway irritation at approximately 75 ppm (420 mg/m³) {4}.

Tests on volutary subjects exposed to turpentine oil vapours resulted in 75 ppm (424 mg/m³) irritation in nose and throat in several of the test subjects.

At concentrations between 750-1000 ppm (4238 – 5650 mg/m³), chest pain and synsforstyrrelser are seen. Prolonged inhalation of concentrations between 750 and 1000 ppm causes eye irritation, headache, dizziness, nausea and abnormal, fast heart rhythm (tachycardia) {2}.

Accidental ingestion causes a burning sensation in the mouth, cough, lung oedema, coma and liver damage {1}. Chemical pneumonia in case of vomit in the lungs.

Oral TD_LO in a single woman who had kidney damage after ingestion was established at 560 mg/kg {1}.

TC_LO through inhalation in a single individual was established at 175 ppm (980 mg/m³) as the substance caused damage to eyes, airways, coma and liver damage {1}. This observation is, however, of only minor importance as it is only one individual.

6.1.4.3 Acute effects, animals

The LD₅₀ value by ingestion in rats is > 5000 mg/kg.

The LC₅₀ value in mice (2 hours) and rats (6 hours) has been reported at 29 mg/m³ (5 ppm) and 12,000 mg/m³ (2143 ppm), respectively {2}.

The lowest lethal dose (LD_LO) in rabbits after application on the skin has been estimated at 5010 mg/kg/bw {2}.

6.1.4.4 Sub-chronic experiments, animals

In a study with guinea pigs in which the animals inhaled 715 ppm (4004 mg/m³), 4 hours/day for 45 to 58 days, no specific or hematological changes were found nor was any pathology that could be contributed to turpentine oil {8}.

In another study, seisures and paralysis was seen in rabbits at a concentration of 750 ppm (4200 mg/m³). The duration of this study has, however, not been stated {8}.

No effects were seeen in dogs after inhalation of 180 ppm (1008 mg/m³), 3.5 hours/day for 8 days {8}.

6.1.4.5 Chronic effects

Prolonged repeated exposure to turpentine oil for more than 5 years may lead to an increased risk of airway cancer {7}.

6.1.4.6 Summary of data

Table 20 Toxicological data for turpentine oil

1) Blisters on the skin
2) Effects on the gastrointestinal tract, kidneys, ureters and the bladder

Table 20 shows the toxicological data found in literature for animals and humans, respectively. The critical effects from exposure to turpentine oil is estimated to be allergy by skin contact and irritation of lungs by inhalation of vapours.

The lowest effect level for airway irritation in humans are set at 75 ppm (420 mg/m³) and the zero-effect-level is set as equal to the limit value in the working environment which is 140 mg/m³. There is no zero-effect-level for sensitisation by skin contact.

6.2 Mineral turpentine (stoddard solvent)

6.2.1 Use

Used as extraction liquid, cleaning liquid, degreasing product and as solvent in a number of product types, including paint.

6.2.2 Identification

Mineral turpentine is a complex mixture of substances defined as: ”Low-boiling unspecified naphtha – A colourless, refined raw oil destillate free of rancid or repellent odours, with a boiling point interval of approximately from 149°C to 204°C”.

Mineral turpentine is thus a mixture of branched and equal-chained paraffins, naphthans and alkyl aromatic carbonhydrids.

The distribution of kulbrinter in traditional mineral turpentine (stoddard solvent) is approximately: 48% alkanes (mainly C_9-12), 26% monocycloalkanes, 12% dicycloalkanes, 14% aromates. The benzene content is usually less than 0.1% {12}.

As it is a complex mixture it is not possible to state an exact molecular weight or an unambiguous molecular structure.

Mineral turpentine (stoddard solvent) is a clear liquid with a characteristic odour.

*The classification as carcinogenic can be omitted if it can be demonstrated that the substance contains less than 0.1 weight percentage benzene which is the case for practically all mineral turpentines contained in the product on the Danish market.
** 1 ppm = 5.80 mg/m³

6.2.3 Physical-chemical data

6.2.4 Toxicological data

6.2.4.1 Absorption

Mineral turpentine is easily absorbed through the airways. Approximately 50% of the aliphatic hydrocarbons and approximately 62% of the aromatic hydrocarbons found in the inhalation air {12}.

Reports of poisoning cases after ingestion indicates that mineral turpentine can be absorbed from the gastrointestinal tract {12}.

There is no data for absorption of mineral turpentine through the skin, but studies of individual substances in mineral turpentine shows that they can be absorbed. If both hands are e.g. dipped in xylen, the amount absorbed through the skin corresponds approximately to the absorption through the lungs at an exposure to 100 ppm (580 mg/m³) during the same time period {12}.

6.2.4.2 Acute effects, humans

Mineral turpentine shows acute, narcotic effects on the central nervous system {12}. Inhalation of vapours leads to headache, dizziness, intoxication and seisures. At very high concentrations there may be fainting and death {1}.

Symptoms after inhalation includes effects on the central nervous system from slight discomfort such as dizziness and headache to reduced performance in neuro-phsycological tests. In serious cases, chronic brain damage has been diagnosed {1}.

Six volunteer test subjects felt no irritation at exposure to an air concentration of 140 mg/m³ (25 ppm) for 15 minutes. One subject felt slight and passing eye irritation at 850 mg/m³ (145 ppm) and at 2700 mg/m³ (465 ppm) all 6 test subjects felt eye irritation of which 3 had eye flux. 2 of the subjects felt slightly groggy. All effects disappeared within 15 minutes after the experiment ended {1}.

Slight irritation of eyes, nose and throat has been described in people at a vapour concentration of 600 mg/m³ (100 ppm) {21}.

At exposure of humans to 288 mg/m³ (50 ppm) for 7 hours, no significant changes were seen in the visomotoric coordination, memory and reaction time {12}.

Mineral turpentine can penetrate the skin and cause systemic effects. Frequent use of hand cleaners containing mineral turpentine has lead to damage to the liver and bone marrow {1}.

Ingestions will lead to discomfort in the form of ingestion and symptoms similar to the ones seen in case of inhalation {1}.

If mineral turpentines gets into the lungs due to vomiting after ingestion it may cause chemical pneumonia {1}.

Mineral turpentine may lead to liver damage in humans {12}.

The narcotic effect of mineral turpentine is well-known from occupational exposures. Commonly registered symptoms are headache, fatigue, light-headedness, reduced appetite and nausea.

Experimental exposures for 7 hours to mineral turpentine in concentrations between 575 mg/m³ and 2300 mg/m³ (100 – 400 ppm) caused headache, fatigue and confusion in test subjects. Clinical-neurological tests as well as neuro-psycological tests found a dose-related impact on the sense of equilibrium, reaction time and eye coordination. Long-term memory was influenced at exposure to 2300 mg/m³ (400 ppm) {12}.

6.2.4.3 Acute effects, animals

In a Draize-test on rabbits, mineral turpentine was classified as slightly irritating to the skin {38}. The potential skin irritating properties of mineral turpentine is likely connected to the content of aromates as a higher aromat content will lead to a larger skin irritation potential.

The lowest lethal concentration by inhalation in rats for 3 and 8 hours respectively has been set at 8200 and 8000 mg/m³ {17}.

6.2.4.4 Sub-chronic effects, animals

After exposure of rabbits, dogs and monkeys to 1271 mg/m³ (220 ppm) mineral turpentine for 24 hours/day for 90 days, bronchitis-like changes of the lung tissue was found. Similar changes could not be demonstrated after exposure for 8 hours/day, 5 days/week for 6 weeks {12}.

The lowest toxic dose in rats by inhalation for 65 weeks varies from 480 mg/m³ to 9860 mg/m³. Among the effects seen were effects on kidneys, ureter and bladder as well as anaemia {17}.

By application to the skin of rabbits for 4 weeks; the lowest dose leading to dermatitis was set at 2000 mg/kg {5}.

6.2.4.5 Chronic effects

Exposure of groups of pregnant rats to 5460 mg/m³ (940 ppm) for 6 hours per day from day 3 to 20 in the gestation period lead to an embryo-toxic effect as the featus weight was significantly reduced and the formation of bone tissue was delayed. At the same time, there was an increased occurrence of featuses with an extra rib {12}.

A number of peidemiological tests of workers exposed to an exposure level estimated at approximately 240 mg/m³ (40 ppm) indicates a link between prolonged exposure to mineral turpentine (and other solvents) and development of chronic effects on the central nervous system, particularly the brain. The symptoms are memory difficulties, fatigue, dizziness, lack of sense of smell as well as reduced intellectual capacity and delicate motor function. The illness is called painters syndrom, pre-senile demensia or chronic toxic encelopaty {12}.

It is estimated that exposure to an average of 240 mg/m³ (40 ppm) for more than 13 years may cause chronic effects on the central nervous system {20}.

In vivo and in vitro mutagenicity tests with mineral turpentine were all negative {2}. Any carcinogenic effects from hydrocarbon destillates are particularly attributed to the content of benzene and polyaromatic hydrocarbons.

6.2.4.6 Summary

Table 21 Toxicological data for mineral turpentine

1) Shaking and seisures.
2) Effects on kidneys, urinleder and bladder including acute kidney failure and acute tubular necrosis. Effects on the blood
3) Anaemia
4) Reduced kidney function and anaemia
5) Dermatitis

The critical effects of mineral turpentine are estimated to be the irritating effect on the mucous membrane as well as acute and chronic effects on the central nervous system. The zero-effect-level for irritation and the impact on the central nervous system in humans is set as equal to the limit value in the working environment, i.e. 25 ppm (145 mg/m³).

6.3 C_9-12 isoalkanes

6.3.1 Use

Used as solvents in a large number of product types, including paint and cleaning products.

6.3.2 Identification

C_9-12 isoalkanes is a mixture of branched saturated aliphatic hydrocarbons with carbon chains of 9-12 carbon atoms which typically contain < 0.01% aromatic compounds.

As they are a complex mixture it is not possible to state an exact molecular weight or an unambiguous molecular structure.

C_9-12 isoalkanes are a clear, volatile liquid

1 ppm = 6 mg/m³ (Isopar G)
1) EXXON {14}

6.3.3 Physical-chemical data

1) Isopar G {44}

6.3.4 Toxicological data

6.3.4.1 Absorption

C_9-12 isoalkanes can be absorbed by inhalation and by ingestion.

6.3.4.2 Acute effects, humans

In many of the aliphatic kulbrinter, dermatitis, irritation, impact on the central nervous system and anaesthetic effects are seen. The effects are increased in case of increased molecular weight. In general, aliphatic hydrocarbons have a neuro-toxic effect at approximately 100 ppm corresponding to 200-600 mg/m³ {17}.

If the liquid gets into the lungs due to vomiting after ingestion, chemical pneumonia may occur {1}.

6.3.4.3 Acute effects, animals

Isopar G gave no sensory irritation in mice that were exposed for 30 minutes to a vapour concentration of 347 ppm. The liquid is degreasing to the skin and repeated or prolonged contact may cause skin problems and ezcema {15}.

A research group has suggested a NOEL-value for C_7-12 alkanes of 200 – 600 mg/m³ in humans based on a general neuro-toxic effect, Larsen et al (1999) {17}.

6.3.4.4 Sub-chronic effects

A zero-effect-level for teratogenic effects in rats has been set at 900 ppm (5400 mg/m³) after inhalation. The same experiment establishes a zero-effect-level for increase in kidney weight in male rats at the same dose.

6.3.4.5 Chronic effects

Isopar G has shown negative results in several mutagenicity tests {1}.

Tests of cell cultures (V79 hamster cells) increased the n-decan, n-dodecan and n-tetradecan frequency of mutations induced from a known mutagen {12}.

6.3.4.6 Summary

Table 24 Toxicological data for C_9-12 isoalkanes

1) Isopar G, EXXON {44}
2) No toxicological effects were seen in the mother animals and no teratogenic effects were seen at this dose level

The critical effect of C_9-12 isoalkanes is estimated to be neuro-toxic effects. The zero-effect-level for a general neuro-toxic effect in humans is set at 200 mg/m³ which is slightly lower than the DWEA limit values for ”Decan, other isomers than n-decan” of 350 mg/m³.

6.4 Propan-2-ol

6.4.1 Use

Propan-2-ol is used as a raw material in the synthesis of acetone, glycerin and other chemicals. In addition, the substance is used as anti-frost liquid and solvent in a number of other product types {1}.

6.4.2 Identification

Propan-2-ol is a volatile substance which is highly flammable at room temperature. The odour of propan-2-ol is similar to a mixture of ethanol and acetone and the substance has a bitter taste.

*S=Skin absorption
*1 ppm = 2,45 mg/m³

6.4.3 Physical-chemical data

6.4.4 Toxicological data

6.4.4.1 Absorption

Propan-2-ol is easily abosorbed by inhalation and through the digestive system {19}. May be absorbed through the skin.

6.4.4.2 Acute effects, humans

Is irritating by eye contact. Prolonged skin contact may cause irritation {19}.

Ingestion or inhalation of high concentrations may cause readness, headache, dizziness, nausea, mental depression, narcotic effect and coma {1}.

Experiments with voluntary test subjects has found that an air concentration of 400 ppm (980 mg/m³) causes slight irritation of nose, eyes and throat. At 800 ppm (1960 mg/m³) the symptoms are intensified without being serious. Most test subjects found this concentration unpleasant {10}.

Propan-2-ol is more toxic than ethanol but less toxic than methanol {1}. Several lethal cases have been described as a result of ingestion of 0.47 L 70% propan-2-ol. Preceeding death was deep coma and chock and the cause of death was respiration stop {1}.

No effects (hematology, blood chemistry, urin analysis and ophtalmoscopy) were found in humans ingesting 2.6-6.4 mg/kg per day for 6 weeks {1}.

It is assumed that the lethal dose in humans is 240 ml but doses as low as 20 ml in water may cause symptoms.

Skin contact may cause drying and irritation {1}.

A few cases of skin allergy to propan-2-ol have been found {1}.

6.4.4.3 Acute effects, animals

L(C)D50 –values in test animals are all very high, higher than 3600 mg/kg by ingestion, higher than 12,000 by application to the skin and higher than 70,000 mg/m³ by inhalation.

0.1 ml propan-2-ol was irritating to the eyes in rabbits while application of the substance on the skin did not lead to irritation.

6.4.4.4 Sub-chronic effects, animals

Studies with rats and mice that inhaled up to 5000 ppm (12.250 mg/m³) propan-2-ol for 6 hours per day, 5 days per week for 13 weeks showed narcotic effects at 5000 ppm. An increased liver weight was observed in female rats at 5000 ppm but no effects were found during autopsy and histopathological examinations. Neuro-pathological tests of the rats showed no effects on the central nervous system {2}.

6.4.4.5 Chronic effects

The substance has given negative results in several mutagenicity tests {1}.

There is insufficient evidence of carcinogenicity in humans and animals (IARC group 3) {1}.

6.4.4.6 Summary

Extrapolation of data from reproduction experiments with animals has lead a group of researchers to conclude that 420 mg/kg/d is the dose which in humans will have no reproduction toxic or developmental effects in foetuses.

The critical effect of the substance is estimated to be narcotic effects by inhalation as well as effects on foetuses.

Table 23 Toxicologicla data for propan-2-ol

1) Blood parameters
2) Reduced body weight and increased mortality

6.5 Heptane

6.5.1 Use

The use as standard in tapping test of gasoline, in orgenic synthesis and inclusion either in pure form or as a component in other kulbrinte destillates used as fule and solvents {9}.

6.5.2 Identification

n-Heptane is a volatile, flammable liquid. The odour limit for heptane is 150 ppm {9}.

* 1ppm = 4,1 mg/m³

6.5.3 Physical-chemical data

6.5.4 Toxicological data

6.5.4.1 Absorption

Heptane can be absorbed by inhalation. In vitro tests regarding absorption through the skin indicates that only a very small amount is absorbed by skin contact. The penetration rate through rat skin was as low as 0.14 µg/cm²/t {13}.

6.5.4.2 Acute effects, humans

Is slightly irritation by contact with the eyes {2}.

Test subjects exposed to 1000 ppm (4200 mg/m³) heptane for 6 minutes or 2000 ppm (8400 mg/m³) for 4 minutes experienced slight dizziness. At exposure to 3500 ppm (14,700 mg/m³), the test subjects experienced moderate dizziness and at 5000 ppm (21,000 mg/m³) for 4 to 7 minutes pronounced dizziness, lack of coordination, lack of balance and euphoria. At exposure to 5000 ppm for 15 minutes the symptoms lasted for 30 minutes after the exposure ended {1}, {13}.

Short (4 minutes) exposure of humans to 5000 ppm lead to nausea, loss of appetite and gasoline-like taste in the mouth which lasted for hours after the exposure ended {9}.

6.5.4.3 Acute effects, animals

The concentration which leads to a 50% decrease in respiration rate in mice (RD₅₀) has been set at 17,400 ppm (73.080 mg/m³).

A comparison between RD₅₀ in mice and humane data has shown that 0.01 x RD₅₀ gives minimal or no irritation of the airways. On this basis, you get an irritation limit for heptane of 175 ppm (735 mg/m³) in humans {13}. Another research group has suggested 0.03 X RD₅₀ as the irritation threshold in humans giving a value of 522 ppm (2200 mg/m³).

6.5.4.4 Sub-chronic effects

Rats exposed to repeated exposures of up to 12,400 mg/m³ (approx. 3000 ppm) for 6 hours per day, 5 days per week for 26 months showed no signs of peripheral neuropathy as it is known from exposure to n-hexan {2}.

6.5.4.5 Chronic effects

Only negative results have been found in in vitro and in vivo mutagenicity tests {34}.

6.5.4.6 Summary

Table 22 Toxicologicla data for heptan

1) At a dose of 17000 mg/kg, one of the rats died
2) Neuro-toxic end-points were examined and no effects were found at the highest dose (12,400 mg/m³)
3) Based on RD₅₀ in mice
4) Acute effects on the central nervous system

The critical effects of heptane are estimated to be airway irritation which is more pronounced than for n-hexan and pentan as well as acute effects on the central nervous system.

The zero-effect-level for airway irritation in humans is set at 175 ppm (715 mg/m³) corresponding ot the lowest of the 2 suggested irritation limits in humans while the zero-effect-level for acute effects on the central nervous system is set at equal to the limit value in the working environment.

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Version 1.0 June 2005, © Danish Environmental Protection Agency