4,4’- Isopropylidenediphenol (bisphenol A) is a white solid present in the form of crystals or flakes. It is used mostly in the production of epoxy resins (appr. 95% of its consumption). It is also used in the polycarbonate plastics, unsaturated polyester, polysulphonte and polyacrylate resins as well as flame retardants. Polycarbonate plastics are used to make products such as emulsions for thermal printers employed for printing tickets, labels, receipts, faxes etc.

The routes of occupational exposure during production and application of bisphenol A are the respiratory system and the skin.

The exact number of occupationally exposed to 4,4’-isopropylidenediphenol is not known but taking into account the wide use of polycarbonate and polyester resins it can be counted in thousands. Because of only trace amounts of bisphenol A in most of the resins, the levels of exposure are usually minimal.

In Poland 4,4’- isopropylidenediphenol is used mainly as a component of glues for electronic parts, PVC stabilizer, addition components of epoxy resins and brake fluids. In 2010 only 4 persons were reported as occupationally exposed to bisphenol A dust in concentrations exceeding Polish OEL (5 mg/ m³) – 2 in the crop and animal production, hunting and related service activities sector and 2 in the water transport sector. In 2013 no workers exposed above OEL value were reported.

Oral LD50 values beyond 2 000 mg/kg bw were found in the rat and mouse, and dermal LD50 values above 2 000 mg/kg are evident in the rabbit.

4,4’- Isopropylidenediphenol has been classified as Repr. 1B, H360F (may damage fertility or the fetus) and substance that causes serious eye damage (H318) and may cause respiratory system irritation (H355).

In workers having occupational contact with 4,4’-isopropylidenediphenol irritation of eyes, skin and respiratory system was observed. In animal experiments it was clearly shown that bisphenol A did not cause skin irritation, however, it was shown that the compound is an eye irritant. Slight and transient nasal tract epithelial damage was observed in rats exposed to bisphenol A dust which suggests that it appears to have a limited respiratory irritation potential.

There are several reports of patients with dermatitis responding to BPA in patch tests, however, it is unclear whether bisphenol A or related epoxy resins were the underlying cause of the hypersensitive state. No reliable sensitisation animal data from experiments meeting the required standards are available.

Toxicity of bisphenol A has been tested on mice, rats and dogs. The compound administered orally caused mainly a decrease in body weight gain; minor changes in organ weight, mostly in liver; respiratory disorders, diarrhea and death. From chronic experiments the liver and kidney seem to be the target organs.

There are no in vivo data on mutagenic activity of bisphenol A. It also does not appear to produce either gene mutations or structural chromosome aberrations in bacteria, fungi or mammalian cells in vitro. The compound did not induce gene mutations in yeasts; sister chromatid exchange tests carried out on mammalian cells also gave negative effects.

No information on human cancerogenicity of 4,4’-isopropylidenediphenol has been found in the literature and databases available. In a 103-week test on rats and mice of both sexes no convincing evidence indicating carcinogenic action of bisphenol A was found.

Some studies indicate negative action of 4,4’-isopropylidenediphenol on reproduction which is a result of a mechanism of its action – in in vivo test the compound was found to bind to the nuclear estrogen receptors. However, data on the embryotoxic activity of bisphenol A and its effects on reproduction are not conclusive. Contradictory findings between the studies have been reported in several studies in rodents which was thoroughly discussed in the EFSA Report of 2015. In studies carried out in accordance with the FDA/NTCR standards 4,4’- isopropylidenediphenol effects on reproduction have been seen only at high doses showing also other toxic effects. Comprehensive tests with a wide range of doses did not confirm effects of 4,4’-isopropylidenediphenol on reproduction and development at low doses below 5 mg/kg bw. In Chinese epidemiological studies, impaired sperm quality in workers occupationally exposed to bisphenol A has been found, however, the effect of other concurrent exposures cannot be excluded.

4,4’-Isopropylidenediphenol in all species studied is conjugated with glucuronic acid and excreted as glucuronid with urine. The major route of excretion is via faeces; regardless of the route of entry 50-80% of the administered dose is eliminated with faeces in the unchanged form. In humans the compound is excreted as glucuronide or sulphate conjugates in urine.

In Poland as well as in most other countries 5 mg/m³ as OEL and 10 mg/m3 as STEL have been established for 4,4’- isopropylidenediphenol.

Scientific Committee on Occupational Exposure Limits (SCOEL) has proposed to establish an Indicative Occupational Exposure Limit (IOEL) in workplace air at the level of 2 mg/m³ taking the inhalation NOAEC of 10 mg/m³ from the rat study as a starting point for recommending an OEL. The critical effect in this study was respiratory tract irritation. According to SCOEL there is no toxicological basis for recommending an additional specific short-term exposure limit (STEL). Assignment of “skin” notation was also not recommended.

The proposed OEL value for 4,4’- isopropylidenediphenol (inhalable fraction) has been derived from its irritating action on nasal tract epithelium in an inhalation study on experimental animals. The proposed OEL value is 2 mg/m³. This value should also protect workers against toxic effects on liver and kidney.

There are no grounds for establishing a short-term exposure limit (STEL) nor for recommending a biological limit value (BLV).

It is also proposed to introduce the following assignments: “I” – irritating substance and “A” – sensitizing substance.

Buta-1,3-diene is a gas used in the production of thermoplastic resins, elastomers and synthetic rubber. Buta-1,3-diene is absorbed mainly in the respiratory tract and then metabolized to monoepoxide – 1,2-epoxybut-3-ene and diepoxide – 1.2:3,4 diepoxybutane, and after their conjugation with glutathione is excreted with urine.

According to data from the Central Registry on Exposure to Substances, Mixtures, Agents or Carcinogenic or Mutagenic Technological Processes, in 2015 the number of people exposed to buta-1,3-diene in Poland was 958 and additionally about 200 were exposed to petroleum substances which carcinogenic effect is depending on the buta-1,3-diene.

According to data from sanitary-epidemiological stations, in Poland in 2013 and 2016, there were no workers exposed to buta-1,3-diene at levels exceeding maximum allowable concentration (MAC) of 4.4 mg/m³. Buta-1,3-diene in small concentrations is a mild narcotic agent for humans, while for occupationally exposed workers it has irritating properties to the mucous membranes of the eyes and airways.

Buta-1,3-diene is a substance with low acute toxicity to animals (LC50 value for rats is 270 000 mg/m³). This substance is mutagenic and genotoxic, it can cause damage to the genetic material of somatic and germ cells. It has been proved that buta-1,3-diene is carcinogenic for B6C3F1 mice and rats. There is also epidemiological evidence that occupational exposure to buta-1,3-diene is associated with the risk of a cancer of a lymphohematopoietic system. According to the IARC classification, buta-1,3-diene is included in group 1, i.e., carcinogenic substances for humans, and according to ACGIH classification to group A2, i.e., substances suspected to be carcinogenic for humans. In Europe, buta-1,3-diene is classified in Cat. 1A.

carcinogens and Cat. 1B. mutagenic compounds.

Buta-1,3-diene does not cause fertility disturbances, and its teratogenic effects appeared when doses were toxic to mothers only.

In Directive 2017/2398 of the European Parliament and of Council (EU) 2017/2398 of 12 December 2017 amending Directive 2004/37/EC on the protection of workers from the risks related to exposure to carcinogens or mutagens at work for buta-1,3-diene, binding occupational exposure limit value (BOELV) was at the level of 2.2 mg/m3 (Official Journal of the EU L 345 of 27/12/2017, p. 87). The directive will be in force in the EU Member States on January 17, 2020. It was proposed to adopt the value of the maximum allowable concentration (MAC) of the buta-1,3-diene at the level of 2.2 mg/m3 and the following values of the biological exposure indices (BEI):

–– 1.6 mg of 1,2-dihydroxy-4-(N-acetyl-cystein-S-yl)butane/g creatinine in urine measured at

the end of working shift

–– 2.1 pmol/g Hb - hemoglobin adducts: mixture of N-[1-(hydroxymethyl)prop-2-enyl]valine and N-(2-hydroxybut-3-enyl)valine in blood showing exposure for the last 120 days.

This standard is additionally marked Carc. 1A – a substance with proven carcinogenic effect for humans and Muta. 1B – a substance that is considered mutagenic for humans. There is no evidence for establishing STEL value for buta-1,3-diene.

The estimated additional risk of leukemia during the 40-year exposure to buta-1,3-diene at a concentration of 2.2 mg/m³ is 8×10^-7, it is lower than the risk for the general population in Poland, which is 7.15×10^-5.

Phenolphthalein is a colorless and odorless crystalline solid; in a powdered form white or pale yellow. It is nonvolatile, practically insoluble in water, but it dissolves in ethanol. Phenolphthalein is not known to occur as a natural product. The synthetic substance is used as a pH indicator in laboratories, during work on metal surfaces in galvanizing plants as well as for measuring the saturation of concrete with carbon dioxide. Until the end of the 20th century, it was widely used as a component of non-prescription laxatives – in 1999 FDA removed phenolphthalein from the list of substances considered safe. In 2016 in Poland 255 enterprises were reported to work with phenolphthalein (mainly laboratories) and there were 2500 occupationally exposed people.

Phenolphthalein used in therapeutic doses was well tolerated. Only a few side effects were reported: abdominal discomfort, nausea, reduced blood pressure and weakness. Chronic use of phenolphthalein resulted in widening of the colon, reduced thickness of the lining of the mucosa, gastric disorders, dehydration and electrolyte imbalance. In a 13-week study in which phenolphthalein was administered to laboratory animals with diets, mice turned out to be a more sensitive species from rats. Changes in testes and epididymides were observed in males and hypoplasia and bone marrow necrosis in males and females. The results of genotoxicity studies indicated that phenolphthalein acts as a promutagen and exerts a clastogenic effect after metabolic activation. Studies on the effect of phenolphthalein on the reproduction of animals indicated its harmful effect on reproductive functions of males. In the EU, phenolphthalein is classified as a category-2 mutagen and category-2 reproductive toxicant (due to its effect on fertility).

A small increase in the risk of colorectal cancer and ovarian cancer was observed in case-control studies in patients using phenolphthalein-based laxatives (especially with intensive use of these agents), but the relationship was not statistically significant. In a 2-year NTP carcinogenicity study a significant increase in the number of benign phaeochromocytomas and adenomas of renal tubular epithelium was observed in male rats. There was also a significant increase in histiocytic sarcomas in mice of both sexes and in malignant lymphomas (of all types) and thymic lymphomas and benign ovarian tumors in females. Based on these experiments phenolphthalein has been identified as a substance reasonably anticipated as human carcinogen (NTP R). The experiment on heterozygous p53 (+/-) mice of both sexes confirmed an increase in lymphoma cases. Phenolphthalein is classified by European Union experts as a category-1B of carcinogenic substances, i.e. known or presumed human carcinogens, however the classification is largely based on animal evidence. The European Chemicals Agency (ECHA) identified phenolphthalein as a substance of very high concern (SVHC).

Based on the NTP test results, the additional risk of malignant lymphoma at 8.25 mg/m³ occupational exposure to phenolphthalein for 40 years is 10^-4. A concentration of 8 mg/m³ was proposed as the MACTWA value for phenolphthalein. Since phenolphthalein is a poorly water-soluble solid, only dust exposure of the substance will occur in the work environment, hence the proposed MAC value should concern the inhalable fraction of the substance. It is proposed to label phenolphthalein as „Carc. 1B” indicating that phenolphthalein is a category-1B carcinogen and „Ft” due to reprotoxicity. There are no bases for establishing the short-term exposure limit value (STEL) and the limit value in biological material (BEI).

Phenylhydrazine at room temperature is a colorless or yellow oily liquid, at lower temperatures it occurs in a form of a crystalline.

Phenylhydrazine is used in an organic synthesis as a powerful reducing agent or as an intermediate in synthesis of other chemical compounds, such as dyes and drugs. Phenylhydrazine is also used as a chemical reagent. At the beginning of the 20th century, phenylhydrazine was used as a drug in polycythemia vera and other blood disorders.

Occupational exposure to phenylhydrazine and its salts may occur during the production, further processing and distribution of these compounds, and also during their use.

In 2014, 711 people were exposed to phenylhydrazine in Poland (including 531 women), of which 2 people only were exposed to phenylhydrazine in the air at a concentration range > 0.1–0.5 of the MAC value (20 mg/m³).

Phenylhydrazine is classified as a toxic substance after oral administration, in contact with skin and after inhalation.

The available literature describes several cases of human poisoning with phenylhydrazine with inhalation and through the skin. Adverse effects of phenylhydrazine exposure are progressive hemolytic anemia with hyperbilirubinaemia and urobilinemia, presence of Heinz bodies in red blood cells, impairment of renal and hepatic function as secondary symptom to the haemolytic activity of phenylhydrazine. Methemoglobinemia andleukocytosis sometimes occurred. General symptoms of poisoning included dizziness, diarrhea, general weakness and reduced blood pressure.

Phenylhydrazine irritates the skin. Several cases of skin hypersensitivity reactions to phenylhydrazine and its hydrochloride have also been described. It has been shown that phenylhydrazine gives cross-reactions with hydrazine salts.

In animals, the main symptoms of acute phenylhydrazine poisoning were the formation of significant amounts of methaemoglobin and its consequences: hemolysis, Heinz bodies formation, reticulocytosis, bone marrow hyperplasia, splenomegaly and liver damage. Motor excitation and tonic-clonic spasms were also observed. As a result of repeated exposure, it was found that phenylhydrazine also causes hemostatic disorders in addition to haemolytic anemia and leads to acute pulmonary thrombosis. The dose-effect relationship cannot be derived from existing data nor the NOAEL value be determined.

Phenylhydrazine is an in vitro mutagen and some evidence points to its genotoxic activity in vivo (DNA methylation and fragmentation ). Phenylhydrazine and its salts have been classified as category 2 mutagenic substances.

In the available literature and databases, no information was found on the carcinogenic activity of phenylhydrazine and its salts in humans.

Carcinogenic activity of phenylhydrazine has been demonstrated in experimental animals. Exposure of mice via oral route resulted in the occurrence of lung tumors and tumors of blood vessels. The International Agency for Research on Cancer (IARC) does not classify phenylhydrazine and its salts as carcinogenic. In the European Union, phenylhydrazine and its salts have been classified as category 1B carcinogens.

There is also insufficient data on the effect of phenylhydrazine on reproduction and developmental toxicity, so it is difficult to assess whether these effects may occur in humans exposed to phenylhydrazine and its salts.

Based on the observed systemic effects in humans and animals exposed to phenylhydrazine and its salts, it can be assumed that these compounds are absorbed into the body by inhalation, oral route, through the skin and after parenteral administration. There are no quantitative data on the absorption efficiency of individual routes.

The main metabolic pathways of phenylhydrazine are hydroxylation to p-hydroxyphenylhydrazine and formation of phenylhydrazones by reaction with natural keto-acids. Metabolites in the form of glucuronides are mainly excreted in the urine.

The existing two studies of the carcinogenic activity of phenylhydrazine hydrochloride have shown that the compound administered via the oral route caused a significant increase in the formation of lung tumors or tumors of blood vessels. In the second study, despite the longer exposure time, no significant increase in lung cancer was observed. Although the results of both studies seem to be unreliable in the light of current criteria and are limited to one species (mice) only and one dose, on the basis of them, phenylhydrazine was classified in the EU as a carcinogen category 1B with the assigned phrase H350 ‒ may cause cancer.

A quantitative evaluation of phenylhydrazine carcinogenicity was performed using data on

the incidence of lung cancer in mice of both genders exposed to phenylhydrazine hydrochloride, administered intragastrically at 1 mg/day. The model adopted for calculations shows that exposure to phenylhydrazine, at the level of the adopted MAC value in Poland (20 mg/m³) over 40 years of work, corresponds to the risk of lung cancer at the level of 5.7 · 10^-2. Such risk is unacceptable.

From the estimation of cancer risk, it appears that the current value of MAC for substance should be reduced.

The existing database on the toxicity of phenylhydrazine and its salts is insufficient to derive a MAC value based on NOAEL/LOAEL values. Due to the mechanism of action and the main toxic effects (haematotoxicity), phenylhydrazine has an aniline-like toxicological profile. It was proposed that the MAC value for phenylhydrazine should be taken analogously to the MAC value for aniline, i.e. 1.9 mg/m³, which corresponds to the risk of lung cancer in occupational exposure conditions of 5.4 · 10^-3.

Due to the dermal absorption of phenylhydrazine, the „skin” notation has been proposed (absorption through the skin may be as important as in the case of inhalation). Additionally, due to irritating, sensitizing, carcinogenic and mutagenic effects of phenylhydrazine, the normative should be marked with the letters „I” (substance with an irritating effect), „A” (a substance with sensitizing effect), Carc. 1B (carcinogenic substance category 1B) and Muta. 2 (mutagen category 2). There are no evidence to establish the STEL and BEI values.

Trimethylamine (TMA) is a gas at ambient temperature, which has a pungent, fishy odour. It is commercially available as a compressed gas, 40% aqueous solution or a 33% solution in ethanol. It is used in organic synthesis, especially of choline salts, as a warning agent for natural gas and flotation agents, in the production of cationic starches, quaternary ammonium compounds, intense sweeteners and strongly basic anion exchange resins. Moreover, it is used in the production of disinfectants and insect attractants. TMA is irritating to the human respiratory tract, skin and eyes. The threshold of irritation was reported to be 1481 mg/m³ (median) after a single dose. No effects were observed in workers exposed to 0.24-19.5 mg/m³, most measurements being below 12.1 mg/m³. A LOAEC of 48 mg/m³ was established for human based on eyes, nose and throat irritation.

Animal data with repeated inhalation exposure over 2 weeks revealed a LOAEC of 183.75 mg/m³ based on respiratory irritation in a rat study.

Embryotoxic effects were observed in mice (NOAEL of 150 mg/kg bw/day).

The Scientific Committee for Occupational Exposure Limits to Chemical Agents (SCOEL) has established OEL of 4.9 mg/m³ and STEL of 12.5 mg/m³.

A MAC value has been derived using the RD50 value (147.62 mg/m³ for TMA) and multiplying it by a factor of 0.03. The Expert Group for Chemicals Agents has proposed to reduce the current MAC value from 12 mg/m³ to 4.9 mg/m³ and the current STEL value from 24 mg/m³ to 12.5 mg/m³, which is also in accordance with the values recommended by SCOEL. It has been proposed to remain the “I” (irritant) labelling of TMA. No bases for a BEI value have been found.

Silver compounds are generally insoluble in water. The few soluble silver compounds include, e.g. silver nitrate, silver fluoride, silver perchlorate. These compounds are used in chemical analysis and organic catalysis to produce other silver compounds (e.g. halides), explosives, antiseptics (in medicine ), mirrors; they are also used in classical photographic technique. Soluble silver compounds are irritating and corrosive to the skin and mucous membranes of the eyes; they also cause permanent damage to the eyes and dysfunction of the respiratory and nervous systems.

Maximum admissible concentrations (MAC) for soluble silver compounds, expressed as silver, was set at 0,01 mg/m³.

The aim of the study was to develop a method for determination of concentrations of soluble silver compounds in the air at workstations in the range from 1/10 to 2 MAC value.

The developed method of determination consists in: taking an air sample on a membrane filter, washing out soluble silver compounds from the filter with deionized water and determination of these compounds as silver by flame (air-acetylene) atomic absorption spectrometry (F-AAS).

The method enables the determination of silver in the concentration range of 0.070÷2.00 μg/ml. The obtained silver calibration curve is characterized by a correlation coefficient R2 = 1.0000. The limit of silver detection (LOD) is 0.009 μg/ml, the limit of quantification (LOQ) is 0.027 μg/ml, and the recovery rate is 0.99.

The developed method allows the determination of soluble silver compounds in the air at workstations in the concentration range of 0.001÷0.028 mg/m³ (for an air sample with a volume of 720 l), which corresponds to 0.1÷2.8 times the MAC value.

The method is characterized by good precision and accuracy and meets the requirements of the European standard PN-EN 482 for chemical determination procedures.

The method for the determination of soluble silver compounds has been recorded in the form of the analytical procedure set out in the Annex.