4-hydroxybenzoic acid

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.4 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.4 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

NOAEC

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.8 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Overall assessment factor (AF):

12.5

Dose descriptor:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.8 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

12.5

Dose descriptor starting point:

NOAEC

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

14.1 mg/kg bw/day

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.6 mg/cm²

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

5

Dose descriptor:

other: NOAEL

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - workers

Summary of toxicological properties.

4-HBA is an organic acid. Those substances do not penetrate the intact skin in relevant amounts. This is also true with 4-HBA as the studies show.

A single dermal application of 2000 mg/kg bw. for 24 hours in an occlusive way to rabbits did not cause any mortality.

 

When 0,5 g 5-HBA were applied to 6 cm² skin of three female New-Zealand White rabbits only one mild local effect was seen with one animal. Exposure was 4 hours with observations at 1, 24, 48, 72 hours post exposure. The results showed a short term mild irritation in one animal. The limits for classification were not surpassed. Concluding, p-Hydroxybenzoic acid does not have to be classified as skin irritant according to CLP classification criteria.

 

Also a dermal sensitisation study with guinea pigs revealed no effects after the dermal application for 6 hours 3 times a week for 3 weeks. The guinea pigs received a dermal dosage of 0.2 cc = 0.282 g on an area of the skin of 6.45 cm² (43 mg/cm²).  The animals weighed 290 to 400 g (Dose = 282 mg / 0.35 kg bw.; = 806 mg/kg bw.). No effects were observed.

 

Investigations with 24 hours dermal application of the radio-labelled compound to the skin of rats showed that only 4 % of the applied dosage were found in the body: 2% at the application site and 2 % in the body.

 

After oral administration of 5 g 4 -HBA every 6 hours up to a total dosage of 20 g to a human/humans. 70% were excreted unchanged with the urine. According to the authors this dosage is the maximum dosage that the human body is able to dispose of in the course of 24 hours (Power and Sherwin, 1927).

 

Oral dosages of 1.0 g/kg bodyweight were given to groups of 3 dogs. After administration of 4-HBA and Methylparaben (the methyl ester of 4 -HBA) the same concentrations of free 4 -HBA and the same kinetics for the elimination of 4 -HBA were found in the plasma (Jones et al., 1956).

 

After the oral administration of 4-HBA to dogs 94% of the dosage were recovered in the urine, 40.1% as free 4-HBA, 30.0% as glucuronic acid conjugate (Jones et al., 1956).

 

These data show that 4-HBA is resorbed relatively fast after oral dosages and it is relatively fast excreted with the urine. No accumulation was observed. Relevant parts of the resorbed substance were excreted unchanged.

 

Daily oral dosages of 0, 40, 200, and 1000 mg/kg bw. were administered by stomach tube to groups of 13 male rats for 42 days. In the same study 13 females per each of the dosage groups were treated also all in all between 38 to 52 days depending on the mating period. The test-article was formulated in 0.5%CMC and administered in 5 ml/kg bw..

At a dosis of 40 mg/kg bw. the animals showed no differences to the control animals (NOEL).

200 mg/kg bw. lead to salivation and abnormal respiratory sounds. The lymphocyte ratio and the platelet count were reduced.

 

1000 mg/kg bw. caused salivation, rhinorrhea, abnormal respiratory sounds, reduced body weight gain, white blood cell count, platelet count and total serum protein as well as increased segmented neutrophil ratio and increased activity of GPT, GOT and anorganic phosphorus in the serum, females: lung: inflammatory foci.

 

As summarised in the OECD SIDS (1999) a NOAEL of 1000 mg/kg bw./day was established: “4-Hydroxybenzoic acid induced rale and temporary salivation (sometimes accompanied by rhinorrhea) at 1,000 mg/kg and slightly at 200 mg/kg. These changes were suggesting the irritation of this chemical to respiratory tract. There were no adverse effects on body weight change and food consumption. At necropsy, no histological and morphological changes were observed. In hematological and blood chemical findings of males, decrease in the percentage of lymphocytes and the blood glucose at 200 mg/kg or more groups and decrease in total protein and increase in A/G ratio, GPT and GOT at 1,000 mg/kg were observed. These changes were significant, but not considered adverse effects. Therefore, NOAEL for systemic toxicity was considered to be 1000 mg/kg/day.”

 

An inhalation toxicity study was performed using 4 groups, one control and 3 dose groups, of 5 male and 5 female Sprague-Dawley rats each exposed to C-194, all in all 40 animals. The exposure period lasted for 6 hours per day for 5 days followed by another 5 day exposure period after an interruption of 2 days. The cumulative mean measured/nominal exposure concentrations were: 23.8, 64.0 and 189 mg/m³; 20, 60 and 200 mg/m3.

Physical examinations revealed increased instances of dried material around the facial area in all exposure groups.

20 mg/m³: no differences to the data of the control animals,

60 mg/m³: no differences to the data of the control animals,

200 mg/m³: The observed changes can be explained by an irritative effect of 4 -HBA to the eyes and in the respiratory tract specially in the nose and the lungs and a possible toxic effects on the liver and on the blood.

 

The local effect on mucous membranes was investigated in a study with rabbits. 0.1 g of 4-HBA was instilled as supplied into the eye of three New Zealand White rabbits. After 1hour the eyes were rinsed as the test item has not been removed. The ocular reactions observed during the study have been moderate to severe and partially reversible.

 

The chemosis remained in one animal in slight intensity until day 21 (last day of study). A corneal opacity remained in one animal until the last day of the study (day 21) with moderate intensity. A presence of a white spot on the lower eyelid and on the conjunctiva between maximal day 1 and maximal day 11 was observed in all three animals. Corneal neovascularisation was seen on day 14 and remaining on day 21 (last day of test, animal 3).

 

According to the rules of the EC regulation No 1272/2008 (OECD EU-GHS) 4-HBA has to be classified as: category 1 "irreversible effects on the eye".

 

These changes were suggesting the irritation of 4-HBA to the respiratory tract or to mucous membranes in general by direct application or inhalative exposure as well as after high oral dosages is the most critical effect of 4-HBA.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified