2-amino-2-methylpropanol

Endpoint summary

Description of key information

Human data on oral drug pamabrom (see Exposure related observations in humans, IUCLID § 7.10.3):

Pamabrom is an Over The Counter (OTC) diuretic agent which is an AMP salt of 8-bromotheophylline, CAS No. 606-04-2.
It is an equimolar mixture of 74.4% w/w 8-Bromotheophylline (CAS No. 10381-75-6) and 25.6% w/w 2-amino-2-methylpropan-1-ol (AMP, CAS No. 124-68-5). Clinical data on this test material can be used for AMP safety assessment based on the AMP/Pamabrom bioequivalence study (see Basic Toxicokinetics /IUCLID §7.1.1) which indicated that Pamabrom's AMP, and AMP as is, were equivalent in terms of AUC0-t, AUC0-inf and AUC0-168h. Pamabrom doses can be converted into equivalent AMP doses based on the AMP content of 25.6% w/w in this drug and assuming a patient weight of 70 kg when not indicated.

A) Oral clinical studies:

Six clinical studies are available on pamabrom. NOAELs are expressed in AMP based on pamabrom posology and AMP content.

They inform on absence of repeat-dose adverse effects, in all cases the below-listed NOAELs were the maximum tested dose:

1) Trial in severe cardiac failure patients (Doherty et al, 1953): Patients (n=19) were given pamabrom at 300 to 900 mg/day for 5 to 137 days. This study included clinical signs, edema, degree of cardiac failure, subjective improvement. Only 2/18 patients reported adverse effects potentially related to pamabrom upon longer treatment: 1/18 case of maculopapular rash (4th week of treatment) and 1/18 case of diarrhea (day 120 of treatment). A third patient stopped treatment after 2 weeks due to therapeutic success. The NOAEL was >= 2.2 mg AMP/kg bw/day x 2 to 17 weeks depending on patient.

2) Trial in women with premenstrual tension - Preliminary study (McGavack et al, 1956): oral treatment (n=9) up to 800 mg pamabrom for 4 weeks (28-days) in women with menstrual cycles. This study included general examination for toxic effects. No adverse effect. The NOAEL was >= 2.9 mg AMP/kg bw/day x 4 weeks.

3) Trial in women with premenstrual tension - Main study (McGavack et al, 1956): oral treatment (n=43) with 100 to 400 mg pamabrom per day, provided in 1 to 14 successive treatment cycles (mean 2-3 treatment cycles per group) of 3-10 days before start of menstruation, mean cumulated treatment duration 2 weeks. This study included general examination and monitoring of degree of improvement of premenstrual tension (less water retention, nervous symptoms, acne, headache, breast engorgement, gastrointestinal symptoms, pelvic pain, menstrual cycle length, amount of flow). No adverse effect: the only effects were therapeutic (benefic): normalisation of symptoms of premenstrual tension (menstrual cycle length, amount of flow). The NOAEL was >= 1.5 mg AMP/kg bw/day x 2 weeks (mean: variable treatment regime).

4) Trial in women with primary dysmenorrhea (Ortiz et al, 2016): n=189 women with mean age 21 years were given 75 mg pamabrom daily for 3 days, in combination with various other drugs. The study involved monitoring of adverse clinical effects and multiple efficacy endpoints (menstrual pain reduction, symptoms of dysmenorrhea, overall clinical response). The only effects were minor effects in 3/189 patients (somnolence, dizziness and increased thirst, 1 case each) and normalisation of symptoms of menstrual pain. The NOAEL was >= 0.32 mg AMP/kg bw/day x 3 days.

5) Trial in pregnant women (Patterson, 1958): >22 week pregnant women with edema classified as mild pre-eclampsia (n=38) were given orally 800 mg of pamabrom daily for 5-7 days. Then, (n=9) patients who failed to loose weight were again given orally 1600 mg of pamabrom daily for 5-7 days. This study included monitoring of edema before and after treatment, nausea, vomiting, edema, changes in vision, headache, miscellaneous side effects, blood pressure, daily intake and output of fluids, gravidity, gestation, fetal movement. No adverse effects. The NOAEL was >= 5.9 mg AMP/kg bw/day x 1 week (if considering only the second treatment cycle), and>= 2.9 mg AMP/kg bw/day x 2 weeks (if considering both treatment cycles in patients treated twice).

6) Trial in pregnant women (James et al, 1957): In 180 pregnant women with edema treated with pamabrom for unknown duration (Klimisch 4 study), the max. NOAEL was >= 2.2 mg AMP/kg bw/day, and in most patients it was >=1.6 mg AMP/kg bw/day.

B) 70 years of safe clinical use - Pharmacovigilance argument:

In the US, pamabrom is used since early 1950's so it has a track-record of >70 years of safe use in an ill population. Based on the National Library of Medicines database, at least 20 US OTC drugs currently contain pamabrom:

• BACKAID MAX: For the temporary relief of: minor aches, pains and related discomforts due to muscle strain, spasms or overexertion including those affecting the back, legs and joints; pressure-caused discomforts due to periodic excess water retention.


• DIUREX: For the relief of following, associated with premenstrual and menstrual periods: temporary water weight gain, bloating, swelling, full feeling.


• GREEN GUARD CRAMP RELIEF + MENSTRUAL RELIEF + MEDI FIRST PMS RELIEF + MEDI FIRST PLUS PMS RELIEF + MENSTRUAL PAIN RELIEF MAXIMUM STRENGTH + MENSTRUAL PAIN RELIEF MAXIMUM STRENGTH / MULTI SYMPTOM + MENSTRUAL RELIEF MAXIMUM STRENGTH + MENSTRUAL RELIEF MAXIMUM STRENGTH MULTI SYMPTOM + PAMPRIN MULTI-SYMPTOM MAXIMUM STRENGTH + PMS RELIEF MAXIMUM STRENGTH + PREMSYN PMS PREMENSTRUAL PAIN RELIEF + THOMPSON CRAMP RELIEF + UNISHIELD PMS RELIEF: For the temporary relief of these symptoms associated with menstrual periods: headache, bloating, cramps, backache, muscular aches, irritability, water-weight gain.


• CRANE SAFETY CRAMP + GREEN GUARD PMS RELIEF + UNISHIELD CRAMP: Temporarily relieves headache, bloating, cramps, backache, water-weight gain, muscular aches and pains associated with the menstrual period.


• MEDI FIRST CRAMP + MEDI FIRST PLUS CRAMP: For the temporary relief of minor aches and pains associated with headache, backaches, menstrual cramps. Temporarily relieves water-weight gain, bloating, swelling and full feeling associated with the premenstrual and menstrual periods.

Based on contents and posology for each drug, AMP has a human NOAEL of at least 0.73 mg AMP/kg/day for up to 10-day treatment cycles, repeated over periods. This weight-of-evidence demonstrates that AMP is devoid of adverse repeat-dose toxic effects to human health at this dose-level.

C) Overall human oral NOAEL for repeat-dose toxicity:

No serious adverse repeat-dose effect was ever reported during 70 years of clinical trials and medication with pamabrom based on 5 publications (6 trials) and posology of 20 OTC drugs. The most robust human NOAEL for repeat-dose toxicity comes from study 2) (preliminary study by McGavack et al, 1956) since this is the only study monitoring hematology and blood biochemistry. The NOAEL was >= 2.9 mg AMP/kg bw/day x 4 weeks. All other studies and drug posology confirm NOAEL values in the mg/kg bw/day range, always the highest tested posology whatever the treatment duration (3 days to 17 weeks).

Skin irritation in cosmetic factory workers

Cipolla et al (1997) reported two cases of airborne skin dermatitis in a cosmetic factory using AMP-100. Patch testing in exposed workers and control workers evidenced that these skin reactions were skin irritation and not skin sensitisation, because they only occured at high test concentrations (>=10% AMP in water or ethanol) and because pre-exsisting exposure to AMP did not lead to significantly worse skin reactions.