2-amino-2-methylpropanol

Toxicity to reproduction: other studies

Administrative data

Endpoint:

toxicity to reproduction: other studies

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

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.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

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.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Principles of method if other than guideline:

1) The National Library of Medicines database was used to retrieve a list of Over The Counter (OTC) US drugs which contain pamabrom
2) Each drug presentation sheet was used to note down drug composition, posology, adverse effects, warnings and information when to stop treatment.

GLP compliance:

no

Remarks:

GLP not applicable to bibliographic search in a public database

Limit test:

no

Species:

other: human

Sex:

female

Route of administration:

oral: capsule

Duration of treatment / exposure:

repeated treatment cycles of up to 3 or 10 days, or longer if prescribed by a doctor

Frequency of treatment:

daily

Key result

Dose descriptor:

NOAEL

Effect level:

>= 0.73 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Remarks:

AMP fraction (in pamabrom)

Sex:

female

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

based on posology of 20 OTC drugs

Critical effects observed:

no

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 the 20 below US OTC drugs currently contain pamabrom:

Drug name	Indications/claims	Pamabrom content (AMP content)	Maximum daily posology	Maximum mg AMP/kg bw/day (assuming 70 kg)	Maximum duration
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	25 mg/caplet (6.4 mg/caplet)	6 caplets	0.55	10 days for pain 3 days for fever longer if prescribed
DIUREX	For the relief of following, associated with premenstrual and menstrual periods: temporary water weight gain, bloating, swelling, full feeling.	50 mg/capsule (12.8 mg/caplet)	4 capsules	0.73	10 days longer if prescribed
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 PMS RELIEF MAXIMUM STRENGTH 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	25 mg/caplet (6.4 mg/caplet)	6 caplets	0.55	10 days for pain 3 days for fever longer if prescribed
PAMPRIN MULTI-SYMPTOM MAXIMUM STRENGTH PREMSYN PMS PREMENSTRUAL PAIN RELIEF	For the temporary relief of these symptoms associated with menstrual periods:  cramps, headache, bloating, backache, water-weight gain, muscular aches, irritability	25 mg/caplet (6.4 mg/caplet)	8 caplets	0.73	10 days for pain 3 days for fever longer if prescribed
CRANE SAFETY CRAMP GREEN GUARD PMS RELIEF	Temporarily relieves headache, bloating, cramps, backache, water-weight gain, muscular aches and pains associated with the menstrual period	25 mg/caplet (6.4 mg/caplet)	8 caplets	0.73	not indicated
UNISHIELD CRAMP	Temporarily relieves headache, bloating, cramps, backache, water-weight gain, muscular aches and pains associated with the menstrual period	25 mg/caplet (6.4 mg/caplet)	8 caplets	0.73	10 days for pain 3 days for fever longer if prescribed
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	25 mg/caplet (6.4 mg/caplet)	8 caplets	0.73	not indicated

All contain the same warnings: "If pregnant or breast-feeding, ask a health professional before use."

This weight-of-evidence demonstrates that AMP is devoid of adverse effects to human health when ingested at 0.73 mg AMP/kg/day for up to 10-day treatment cycles, repeated over periods.

Conclusions:

In a target population consisting mostly (19 of 20 OTC drugs) of women with menstrual periods, AMP has a human oral NOAEL of at least 0.73 mg AMP/kg bw/day for up to 10-day treatment cycles, which can be repeated at each menstrual period.

Executive summary:

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). In the US, pamabrom is used since early 1950's so it has a track-record of >70 years of safe use.

Based on the National Library of Medicines database, at least 20 US OTC drugs currently contain pamabrom, 19 of which specifically target women with menstrual periods. Based on contents and posology for each drug, AMP has a human NOAEL of at least 0.73 mg AMP/kg bw/day for up to 10-day treatment cycles, repeated over periods. This weight-of-evidence demonstrates that AMP is devoid of adverse effects to human health at this dose-level.

Cross-reference 2

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

epidemiological data

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

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.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Study type:

other: data on posology of OTC drugs containing AMP (inside pamabrom)

Principles of method if other than guideline:

1) The National Library of Medicines database was used to retrieve a list of Over The Counter (OTC) US drugs which contain pamabrom
2) Each drug presentation sheet was used to note down drug composition, posology, adverse effects, warnings and information when to stop treatment.

GLP compliance:

no

Remarks:

GLP not applicable to bibliographic search in a public database

Type of population:

general

Exposure assessment:

measured

Remarks:

based on drug posology

Details on exposure:

oral: capsules
repeated treatment cycles of up to 3 or 10 days, or longer if prescribed by a doctor

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 the 20 below US OTC drugs currently contain pamabrom:

Drug name	Indications/claims	Pamabrom content (AMP content)	Maximum daily posology	Maximum mg AMP/kg bw/day (assuming 70 kg)	Maximum duration
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	25 mg/caplet (6.4 mg/caplet)	6 caplets	0.55	10 days for pain 3 days for fever longer if prescribed
DIUREX	For the relief of following, associated with premenstrual and menstrual periods: temporary water weight gain, bloating, swelling, full feeling.	50 mg/capsule (12.8 mg/caplet)	4 capsules	0.73	10 days longer if prescribed
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 PMS RELIEF MAXIMUM STRENGTH 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	25 mg/caplet (6.4 mg/caplet)	6 caplets	0.55	10 days for pain 3 days for fever longer if prescribed
PAMPRIN MULTI-SYMPTOM MAXIMUM STRENGTH PREMSYN PMS PREMENSTRUAL PAIN RELIEF	For the temporary relief of these symptoms associated with menstrual periods:  cramps, headache, bloating, backache, water-weight gain, muscular aches, irritability	25 mg/caplet (6.4 mg/caplet)	8 caplets	0.73	10 days for pain 3 days for fever longer if prescribed
CRANE SAFETY CRAMP GREEN GUARD PMS RELIEF	Temporarily relieves headache, bloating, cramps, backache, water-weight gain, muscular aches and pains associated with the menstrual period	25 mg/caplet (6.4 mg/caplet)	8 caplets	0.73	not indicated
UNISHIELD CRAMP	Temporarily relieves headache, bloating, cramps, backache, water-weight gain, muscular aches and pains associated with the menstrual period	25 mg/caplet (6.4 mg/caplet)	8 caplets	0.73	10 days for pain 3 days for fever longer if prescribed
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	25 mg/caplet (6.4 mg/caplet)	8 caplets	0.73	not indicated

All contain the same warnings: "If pregnant or breast-feeding, ask a health professional before use."

This weight-of-evidence demonstrates that AMP is devoid of adverse effects to human health when ingested at 0.73 mg AMP/kg/day for up to 10-day treatment cycles, repeated over periods.

Conclusions:

In a target population consisting mostly (19 or 20 OTC drugs) of women with menstrual periods, AMP has a human oral NOAEL of at least 0.73 mg AMP/kg bw/day for up to 10-day treatment cycles, which can be repeated at each menstrual period.

Executive summary:

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). In the US, pamabrom is used since early 1950's so it has a track-record of >70 years of safe use.

Based on the National Library of Medicines database, at least 20 US OTC drugs currently contain pamabrom, 19 of which specifically target women with menstrual periods. Based on contents and posology for each drug, AMP has a human NOAEL of at least 0.73 mg AMP/kg bw/day for up to 10-day treatment cycles, repeated over periods. This weight-of-evidence demonstrates that AMP is devoid of adverse effects to human health at this dose-level.

Cross-reference 3

Reason / purpose for cross-reference:

reference to other study

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Aug 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Justification for type of information:

Pamabrom is a diuretic agent. This is 2-amino-2-methylpropanol 8-bromotheophyllinate, 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 (CAS No. 124-68-5). Clinical data on this test material are provided in IUCLID section 7.10.3 and can be used for AMP safety assessment based on this AMP/Pamabrom bioequivalence study which indicated that Pamabrom and AMP 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.

Objective of study:

toxicokinetics

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

AMP- 95% AMP in water
Pamabrom - Equimolar mixture of AMP and 8-bromotheophylline

Radiolabelling:

no

Species:

rat

Strain:

Fischer 344

Details on species / strain selection:

Fischer 344 (F344/NHsd) from Envigo RMS, Inc

Sex:

male

Details on test animals or test system and environmental conditions:

Species
Rat
Number and Sex
12 males
Strain and Source
Fischer 344 (F344/NHsd) from Envigo RMS, Inc.
Acclimation
At least 3 days
Weight at Dose Administration
250 to 325 g
Age at Dose Administration
9 to 15 weeks
Housing
During acclimation and test period, animals will be group housed (up to five
animals/cage/group) in polycarbonate cages with hardwood chip bedding.
Animals may be individually housed for study-related procedures or behavioral or health
reasons.
Feed
Certified Rodent Diet #2016C and/or 2016CM (Envigo RMS, Inc.) will be provided ad
libitum, except as specified under dosing procedures.
Water
Ad libitum, provided fresh daily
Environment
Environmental controls for the animal room will be set to maintain a temperature of 20 to
26°C, a relative humidity of 50 ± 20%, and a 12-hour light/12-hour dark cycle. The
12-hour dark cycle may be interrupted to accommodate study procedures.

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

Single oral dose
Dose Preparation and Analyses
The test articles will be prepared in water at Covance. The pH of the AMP dose
formulation will be adjusted to approximately pH 7 with HCl (Saghir 2008). The pH of
the Pamabrom dose formulation will be recorded and adjusted to approximately pH 7, as
needed.
Triplicate sets of two aliquots (1 mL; top, middle and bottom) of each formulation will be
taken and stored at approximately 5°C until analysis. Analysis of the dose formulations
will be conducted at Covance-Salt Lake City. Any dose formulations remaining
following administration will be stored at approximately 5°C.
Dose Procedures
Individual doses will be calculated based on body weights recorded on the day of dose
administration.
Fasting
All animals will be fasted overnight through approximately 4 hours postdose.
Dose Administration
The oral dose will be administered via a gavage needle.

Duration and frequency of treatment / exposure:

Single oral dose

Remarks:

AMP:
Target dose 12.5 mg/kg, Target Dose Conc (Mg/ml)= 2.5 ; Target Dose Vol (ml/kg) = 5

Pamabrom:
Target dose 50 mg/kg ( equivalent to 12.5 mg/kg AMP), Target Dose Conc (Mg/ml)= 10; Target Dose Vol (ml/kg) =5

No. of animals per sex per dose / concentration:

6 animals per test material

Control animals:

no

Details on study design:

The purpose of this study is to determine the pharmacokinetics of AMP after a single oral
dose of AMP or Pamabrom to rats.

Details on dosing and sampling:

Single oral dose of AMP or Pamabrom in water.
Dose Preparation and Analyses
The test articles will be prepared in water at Covance. The pH of the AMP dose
formulation will be adjusted to approximately pH 7 with HCl (Saghir 2008). The pH of
the Pamabrom dose formulation will be recorded and adjusted to approximately pH 7, as
needed.
Triplicate sets of two aliquots (1 mL; top, middle and bottom) of each formulation will be
taken and stored at approximately 5°C until analysis. Analysis of the dose formulations
will be conducted at Covance-Salt Lake City. Any dose formulations remaining
following administration will be stored at approximately 5°C.
Dose Procedures
Individual doses will be calculated based on body weights recorded on the day of dose
administration.
Fasting
All animals will be fasted overnight through approximately 4 hours postdose.
Dose Administration
The oral dose will be administered via a gavage needle.
Sample Collection
Blood
Blood (approximately 0.3 mL) will be collected via a jugular vein via syringe and needle
and transferred into tubes containing K2EDTA anticoagulant from each animal predose
and at approximately 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours
postdose.
Blood will be maintained on wet ice, in chilled cryoracks, or at approximately 5°C prior
to centrifugation to obtain plasma. Centrifugation will begin within 30 minutes of
collection. Plasma will be placed into 96-well tubes and maintained on dry ice prior to
storage at approximately-70°C.

Statistics:

Statistical Analyses
Bioequivalence of Pamabrom and AMP will be evaluated. Dose normalized PK
parameters Cmax, AUC0-24, AUC0-t, AUC0-inf, and AUC0-168 will be natural log
transformed (ln) prior to analysis. Due to measureable AMP plasma levels beyond
24 hours for some animals, the AUC0-24 values are not useful for calculating
bioequivalence and will not be included in the report. A two-sample t-test will be used
to analyze each of the parameters. Treatment means and the difference for the group
comparison, along with the associated 90% confidence interval for the difference, will be
estimated on the ln-scale. These will be back transformed to generate geometric means
and a geometric mean ratio for the group comparison, along with the associated 90%
confidence interval. Results will be presented as Pamabrom/AMP.

Preliminary studies:

A single dose study at the highest approved dose will generally be adequate for the demonstration of bioequivalence.
The extent of product bioavailability is estimated by the area under the blood concentration vs time curve (AUC).
For a single dose bioequivalence study, AUC should be calculated from time 0 (predose) to the last sampling time associated with quantifiable drug concentration AUC(0-LOQ). The comparison of the test and reference product value for this noninfinity estimate provides the closest approximation of the measure of uncertainty (variance) and the relative bioavailability estimate associated with AUC(0-INF), the full extent of product bioavailability
Results:
Dose normalized PK parameters Cmax, AUC0-t, AUC0-inf and AUC0-168 were natural log transformed (ln) prior to analysis. A two-sample t-test was used to analyze each of the parameters. Treatment means and the difference for the group comparison, along with the associated 90% confidence interval for the difference, were estimated on the ln-scale. These were back transformed to generate geometric means and a geometric mean ratio for the group comparison, along with the associated 90% confidence interval.

Metabolites identified:

no

Conclusions:

The results indicated that Pamabrom and AMP were equivalent for AUC0-t, AUC0-inf and AUC0-168, justifying the use of Pamabrom data for read across to AMP.
The bioequivalence results showed the 90% confidence interval was from 1.050 to 1.465
for Cmax, from 0.921 to 1.177 for AUC0-t, from 0.848 to 1.099 for AUC0-inf and from
0.929 to 1.177 for AUC0-168.

Data source

Reference

Reference Type:

other: online database

Title:

Dailymed

Author:

National Library of Medicine

Year:

2023

Bibliographic source:

https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=pamabrom&pagesize=200&page=1

Materials and methods

Principles of method if other than guideline:

1) The National Library of Medicines database was used to retrieve a list of Over The Counter (OTC) US drugs which contain pamabrom
2) Each drug presentation sheet was used to note down drug composition, posology, adverse effects, warnings and information when to stop treatment.

GLP compliance:

no

Remarks:

GLP not applicable to bibliographic search in a public database

Type of method:

in vivo

Test material

Test material information

Constituent 1

Reference substance name:

8-bromotheophylline

EC Number:

233-846-6

EC Name:

8-bromotheophylline

Cas Number:

10381-75-6

Molecular formula:

C7H7BrN4O2

IUPAC Name:

8-Bromotheophylline

Constituent 2

Reference substance name:

2-amino-2-methylpropanol

EC Number:

204-709-8

EC Name:

2-amino-2-methylpropanol

Cas Number:

124-68-5

Molecular formula:

C4H11NO

IUPAC Name:

2-amino-2-methylpropan-1-ol

Details on test material:

Drug name: NeoBromth

Test animals

Species:

other: human

Sex:

female

Administration / exposure

Route of administration:

oral: capsule

Duration of treatment / exposure:

repeated treatment cycles of up to 3 or 10 days, or longer if prescribed by a doctor

Frequency of treatment:

daily

Results and discussion

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

>= 0.73 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Remarks:

AMP (inside drug pamabrom)

Sex:

female

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

based on posology of 19 OTC drugs in women with periods

Any other information on results incl. tables

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 the 20 below US OTC drugs currently contain pamabrom, 19 of which specifically target women with menstrual periods, i.e. a sensitive population for reproductive effects:

Drug name	Indications/claims	Pamabrom content (AMP content)	Maximum daily posology	Maximum mg AMP/kg bw/day (assuming 70 kg)	Maximum duration
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	25 mg/caplet (6.4 mg/caplet)	6 caplets	0.55	10 days for pain 3 days for fever longer if prescribed
DIUREX	For the relief of following, associated with premenstrual and menstrual periods: temporary water weight gain, bloating, swelling, full feeling.	50 mg/capsule (12.8 mg/caplet)	4 capsules	0.73	10 days longer if prescribed
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 PMS RELIEF MAXIMUM STRENGTH 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	25 mg/caplet (6.4 mg/caplet)	6 caplets	0.55	10 days for pain 3 days for fever longer if prescribed
PAMPRIN MULTI-SYMPTOM MAXIMUM STRENGTH PREMSYN PMS PREMENSTRUAL PAIN RELIEF	For the temporary relief of these symptoms associated with menstrual periods:  cramps, headache, bloating, backache, water-weight gain, muscular aches, irritability	25 mg/caplet (6.4 mg/caplet)	8 caplets	0.73	10 days for pain 3 days for fever longer if prescribed
CRANE SAFETY CRAMP GREEN GUARD PMS RELIEF	Temporarily relieves headache, bloating, cramps, backache, water-weight gain, muscular aches and pains associated with the menstrual period	25 mg/caplet (6.4 mg/caplet)	8 caplets	0.73	not indicated
UNISHIELD CRAMP	Temporarily relieves headache, bloating, cramps, backache, water-weight gain, muscular aches and pains associated with the menstrual period	25 mg/caplet (6.4 mg/caplet)	8 caplets	0.73	10 days for pain 3 days for fever longer if prescribed
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	25 mg/caplet (6.4 mg/caplet)	8 caplets	0.73	not indicated

All contain the same warnings: "If pregnant or breast-feeding, ask a health professional before use."

This weight-of-evidence demonstrates that AMP is devoid of adverse effects to human health in a sensitive population (women with menstrual cycles) when ingested at 0.73 mg AMP/kg/day for up to 10-day treatment cycles, repeated over periods.

Applicant's summary and conclusion

Conclusions:

In women with menstrual periods, AMP has a human oral NOAEL of at least 0.73 mg AMP/kg bw/day for up to 10-day treatment cycles, which can be repeated at each menstrual period.

Executive summary:

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).
In the US, pamabrom is used since early 1950's so it has a track-record of >70 years of safe use.

Based on the National Library of Medicines database, at least 20 US OTC drugs currently contain pamabrom, 19 of which specifically target women with menstrual periods. Based on contents and posology for each drug, AMP has a human NOAEL of at least 0.73 mg AMP/kg bw/day for up to 10-day treatment cycles, repeated over periods. This weight-of-evidence demonstrates that AMP is devoid of adverse effects to human health at this dose-level, in a sensitive population (women with menstrual cycles).