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Key value for chemical safety assessment

Effects on fertility

Description of key information
.
Link to relevant study records
Reference
Endpoint:
toxicity to reproduction
Remarks:
other: testicular observation (after ingestion of capsules)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data have been obtained from secondary source.
Principles of method if other than guideline:
The method was based on an exposure to dogs via capsules of 2,4-dinitrophenol for six months. No further details were specified.
GLP compliance:
not specified
Species:
other: dog
Strain:
not specified
Sex:
not specified
Route of administration:
other: capsules
Duration of treatment / exposure:
six months
Remarks:
Doses / Concentrations:
5 mg/kg/day
Basis:
other: in capsules
Remarks:
Doses / Concentrations:
10 mg/Kg/day
Basis:
other: in capsules
No. of animals per sex per dose:
3 per dose group
Dose descriptor:
NOAEL
Effect level:
10 other: capsules
Sex:
male
Reproductive effects observed:
not specified

No gross histological evidence of treatment-related testicular damage was reported following 2,4-dinitrophenol at 5 or 10 mg/Kg/day.

Conclusions:
No gross histological evidence of treatment-related testicular damage was reported following 2,4-dinitrophenol at 5 or 10 mg/Kg/day.
Executive summary:

Data have been obtained from secondary source that mentions Tainter ML, Cutting WC, Wood DA, et al. 1934b. Di-nitrophenol. Studies of blood, urine, and tissues of dogs on continued medication and after acute fatal poisoning. Arch Pathol 18:881. The method was based on an exposure to dogs via capsules of 2,4-dinitrophenol for six months. No further details were specified.

Testicular tissue vas histologically analysed after the 2,4 -dinitrophenol exposure and no gross histological evidence of treatment-related testicular damage. No gross histological evidence of treatment-related testicular damage was reported following 2,4-dinitrophenol at 5 or 10 mg/Kg/day.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
10
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data on human, on support to the repoductive toxicity on animals are available.
Additional information

In three studies on animals , methods were based on a treatment focused to testicular damage in vivo.

Spencer et al. 1948, exposed rats in a diet with a range of 5 -50 mg/Kg/day (NOAEL) of 2,4-dinitrophenol for six months. Testicular tissue vas histologically analysed after the 2,4 -dinitrophenol exposure in diet and no gross histological evidence of treatment-related testicular damage at 5 -50 mg/Kg/day were noted. However, rats exposed at 350 mg/kg/day (LOAEL) did show signs of testicular atrophy (Spencer et al. 1948) but this may have been the result of starvation.Studies of blood, urine, and tissues of dogs on continued medication after acute fatal poisoning via capsules of 2,4-dinitrophenol for six months revealedno gross histological evidence of treatment-related testicular damage. No gross histological evidence of treatment-related testicular damage was reported following 2,4-dinitrophenol also at 5 or 10 mg/Kg/day (NOAEL) (Tainter at al, 1934b).In a further study of Tainter ML. 1938, the method was based on a treatment focused to testicular damage in vivo. Rats were exposed in the diet at 60 mg/Kg/day of 2,4-dinitrophenol for the lifetime (NOAEL). Testicular tissue vas histologically analysed and no gross histological evidence of treatment-related testicular damage.

Human reproductive toxicity

Three case reports and a clinical study of women taking 2,4-DNP orally for weight reduction suggest that 2,4-DNP may affect the female reproductive system (Beinhauer 1934; Epstein and Rosenblum 1935; Goldman and Haber 1936; Simkins 1937a, 1937b), but this limited information is inconclusive.

Menstrual disorders in 15-18 women of an unspecified number of women treated with 2,4-dinitrophenol sodium salt (dose not specified) were described in a study of Simkins S. 1937a, 1937b.

Beinhauer LG. 1934 observed fibroid degeneration of the uterus and cystic left ovary in a woman that took a dose of 2.32 mg/Kg/day for 37 days by capsules (whether or not these were pre-existing conditions is not known)

In a study described (Epstein E, Rosenblum H. 1935) a woman patient took a dose of 3.3 mg/Kg/day of sodium salt for 143 days. After 98 days from observations the authors concluded the 2,4-DNP caused a premature separation of the placenta, resulting in miscarriage.

In the last study of Goldman A, Haber M. 1936. Data obtained from an observation on human poisoning of 2,4-dinitrophenol revealed that a young woman died after had taken a dose of 1.03 mg/Kg/day for 46 days and a small and infantile uterus and numerous follicular cysts in the ovary have been found.


Short description of key information:
From studies available, the NOAEL choosen is 10 mg/kg/day, from Tainter at al, 1934b study. At this dose, no gross histological evidence of treatment-related testicular damage was reported following 2,4-dinitrophenol. The study was performed for 6 months, in rats by diet (oral).

Justification for selection of Effect on fertility via oral route:
The secondary source report (Toxicological profile for dinitrophenols, U.S. Department of heath and human services, Agency for Toxic Substances and disease Registry, 1995) describes in a short manner the study of Tainter et al., 1934b. Anyhow, details of the method have not been specified

Effects on developmental toxicity

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data have been obtained from secondary source.
Principles of method if other than guideline:
The study measured important developmental toxicity and points, including teratogenicity.
GLP compliance:
not specified
Species:
mouse
Strain:
Swiss Webster
Route of administration:
oral: gavage
Duration of treatment / exposure:
Treatment was done on gestation day 10-12, than mice were sacrificed on gestation day 19.
Remarks:
Doses / Concentrations:
0
Basis:
no data
mg/Kg/day
Remarks:
Doses / Concentrations:
25.5
Basis:
no data
mg/Kg/day
Remarks:
Doses / Concentrations:
38.3
Basis:
no data
mg/Kg/day
Dose descriptor:
NOAEL
Remarks:
25.5 mg/Kg/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Remarks:
38.3 mg/Kg/day
Basis for effect level:
other: developmental toxicity
Abnormalities:
not specified
Developmental effects observed:
not specified

In this study the lower dose 25.5 mg/Kg/day apparently did not produce maternal toxicity (NOAEL).

The high dose 38.3 mg/Kg/day produced overt toxicity (hyperexcitability and hyperthermia) in dams (data not presented), but no deaths (LOAEL).

The percentage resorption increased, but the effect was not significant or dose-related; no other abnormalities were observed.

Conclusions:
The authors indicated that the high dose 38.3 mg/Kg/day produced overt toxicity (hyperexcitability and hyperthermia) in dams (data not presented), but no deaths. The percentage resorption increased, but the effect was not significant or dose-related; no other abnormalities were observed. Thus, treatment of mice at a dose level producing maternal toxicity did not result in adverse developmental effects.
Executive summary:

Data have been obtained from secondary source that mentions Gibson JE. 1973. Teratology studies in mice with 2-set-butyl-4,6 dinitro phenol (Dinoseb). Food Cosmet Toxicol 11:31-43. This study measured important developmental toxicity and points, including teratogenicity. Three doses 0, 25.5, 38.5 mg/Kg/day of 2,4 -dinitrophenol were administered by gavage to Swiss-Webster mice on gestaetion day 10 -12. On gestation day 19 mice were sacrified and important developmental toxicity end points, including teratogenicity observed. The authors indicated that the high dose 38.3 mg/Kg/day produced overt toxicity (hyperexcitability and hyperthermia) in dams (data not presented), but no deaths. The percentage resorption increased, but the effect was not significant or dose-related; no other abnormalities were observed. Thus, treatment of mice at a dose level producing maternal toxicity did not result in adverse developmental effects.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
25.5 mg/kg bw/day
Study duration:
subacute
Species:
mouse
Quality of whole database:
Only two studies on developmental toxicity are available. Of this two, only the study of Gibson, 1973 measured important developmental toxicity endpoints, including teratogenenicity study. Anyhow, details of the method have not been specified and the study is limited because dosing only occurred during the first part of organogenesis.
Additional information

Gibson JE. 1973 measured important developmental toxicity and points, including teratogenicity. Three doses 0, 25.5, 38.5 mg/Kg/day of 2,4 -dinitrophenol were administered by gavage to Swiss-Webster mice on gestation day 10 -12. On gestation day 19 mice were sacrified and important developmental toxicity end points, including teratogenicity observed. The authors indicated that the high dose 38.3 mg/Kg/day produced overt toxicity (hyperexcitability and hyperthermia) in dams (data not presented), but no deaths. The percentage resorption increased, but the effect was not significant or dose-related; no other abnormalities were observed. Thus, treatment of mice at a dose level producing maternal toxicity did not result in adverse developmental effects.

The TDLo lowest published toxic dose in reproductive study on rat is 2040 mg/Kg, based on effects on newborn - stillbirth and weaning or lactation index (PSEBAA, 1935).

2,4-nitrophenol has been administerd (20 mg/kg/day) to female rats for 8 days before introducing the males. 2,4-initrophenol was then administered orally twice daily until the litters were weaned.

There was no effect on the weight gain of the mothers during pregnancy, the average number of offspring in each litter, nor were neonatal

malformations detected. However, 25% of the offspring of treated females were stillborn, compared to only 6.8% of those born to the controls. Moreover, the mortality during the nursing period among the viable offspring of the treatedmothers was 30.9%, compared to 13.4% for the young of the control mothers (Wulff, 1935).


Justification for selection of Effect on developmental toxicity: via oral route:
The secondary source report (Toxicological profile for dinitrophenols, U.S. Department of heath and human services, Agency for Toxic Substances and disease Registry, 1995) define the study of Gibson, 1973, as a study that measured important developmental toxicity endpoints, including teratogenenicity study. Anyhow, details of the method have not been specified and the study is limited because dosing only occurred during the first part of organogenesis.

Toxicity to reproduction: other studies

Additional information

On the base of data available on reproductive toxicity, the evaluation for the classification according to Regulation 1278/2008 can be considered inconclusive.

Justification for classification or non-classification

On the base of data available on reproductive toxicity, the evaluation for the classification according to Regulation 1278/2008 can be considered inconclusive.