Benzene-1,4-diammonium sulphate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

The No Observed Adverse Effect level (NOAEL) for the test chemical  Benzene-1,4-diammonium sulphate (16245-77-5)for reproduction toxicity in test animals were  considered to be of 50mg/Kg bw/day.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Remarks:

experimental data of read across substances

Justification for type of information:

Data for the target chemical is summarized based on the structurally similar read across chemicals

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

WoE derived based on the experimental data from structurally and functionally similar read across chemicals.

GLP compliance:

not specified

Limit test:

no

Justification for study design:

No data available

Species:

other: Study 1; rabbit Study 2; Rat

Strain:

other: Study 1; New zealand Study 2; Sprague Dawley ( Him:OFA)

Details on species / strain selection:

No data available

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

distilled water

Details on exposure:

Study 1;Details on exposurePREPARATION OF DOSING SOLUTIONS: test material dissolved in distilled water DIET PREPARATION- Rate of preparation of diet (frequency):No data available- Mixing appropriate amounts with (Type of food )- Storage temperature of food: No data availableVEHICLE- Justification for use and choice of vehicle (if other than water): - Concentration in vehicle: 0, 10, 25, 50 mg/kg bw/d, - Amount of vehicle (if gavage): No data available- Lot/batch no. (if required): No data available- Purity: No data availableStudy 2;Details on exposurePREPARATION OF DOSING SOLUTIONS:0, 5, 15 and 45 mg/kg bw/d in deionised water, 50 μl 25 % ammonia per g test substance addedDIET PREPARATION- Rate of preparation of diet (frequency):No data available- Mixing appropriate amounts with (Type of food )- Storage temperature of food: No data availableVEHICLE- Justification for use and choice of vehicle (if other than water): - Concentration in vehicle: 0, 5, 15 and 45 mg/kg bw/d - Amount of vehicle (if gavage): No data available- Lot/batch no. (if required): No data available- Purity: No data available

Details on mating procedure:

Study 1;- M/F ratio per cage:No data available - Length of cohabitation: No data available - Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancyNo data available - After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.No data available - Further matings after two unsuccessful attempts: [no / yes (explain)]No data available - After successful mating each pregnant female was caged (how): No data available - Any other deviations from standard protocol:The females were fertilised by natural mating. After coitus HCG was given i.v. to ensure ovulation. Study 2;Not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Study 1;12 days (from day 6 to 18 of gestation)Study 2;males: 70 d before matingfemales: prior to mating for 14 d, during mating period, gravidity,lactation until the end of the experimentF1: from weaning for appr. 80 days until the end of the experiment

Frequency of treatment:

once daily

Details on study schedule:

No data available

Remarks:

0, 10, 25, 50 mg/kg bw/d,

Remarks:

0, 5, 15 and 45 mg/kg bw/day

No. of animals per sex per dose:

Study1;0 mg/kg bw/day:1610mg/kg bw/day:1625mg/kg bw/day:1650 mg/kg bw/day:16Positive control group:18Study2;Total:1920 mg/kg bw/day:24male and 24 female 5mg/kg bw/day:24male and 24 female 15mg/kg bw/day:24male and 24 female 45 mg/kg bw/day:24male and 24 female

Control animals:

yes, concurrent vehicle

Details on study design:

No data available

Positive control:

No data available

Parental animals: Observations and examinations:

Study1;Parental animals observation and examinationsCAGE SIDE OBSERVATIONS: yes DETAILED CLINICAL OBSERVATIONS: Yes Time schedule: daily BODY WEIGHT: YesTime schedule for examinations: The body weights were determined on days 0, 6, 18 and 28 of gestation.FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data availableWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data Study2;Parental animals observation and examinationsCAGE SIDE OBSERVATIONS: yes DETAILED CLINICAL OBSERVATIONS: Yes Time schedule: BODY WEIGHT: YesTime schedule for examinations: FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data availableWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data Time schedule for examinations:

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

No data available

Postmortem examinations (parental animals):

Study1;Postmortem examinations (Parent Animal)SACRIFICE :On day 28 of gestation the animals were sacrificed,Male animals: All surviving animals [describe when, e.g. as soon as possible after the last litters in each generation were produced.]: No dataMaternal animals: yes All surviving animals [describe when, e.g. after the last litter of each generation was weaned :GROSS NECROPSY: No data available HISTOPATHOLOGY / ORGAN WEIGHTSThe tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.: macroscopic examination was performed Study2;Postmortem examinations (Parent Animal)SACRIFICE : Male animals: All surviving animals [describe when, e.g. as soon as possible after the last litters in each generation were produced.]: No dataMaternal animals: No dataAll surviving animals [describe when, e.g. after the last litter of each generation was weaned :GROSS NECROPSY: Thereproduction organs (pituitary gland, mamma, vulva, vagina, cervix, uterus, tubes, ovaries,penis, testes, epididymides, ducti referentes, coagulation gland, prostate gland, vesiculargland) were examined microscopically.HISTOPATHOLOGY / ORGAN WEIGHTSThe tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.: macroscopic examination was performed

Postmortem examinations (offspring):

Study 1;Postmortem examinations (offspring)SACRIFICE- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at [#?] days of age.- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows: the foetuses were dissected and examined for congenital abnormalities and macroscopic changes. The common section parameters were recorded. Half of the foetuses were examined for skeletal and the other half for visceral abnormalities.Study 2;Postmortem examinations (offspring)SACRIFICE- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at [#?] days of age.- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows postnatal weight and physiological development were observed

Statistics:

No data available

Reproductive indices:

No data available

Offspring viability indices:

No data available

Clinical signs:

no effects observed

Description (incidence and severity):

Study1No clinical signs were observed.study 2;No treatment-related clinical signs wereobserved

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, non-treatment-related

Description (incidence):

1 female at 10 and 1 female at 25 mg/kg bw/d died, at 50 mg/kg 3 females died presumably because of the intubation procedure.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Study 1;Body weights of the females in the dose groups were similar to the controls.Study2;Body weight development, feed consumption and observation of the animals did not show substance treatment related differences.

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Description (incidence and severity):

Study2;There were no treatment-related effects on female estrous cycle

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

Remarks on result:

other: No effects on reproductive performance

Dose descriptor:

NOAEL

Effect level:

45 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No significant effect were observed at this dose

Remarks on result:

other: No toxic effect were observed

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

no mortality observed

Description (incidence and severity):

The number of the foetuses were not influenced by substance treatment

Body weight and weight changes:

no effects observed

Description (incidence and severity):

The foetal body weights were not influenced by substance treatment

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Description (incidence and severity):

The frequencies of external abnormalities, visceral malformations and variations as well as skeletal defects exhibited no substance-related changes.

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

viability

mortality

body weight and weight gain

gross pathology

Remarks on result:

other: no effects on overall developmental parameters

Dose descriptor:

other: Not specified

Basis for effect level:

other: Not specified

Remarks on result:

other: Not specified

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Reproductive effects observed:

not specified

Treatment related:

not specified

Relation to other toxic effects:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Conclusions:

The No Observed Adverse Effect level (NOAEL) for the test chemical Benzene-1,4-diammonium sulphate (16245-77-5)for reproduction toxicity in test animals were considered to be in range of 45-50mg/Kg bw/day.

Executive summary:

Data available for the target chemicals was reviewed to determine the toxic nature of the test chemical Benzene-1,4-diammonium sulphate (16245-77-5). The studies are as mentioned below:

Two generation reproduction toxicity study of test chemical was performed on male and female Sprague Dawley Him:OFA rats according to OECD 416 Guideline. 0, 5, 15 and 45 mg/kg bw/d in deionised water, 50 μl 25 % ammonia per g test substance added and administered by oral gavage route to males for 70 days and to females for 14 days until mating. The animals were monogamously mated within the dose groups. Dams were further dosed until weaning of the pubs. Starting on day 21 after birth the F1 generation was dosed for approximately 80 d. After mating the F2 generation was kept until weaning. 24 male and 24 female were placed each dose level. The common parameters were evaluated (female sexual cycle, mating, insemination, gravidity, birth and litter data, postnatal weight and physiological development). Histopathology was performed for organs with obvious abnormalities, for parents without live offspring and for all parent animals of the control and the highest dose group. The reproduction organs (pituitary gland, mamma, vulva, vagina, cervix, uterus, tubes, ovaries, penis, testes, epididymides, ducti referentes, coagulation gland, prostate gland, vesicular gland) were examined microscopically. 4 animals (one of P- and 3 of F1-generation) died due to intubation-induced lesions. Body weight development, feed consumption and observation of the animals did not show substance treatment related differences. Observations and measurements in the pups of both generations until weaning did not show differences in the parameters evaluated. No detrimental effect on male and female fertility was found. Hence No Observed Adverse Effect Level (NOAEL) was considered to be 45 mg/kg/day, when male and female Sprague Dawley rats were treated with test chemical orally.

 

The reproductive and developmental toxicity study of test chemical was performed in female New Zealand White Rabbit. The test material dissolved in distilled water and administered in dose concentration 0, 10, 25, 50 mg/kg bw/d, by oral gavage route from day 6 to 18 of gestation while positive control Vitamin A in rape seed oil in dose concentration 6 mg/kg bw/d given by same route. The females were fertilised by natural mating. After coitus HCG was given i.v. to ensure ovulation. The animals were examined daily for mortality and clinical signs. The body weights were determined on days 0, 6, 18 and 28 of gestation. On day 28 of gestation the animals were sacrificed, the foetuses were dissected and examined for congenital abnormalities and macroscopic changes. The common section parameters were recorded. Half of the foetuses were examined for skeletal and the other half for visceral abnormalities. 1 female at 10 and 1 female at 25 mg/kg bw/d died, at 50 mg/kg 3 females died presumably because of the intubation procedure. No clinical signs were observed. Body weights of the females in the dose groups were similar to the controls. The changes in the incidences of intrauterine death observed were not dose-related. The number and sex of the foetuses as well as the foetal body weights were not influenced by substance treatment. The frequencies of external abnormalities, visceral malformations and variations as well as skeletal defects exhibited no substance-related changes. The positive control (Vitamin A) did not show teratogenicity and only slight embryotoxicity. Hence No Observed Adverse Effect Level (NOAEL) for maternal toxicity and embryotoxicity was considered to be 50 mg/kg/day. When female New Zealand White Rabbit were treated with test chemical orally from day 6 to 18 of gestation.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Quality of whole database:

Weight of evidence prepared from two well qualified publication.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Data available for the target chemicals was reviewed to determine the toxic nature of the test chemical Benzene-1,4-diammonium sulphate (16245-77-5). The studies are as mentioned below:

Two generation reproduction toxicity study of test chemical was performed on male and female Sprague Dawley Him:OFA rats according to OECD 416 Guideline. 0, 5, 15 and 45 mg/kg bw/d in deionised water, 50 μl 25 % ammonia per g test substance added and administered by oral gavage route to males for 70 days and to females for 14 days until mating. The animals were monogamously mated within the dose groups. Dams were further dosed until weaning of the pubs. Starting on day 21 after birth the F1 generation was dosed for approximately 80 d. After mating the F2 generation was kept until weaning. 24 male and 24 female were placed each dose level. The common parameters were evaluated (female sexual cycle, mating, insemination, gravidity, birth and litter data, postnatal weight and physiological development). Histopathology was performed for organs with obvious abnormalities, for parents without live offspring and for all parent animals of the control and the highest dose group. The reproduction organs (pituitary gland, mamma, vulva, vagina, cervix, uterus, tubes, ovaries, penis, testes, epididymides, ducti referentes, coagulation gland, prostate gland, vesicular gland) were examined microscopically. 4 animals (one of P- and 3 of F1-generation) died due to intubation-induced lesions. Body weight development, feed consumption and observation of the animals did not show substance treatment related differences. Observations and measurements in the pups of both generations until weaning did not show differences in the parameters evaluated. No detrimental effect on male and female fertility was found. Hence No Observed Adverse Effect Level (NOAEL) was considered to be 45 mg/kg/day, when male and female Sprague Dawley rats were treated with test chemical orally.

 

The reproductive and developmental toxicity study of test chemical was performed in female New Zealand White Rabbit. The test material dissolved in distilled water and administered in dose concentration 0, 10, 25, 50 mg/kg bw/d, by oral gavage route from day 6 to 18 of gestation while positive control Vitamin A in rape seed oil in dose concentration 6 mg/kg bw/d given by same route. The females were fertilised by natural mating. After coitus HCG was given i.v. to ensure ovulation. The animals were examined daily for mortality and clinical signs. The body weights were determined on days 0, 6, 18 and 28 of gestation. On day 28 of gestation the animals were sacrificed, the foetuses were dissected and examined for congenital abnormalities and macroscopic changes. The common section parameters were recorded. Half of the foetuses were examined for skeletal and the other half for visceral abnormalities. 1 female at 10 and 1 female at 25 mg/kg bw/d died, at 50 mg/kg 3 females died presumably because of the intubation procedure. No clinical signs were observed. Body weights of the females in the dose groups were similar to the controls. The changes in the incidences of intrauterine death observed were not dose-related. The number and sex of the foetuses as well as the foetal body weights were not influenced by substance treatment. The frequencies of external abnormalities, visceral malformations and variations as well as skeletal defects exhibited no substance-related changes. The positive control (Vitamin A) did not show teratogenicity and only slight embryotoxicity. Hence No Observed Adverse Effect Level (NOAEL) for maternal toxicity and embryotoxicity was considered to be 50 mg/kg/day. When female New Zealand White Rabbit were treated with test chemical orally from day 6 to 18 of gestation.

Thus based on the above annotation and CLP criteria the test chemical Benzene-1,4-diammonium sulphate (16245-77-5) is not likely to exhibit reproductive toxicant substance. Hence the substance cannot be classified as reproductive toxicant.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Thus based on the above annotation and CLP criteria the test chemical Benzene-1,4-diammonium sulphate (16245-77-5) is not likely to exhibit reproductive toxicant substance. Hence the substance cannot be classified as reproductive toxicant.