Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity study

 The data available for diphenylacetonitrile (86-29-3) and structurally similar read across chemicals was reviewed to determine the reproductive toxicity.The NOAEL for reproductive toxicity was considered to be in between 500-1000mg/kg bw/day as No effects on reproductive parameters were observed .When female rats or mice were treated withdiphenylacetonitrile (86-29-3).Thus, comparing this value with the criteria of CLP regulation diphenylacetonitrile (86-29-3)not likely to classify as reproductive toxicant.

 

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:
Weight of evidence approach based on structurally similar chemicals
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Qualifier:
equivalent or similar to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
WoE report is based on two reproductive toxicity studies on rats and mice
1.Reproductive toxicity study of test material was performed on CD 1 female mice.
2.Reproductive and developmental toxicity study of test material was performed on Sprague Dawley rats.
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available
Species:
other: 1.mouse 2.rats
Strain:
other: 1.CD-1 2.Sprague-Dawley
Details on species / strain selection:
1.These animals were selected because the assay was originally developed in mice and hence there is anample database on the response of this species under these experimental conditions
Sex:
female
Details on test animals and environmental conditions:
1. Details on test animals and env. conditions
TEST ANIMALS
- Source: Charles River Breeding Labora-
tories, Portage, MI
- Age at study initiation: 74 days
- Weight at study initiation: 21-31 g
- Fasting period before study:
- Housing: , each female was individually housed in a plastic cage with wood chip bedding.

- Use of restrainers for preventing ingestion (if dermal): yes/no
- Diet (e.g. ad libitum): feed (Purina No. 5002) ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period:2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%):No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): 12-hr dark/ 12-hr light cycle

IN-LIFE DATES: From: To:
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
1.Details on exposure
PREPARATION OF DOSING SOLUTIONS:
Test material diluted with corn oil
DIET PREPARATION
- Rate of preparation of diet (frequency):No data available
- Mixing appropriate amounts with (Type of food )
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): test material mixed with corn oil
- Concentration in vehicle: 0, 100, 300, and 1000 mg/kg/day

- Amount of vehicle (if gavage): 0.5ml/day

- Lot/batch no. (if required): No data available
2.Details on exposure
PREPARATION OF DOSING SOLUTIONS:
Test material 73.5% test material & 26.5% biphenyl mixed in corn oil.
DIET PREPARATION
- Rate of preparation of diet (frequency):No data available
- Mixing appropriate amounts with (Type of food )
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): corn oil
- Concentration in vehicle: 50, 200, 500 mg/kg/day - Amount of vehicle (if gavage): 5ml/kg

- Lot/batch no. (if required): No data available
- Purity: No data available
Details on mating procedure:
Study 1
- M/F ratio per cage:1:1
- Length of cohabitation:No data available

- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy:The day a vaginal plug was noted was designated Gestation Day 0
- 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):each female was individually housed in a plastic cage with wood chip bedding.

- Any other deviations from standard protocol:No data available

Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Study 1
5 days ( from Days 8 through 12 of Gestation)
Study 2
10 days ( on gestation days 6-15)
Frequency of treatment:
Daily
Details on study schedule:
No data available
Remarks:
Study 1
0, 100, 300, and 1000 mg/kg/day
Study 2
0,50, 200, 500 mg/kg/day
No. of animals per sex per dose:
Study 1
Total:48
0 mg/kg bw/day:12
100mg/kg bw/day:12
300mg/kg bw/day:12
1000mg/kg bw/day:12
Study 2
Total:96
0 mg/kg bw/day:24
50mg/kg bw/day:24
200mg/kg bw/day:24
500mg/kg bw/day:24
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Positive control:
No data available
Parental animals: Observations and examinations:
Study 1&2
Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes

DETAILED CLINICAL OBSERVATIONS: Yes

Time schedule: As each dam approached the
end of its gestation period,the animals were observed at hourly intervals beginning at 8:00 AM (EST) and ending at 5:00 PM (EST). The dams were not observed during the night.


BODY WEIGHT: Yes
Time schedule for examinations: Body weights for each dam were recorded on Days 0, 8, and 13 of gestation and on Day 1 of lactation
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data available

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 available


WATER 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:
Study 1
the number of live and dead pups was recorded for each darn. Pups were weighed individually on Lactation Days 1 and 3. On Lactation Day 3. all pups were externally examined,
Postmortem examinations (parental animals):
Study 1&2
Postmortem examinations (Parent Animal)
SACRIFICE :When delivery was completed, All the dams terminated by carbon dioxide inhalation, and discarded. Dams which failed to deliver by Day 22 of gestation were aterminated
GROSS NECROPSY: yes ( all dams were externally examined)
HISTOPATHOLOGY / ORGAN WEIGHTS
uteri placed in ammonium sulfide for detection of resorptions (Kopf et at. 1964).
Postmortem examinations (offspring):
Study 1
Postmortem examinations (offspring)
SACRIFICE
On Lactation Day 3. all pups were terminated by carbon dioxide inhalation, and discarded.

GROSS NECROPSY
On Lactation Day 3. all pups were externally examined Pups were weighed individually on Lactation Days 1 and 3
GROSS NECROPSY: yes
Study 2
- Approximately 1/2 of the fetuses in each litter were processed for soft-tissue evaluations while the other half for skeletal evaluations

Statistics:
Study 1
Homogeneity of variance for data from the oral developmental toxicity studies was assessed by Bartlett’s test(Steele and Torrie, 1960). Following appropriate analysis of variance (ANOVA) design, as dictated by Bartlett’s criterion, post hoc comparisons between individual means were done by Fisher’s LSD for multiple comparisons or by Dunnett’s test for multiple comparisons against a single control mean (homogenous variance) (Winer, 1971) or by the Wilcoxon-Mann- Whitney test (heterogenous variance) (Snedecor and Cochran, 1967). For the oral developmental toxicity study in particular, litter weights were analysed by analysis of covariance (Winer, 1971) using litter size as the covariate (live and dead pups included) to control for a possible litter size effect on litter weight that may occur independently of test material -associated effects. Dose-response trend analysis was done by the Cochran-Armitage test (Armitage, 1971)
Study 2
Statistical evaluation of equality of means was made by the appropriate one-way analysis of variance technique (ANOVA) for parametric procedures and Kruskal-Wallis test for nonparametric procedures were used after applying Bartlett's test for determination of equal variance. Statistical tests for trend, using either standard regression techniques (parametric cases) or Jonckheere's test in nonparametric cases. Levels of statistical significance used were either p<0.05 or p<0.01.
Reproductive indices:
No data available
Offspring viability indices:
No data available
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
2.Excessive alopecia, salivation and/or anogenital staining was observed but no pattern of treatment relationship could be determined.
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, treatment-related
Description (incidence):
1.no mortality observed

2. deaths occurred at 500 mg/kg
Body weight and weight changes:
no effects observed
Description (incidence and severity):
1.Maternal body weight changes were comparable across all treatment groups.
2.Statistically reduced maternal weight gain were observed at 200 and 500 mg/kg/d.
Food consumption and compound intake (if feeding study):
not specified
Description (incidence and severity):
2.Statistically reduced food consumption were observed at 200 and 500 mg/kg/d.
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):
1.pregnancy rate was lower in the group 1000 mg/kg/day,but this observation cannot be attributed to a drug treatment effect, which began after mating of the females.
2.No effects observed on fetal resorptions, fetal viability, postimplantation loss or total implantations
Dose descriptor:
NOAEL
Effect level:
> 500 - <= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
reproductive performance
Remarks on result:
other: overall no toxic effects 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:
no effects observed
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Description (incidence and severity):
1.No statistically significant differences in litter size or numbers of live and dead pups delivered were noted
Body weight and weight changes:
no effects observed
Description (incidence and severity):
1.body weight gain of pups were unaffected
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):
2.No increases were observed in incidence of malformations or variations at any treatment level.
Histopathological findings:
not specified
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 500 - <= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
viability
clinical signs
mortality
body weight and weight gain
Remarks on result:
other: no effects on developmental parameters
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

Maternal, Reproductive, and Developmental Observations in Mice Treated Orally with Various Doses

of test material on Days 8-12 of Gestation

Parameterc

Dose of Octocrylene (mg/kg/day) administeredb

0

100

300

1000

A Pregnancy status

Number of females mated

12

12

12

12

Number of females pregnant

12

9

11

7

Number of females which delivered

10

8

9

7

B. Body weight of dams (g) (Mean±SD)

 

Gestation Day 0

24 ±1.7

25 ±2.9

25 ±1.7

25 ±1.1

Gestation Day 8

28± 3.1

28 ±4.1

29 ±2.3

29 ±1.8

Gestation Day 13

34 ±4.2

35 ± 5.7

33 ± 4.0

36 ± 2.9

Lactation Day 1

33 ±2.8

32 ±6.7

28 ± 2.9

33 ±1.9

C. Offspring status (Mean± SD)

 

Total number of litters studied

10

8

9

7

Number dead at birth

0.2± 1.1

0.1± 0.4

0.2 ±0.7

0.3 ±0.8

Number live at birth

10.1 ±1.0

10.3± 3.4

7.0 ±4.2

10.6 ±2.1

Number live 24 hr after birth

10.1± 1.0

9.9 ± 3.6

6.7± 4.1

9.9 ±2.7

Number live 72 hr after birth

10.1 ± 1.0

9.8 ±3.9

6.7± 4.1

9.9± 2.7

Mean pup weight (g) 24 hr after birth

1.8± 0.3

1.8 ±0.3

1.9± 0.6

1.6± 0.2

Mean pup weight (g) 72 hr after birth

2.5 ±0.5

2.5± 0.5

2.9 ±0.6

2.5± 0.3

 

Control and Octocrylene solutions were administered by gavage to dams on presumed Gestation Days 8 through 12 (inclusive).

b Octocrylene dose volumes were adjusted such that each animal received 0.5 ml solution per day. Control dams received 0.5 ml of corn oil/day.

‘Data shown are means i SD of the indicated number of dams. For statistical analysis purposes, the adult or the litter was considered as the

experimental unit, as apprOpriate. Data are analyzed by analysis of variance and pairwise multiple mean comparisons to the control treatment were done

by Dunnet’s test. No significant effects at the 0.05 probability level were noted.

 

Conclusions:
No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be in between 500- 1000mg/kg bw . When female mice or rats were treated with diphenylacetonitrile (86-29-3)orally.
Executive summary:

Reproductive toxicity study

Data available from different studies were reviewed to determine the reproductive toxicity of diphenylacetonitrile (86-29-3).The studies are as mentioned below:

Study 1

The reproductive and developmental toxicity study of test material was performed on female CD 1 mice.These animals were selected because the assay was originally developed in mice and hence there is anample database on the response of this species under these experimental conditions.The test material was dissolved in corn oil and administered in dose concentration 0,100,300,1000mg/kg bw by oral gavage fromDays 8 through 12 of Gestation. 12 females were used in dose group. Control dams received 0.5 ml of corn oil per day. At the end of the 2-week acclimation period, each healthy female was housed together with a male of the same source and strain for breeding (1 female and 1 male per cage). Copulation was established by daily inspection of dams for presence of vaginal plug. . Body weights for each dam were recorded on Days 0, 8, and 13 of gestation and on Day 1 of lactation. All bred animals were allowed to give birth. As each dam approached the end of its gestation period, the animals were observed at hourly intervals beginning at 8:00 AM (EST) and ending at 5:00 PM (EST). The dams were not observed during the night. This is a limitation of the study which leaves open the possibility that cannibalization of dead pups may not be noticed and, hence, might lead to artifactually decreased litter size observations.The day on which pups were delivered was Lactation Day 0. When delivery was completed, the number of live and dead pups was recorded for each darn. Pups were weighed individually on Lactation Days 1 and 3. On lactation Day 3,all dams and their pups were externally examined, terminated by carbon dioxide inhalation, and discarded. Dams which failed to deliver by Day 22 of gestation were terminated and their uteri placed in ammonium sulfide for detection of resorptions. All dams included in the study survived to offspring delivery. Maternal body weight changes were comparable across all treatment groups. Among mated dams, pregnancy rate was lower in the group receiving 1000 mg/kg/day Octocrylene, but this observation cannot be attributed to a drug treatment effect, which began after mating of the females. No statistically significant differences in litter size or numbers of live and dead pups delivered were noted. Pup mortality between Day 0 and Day 1 ranged between 4 and 7% of total pups born in each treatment group for dams, for dams receiving the control treatment, all pups survived to Day 3. Although this suggested the possibility of a trend toward decreased survival of pups born to test material treated compared to control dams, the observation did not achieve statistical significance.HenceNo Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 1000mg/kg bw .When femaleCD1 mice were treated with test material orally.

Study 2

Reproductive and development toxicity study of test material was performed on mated female SpragueDawley rats according toOECD Test Guideline 414.The test material73.5% test material & 26.5% biphenyl mixed in corn oil at volume of 5 ml/kg wereadministered in dose concentration 0,50, 200, 500 mg/kg/day on gestation days 6-15by oral gavage route..96 rats were divided as 24 rats /dose group

.Animals was checked daily for clinical signs. Food consumption and body weight were recorded; the dams were sacrificed and subjected to a macroscopic examination. Approximately 1/2 of the fetuses in each litter were processed for soft-tissue evaluations while the other half for skeletal evaluations. Statistical evaluation of equality of means was made by the appropriate one-way analysis of variance technique (ANOVA) for parametric procedures and Kruskal-Wallis test for nonparametric procedures were used after applying Bartlett's test for determination of equal variance. Statistical tests for trend, using either standard regression techniques (parametric cases) or Jonckheere's test in nonparametric cases. Levels of statistical significance used were either p<0.05 or p<0.01. Two deaths occurred at 500 mg/kg. Statistically reduced maternal weight gain and food consumption were observed at 200 and 500 mg/kg/d. Excessive alopecia, salivation and/or anogenital staining was observed but no pattern of treatment relationship could be determined. No effects observed on fetal resorptions, fetal viability, postimplantation loss or total implantations. Mean litter weights in treated and control groups were similar. No significant increases were observed in incidence of malformations or variations at any treatment level. Therefore No Observed Adverse Effect Level (NOAEL) for maternal toxicity was considered to be 50 mg/kg/day, andNo indications of any influence on reproductive parameters or damage to reproductive organs were foundand No developmental toxic effects were seen up to the highest dose of 500 mg/kg bw. Hencethe dose-level of 500 mg/kg/day was considered to be the NOAEL for embryo-foetal toxicity and reproductive toxicity .When femaleSprague Dawley rats were treated with test material orally.

Based on the data available from different studies, diphenylacetonitrile (86-29-3)did not showed reproductive toxicity at dose concentration below 1000mg/kg bw . Hence the test chemical is not likely to classify as a reproductive toxicant as per the criteria mentioned in CLP regulation.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
mouse
Quality of whole database:
Data is Klimicsh 2 and from authoritative database
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproductive toxicity study

Data available from different studies were reviewed to determine the reproductive toxicity of diphenylacetonitrile (86-29-3).The studies are as mentioned below:

Study 1

The reproductive and developmental toxicity study of test material was performed on female CD 1 mice.These animals were selected because the assay was originally developed in mice and hence there is anample database on the response of this species under these experimental conditions.The test material was dissolved in corn oil and administered in dose concentration 0,100,300,1000mg/kg bw by oral gavage fromDays 8 through 12 of Gestation. 12 females were used in dose group. Control dams received 0.5 ml of corn oil per day. At the end of the 2-week acclimation period, each healthy female was housed together with a male of the same source and strain for breeding (1 female and 1 male per cage). Copulation was established by daily inspection of dams for presence of vaginal plug. . Body weights for each dam were recorded on Days 0, 8, and 13 of gestation and on Day 1 of lactation. All bred animals were allowed to give birth. As each dam approached the end of its gestation period, the animals were observed at hourly intervals beginning at 8:00 AM (EST) and ending at 5:00 PM (EST). The dams were not observed during the night. This is a limitation of the study which leaves open the possibility that cannibalization of dead pups may not be noticed and, hence, might lead to artifactually decreased litter size observations.The day on which pups were delivered was Lactation Day 0. When delivery was completed, the number of live and dead pups was recorded for each darn. Pups were weighed individually on Lactation Days 1 and 3. On lactation Day 3,all dams and their pups were externally examined, terminated by carbon dioxide inhalation, and discarded. Dams which failed to deliver by Day 22 of gestation were terminated and their uteri placed in ammonium sulfide for detection of resorptions. All dams included in the study survived to offspring delivery. Maternal body weight changes were comparable across all treatment groups. Among mated dams, pregnancy rate was lower in the group receiving 1000 mg/kg/day Octocrylene, but this observation cannot be attributed to a drug treatment effect, which began after mating of the females. No statistically significant differences in litter size or numbers of live and dead pups delivered were noted. Pup mortality between Day 0 and Day 1 ranged between 4 and 7% of total pups born in each treatment group for dams, for dams receiving the control treatment, all pups survived to Day 3. Although this suggested the possibility of a trend toward decreased survival of pups born to test material treated compared to control dams, the observation did not achieve statistical significance.HenceNo Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 1000mg/kg bw .When femaleCD1 mice were treated with test material orally.

Study 2

Reproductive and development toxicity study of test material was performed on mated female SpragueDawley rats according toOECD Test Guideline 414.The test material73.5% test material & 26.5% biphenyl mixed in corn oil at volume of 5 ml/kg wereadministered in dose concentration 0,50, 200, 500 mg/kg/day on gestation days 6-15by oral gavage route..96 rats were divided as 24 rats /dose group

.Animals was checked daily for clinical signs. Food consumption and body weight were recorded; the dams were sacrificed and subjected to a macroscopic examination. Approximately 1/2 of the fetuses in each litter were processed for soft-tissue evaluations while the other half for skeletal evaluations. Statistical evaluation of equality of means was made by the appropriate one-way analysis of variance technique (ANOVA) for parametric procedures and Kruskal-Wallis test for nonparametric procedures were used after applying Bartlett's test for determination of equal variance. Statistical tests for trend, using either standard regression techniques (parametric cases) or Jonckheere's test in nonparametric cases. Levels of statistical significance used were either p<0.05 or p<0.01. Two deaths occurred at 500 mg/kg. Statistically reduced maternal weight gain and food consumption were observed at 200 and 500 mg/kg/d. Excessive alopecia, salivation and/or anogenital staining was observed but no pattern of treatment relationship could be determined. No effects observed on fetal resorptions, fetal viability, postimplantation loss or total implantations. Mean litter weights in treated and control groups were similar. No significant increases were observed in incidence of malformations or variations at any treatment level. Therefore No Observed Adverse Effect Level (NOAEL) for maternal toxicity was considered to be 50 mg/kg/day, andNo indications of any influence on reproductive parameters or damage to reproductive organs were foundand No developmental toxic effects were seen up to the highest dose of 500 mg/kg bw. Hencethe dose-level of 500 mg/kg/day was considered to be the NOAEL for embryo-foetal toxicity and reproductive toxicity .When femaleSprague Dawley rats were treated with test material orally.

Based on the data available from different studies, diphenylacetonitrile (86-29-3)did not showed reproductive toxicity at dose concentration below 1000mg/kg bw . Hence the test chemical is not likely to classify as a reproductive toxicant as per the criteria mentioned in CLP regulation.

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, comparing this value with the criteria of CLP regulation diphenylacetonitrile (86-29-3)not likely to classify as reproductive toxicant.