α-bromo-m-toluonitrile

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Toxicity to reproduction

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for 3-(bromomethyl)benzonitrile (28188-41-2).NOAEL was estimated to be 58.69mg/kg bw. When male and female Sprague-Dawley rats were exposed with 3-(bromomethyl)benzonitrile (28188-41-2) orally.

Thus, based on the studies and predictions on 3-(bromomethyl)benzonitrile (28188-41-2). It was considered that no adverse effects on reproductive parameter were observed. Thus, comparing this value with the criteria of CLP regulation 3-(bromomethyl)benzonitrile (28188-41-2) cannot be classified as reproductive toxicant.

 

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

Data is from OECD QSAR toolbox v3.3 and the QMRF report has been attached.

Qualifier:

equivalent or similar to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3, 2017

GLP compliance:

not specified

Limit test:

no

Justification for study design:

No data available

Specific details on test material used for the study:

- Name of the test material: α-bromo-m-toluonitrile
- IUPAC name: 3-(bromomethyl)benzonitrile
- Molecular formula: C8H6BrN
- Molecular weight: 196.046 g/mol
- Smiles: N#Cc1cc(CBr)ccc1
- Inchi: 1S/C8H6BrN/c9-5-7-2-1-3-8(4-7)6-10/h1-4H,5H2
- Substance type: Organic
- Physical state : Solid crystalline powder (Off white)

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

No data available

Details on mating procedure:

No data available

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Exposure period: male: 14 days before mating and thereafter 31 days, female: 14 days before mating to day 3 of lactationPremating exposure period (males): 14 daysPremating exposure period (females): 14 daysDuration of test: male: to day 45 female: to day 3 of lactation

Frequency of treatment:

daily

Dose / conc.:

58.69 mg/kg bw/day (nominal)

No. of animals per sex per dose:

12

Control animals:

yes

Details on study design:

No data available

Positive control:

No data available

Parental animals: Observations and examinations:

No data available

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

No data available

Postmortem examinations (parental animals):

No data available

Postmortem examinations (offspring):

No data available

Statistics:

No data available

Reproductive indices:

No data available

Offspring viability indices:

No data available

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

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:

no effects observed

Histopathological findings: neoplastic:

not specified

Other effects:

no effects observed

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Dose descriptor:

NOAEL

Effect level:

58.69 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

gross pathology

histopathology: non-neoplastic

reproductive performance

Remarks on result:

other: No effects on reperoductive 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

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

not specified

Body weight and weight changes:

no effects observed

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

Histopathological findings:

no effects observed

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

58.69 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

body weight and weight gain

gross pathology

histopathology: non-neoplastic

Remarks on result:

other: No overall developmental effects was 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

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

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 6 nearest neighbours
Domain  logical expression:Result: In Domain

((("a" or "b" or "c" or "d" or "e" )  and "f" )  and ("g" and "h" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Benzyl Halides by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as SN2 OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl halides OR SN2 >> SN2 reaction at sp3 carbon atom >> alpha-Halobenzyls (and related cyano, sulfate and sulphonate subs. chem.) by Protein binding by OECD ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as SN2 OR SN2 >> Nucleophilic substitution at sp3 carbon atom OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> Alkyl halides  OR SN2 >> Nucleophilic substitution on benzilyc carbon atom OR SN2 >> Nucleophilic substitution on benzilyc carbon atom >> alpha-Activated benzyls  by Protein binding by OASIS v1.3 ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as SN2 OR SN2 >> SN2 at an sp3 Carbon atom OR SN2 >> SN2 at an sp3 Carbon atom >> Aliphatic halides by DNA binding by OECD ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Shiff base formation for aldehydes OR AN2 >> Shiff base formation for aldehydes >> Haloalkane Derivatives with Labile Halogen OR SN2 OR SN2 >> Acylation involving a leaving group  OR SN2 >> Acylation involving a leaving group  >> Haloalkane Derivatives with Labile Halogen OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Haloalkane Derivatives with Labile Halogen by DNA binding by OASIS v.1.3 ONLY

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Not calculated by Hydrolysis half-life (Ka, pH 7)(Hydrowin) ONLY

Domain logical expression index: "g"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.538

Domain logical expression index: "h"

Parametric boundary:The target chemical should have a value of log Kow which is <= 7.75

Conclusions:

In reproductive toxicity study, NOAEL was estimated to be 58.69mg/kg bw. When male and female Sprague-Dawley rats were exposed with 3-(bromomethyl)benzonitrile (28188-41-2) orally.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for 3-(bromomethyl)benzonitrile (28188-41-2).Male and female reproductive parameters were unaffected by test material administration. Hence, NOAEL was estimated to be 58.69mg/kg bw. When male and femaleSprague-Dawley ratswere exposed with 3-(bromomethyl)benzonitrile (28188-41-2) orally.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

58.69 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimicsh 2 and from QSAR Toolbox 3.3. (2017)

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

In different studies, 3-(bromomethyl)benzonitrile (28188-41-2) has been investigated for reproductive toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for 3-(bromomethyl)benzonitrile (28188-41-2).The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies performed on structurally similar read across substance.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for 3-(bromomethyl)benzonitrile (28188-41-2).NOAEL was estimated to be 58.69mg/kg bw. When male and female Sprague-Dawley rats were exposed with 3-(bromomethyl)benzonitrile (28188-41-2) orally.

It is supported by experimental study conducted by HPVIS (HPVIS, United States Environmental protection, 2006)on structurally similar read across substance 1,3-Benzenedicarbonitrile (626-17-5). The reproductive toxicity study of 1,3-Benzenedicarbonitrile (626-17-5) was performed in male and female rats. The teat material mixed with fed Purina B Certified Rodent Chow No. 5002 in dose concentration 0, 5, 10, 25 and 50 mg/kg/day. The concentration of test material administered to the rats was adjusted weekly in order to achieve as closely as possible the desired dietary intake of treatment. The achieved dosages of test material were calculated at the end of each week based on the dietary concentrations and body weights and food consumption for that week. After initiation of mating on Study Day 81, diets were prepared weekly at constant concentration based on Week 11 body weight and food consumption data for the remainder of the study. Control animals were fed PurinaB Certified Rodent Chow No. 5002 without test substance ad libitum and fresh tap water was available ad libitum. 25 rats of each sex were assigned to each group. Ten animals per sex from each group were killed after at least 31 days on the test diets, and the remaining 15 of each sex per group were exposed to test material for a total of at least 122 days. For the one-generation reproduction phase, mating commenced of Week 11. Rats were mated for a total of 14 days during which no body weight or food consumption measurements were recorded.  

Compound-related effects on body weight and body weight gain with corresponding changes in food consumption were observed in males at 25 and 50 mg/kg/day and females at 10, 25 and 50 mg/kg/day during the 28- day feeding phase of the study. Histopathologic examinations revealed compound-related increases in the incidence of centrilobular hepatocytomegaly in males and females at 50 mg/kg/day and males at 25 mg/kg/day. Furthermore, a compound related increase in hyaline droplet formation was noted in the kidneys of males when compared to controls. No females exhibited this finding. Hyaline droplet formation in the proximal tubular epithelium of kidneys in male rats is indicative of abnormal accumulation of alpha-2 m-globulin, a protein reported to be unique to the rat. Clinical chemistry analyses revealed significant increases in ALT in males at 10 and 50 mg/kg/day and in females at 10 mg/kg/day and higher. In addition, serum cholesterol was in 50mg/kg bw dose group males than controls.

Urine volume was higher and specific gravity was lower in males at 25 and 50 mg/kg/day and females at 50 mg/kg/day. Parental reproductive parameters appeared to be unaffected. No compound-related effects were seen on mating, fertility or gestation length .Apparent compound-related reproductive effects on offspring survival in utero were noted. This was evidenced by an increase in the number of stillborn pups with a corresponding decrease in the number of live born pups and litter size at 50 mg/kg/day. Similar effects were not observed at lower dietary concentrations,(10,25 mg/kg /day).Hence in the 28-day feeding phase ,LOEL was considered to be 5mg/kg bw in male rats because of the increased incidence of hyaline droplet formation in the kidneys of males at all dietary levels. The LOEL was considered to be 10mg/kg bw for females. Based on the reductions in body weight, body weight gain, food consumption and increases in ALT at 10 mg/kg/day and higher, While for the reproductive phase No Observed Adverse Effect Level (NOAEL) was considered to be 25mg/kg/day, on the bases of No compound-related effects were seen on mating, fertility or gestation length and LOAEL was considered to be 50mg/g bw , on the bases of an increase in the number of stillborn pups with a corresponding decrease in the number of live born pups and litter size at 50 mg/kg/day. When male and female rats were treated with1,3-Benzenedicarbonitrile (626-17-5)orally.

 It is further supported by experimental study conducted by OECD SIDS (SIDS initial assessment report for SIAM 17(benzene, 1-chloro-2-(chloromethyl) 2003) on structurally similar read across substance 2-Chlorobenzyl chloride (611-19 -8) The reproductive toxicity study of 2-Chlorobenzyl chloride (611-19-8) was performed in male and female Sprague-Dawley rats according OECD Guideline 422, "Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test". The test material diluted with 0.1% Tween 80 solution and administered in dose concentration0, 2, 10, and 50 mg/kg/day by oral gavage.12 males and 12 females were used in each dose level. Males were dosed for 14 days before mating; during the mating period and up to the day before scheduled kill (total 45 days). Females were dosed for 14 days before mating, during the mating period, during the gestation and four days after delivery (total 41-48 days). For mating, one male to one female mating was used, and the female was placed with the same male until pregnancy occurs or 7 days have elapsed. Day 0 of pregnancy was defined as the day a vaginal plug or sperm was found. The rats were weighed at Day 3, 7 and 14, and weekly thereafter. During the gestation, females were weighed at Day 0, 7, 14 and 20 of gestation, and Day 0 and 4 of lactation. The body weights of the live pups were also recorded. Gestated females were delivered and lactated through Day 4 of lactation. At the termination of the experiment, all rats were sacrificed and necropsied. All pups were also sacrificed and necropsied.

Test substance had no effects in reproductive parameters such as the mating index, the fertility index, number of corpora lutea or implantations, the implantation index, the delivery index, the gestation index, gestation length, parturition or maternal behaviour., On examination of neonates, there were no significant differences in number of offspring or live offspring, the sex ratio, the live birth index, the viability index or body weight. No abnormal findings related to the test substance were found for external features, clinical signs or necropsy of the offspring. Hence NOAEL was considered to >50mg/kg bw for parental and F1 offspring on the bases no effects were observed on reproductive and developmental parameters. When male and female were treated with 2-Chlorobenzyl chloride (611-19-8) orally.

 Thus, based on the above studies and predictions on 3-(bromomethyl)benzonitrile (28188-41-2). It was considered that no adverse effects on reproductive parameter were observed. Thus, comparing this value with the criteria of CLP regulation 3-(bromomethyl)benzonitrile (28188-41-2) 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, comparing this value with the criteria of CLP regulation 3-(bromomethyl)benzonitrile (28188-41-2) cannot be classified as reproductive toxicant.